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Beth benderfynodd Grŵp Asesu Meddyginiaethau Cymru’n Un?

Gellir rhoi venetoclax ar y cyd ag azacitidine i drin lewcemia myeloid acíwt (AML) nad yw wedi ymateb i gemotherapi neu sydd wedi ailwaelu wedyn. Argymhellir triniaeth yn unig ar gyfer oedolion ag AML sydd wedi cael o leiaf un cwrs o gemotherapi dwys cyn neu ar ôl cael trawsblaniad mêr esgyrn.

Bydd venetoclax ac azacitidine ar gael i gleifion cymwys sydd wedi cofrestru gyda phractis meddyg teulu yng Nghymru, hyd yn oed os oes angen iddynt dderbyn eu triniaeth y tu allan i Gymru.

Nid yw venetoclax wedi'i drwyddedu i'w ddefnyddio mewn cyfuniad ag azacitidine i drin AML, felly os caiff ei ddefnyddio i drin felly gelwir ei ddefnyddio yn y modd hwn yn ddefnydd “all-drwydded”. Pan gaiff meddyginiaeth ei defnyddio yn “all-drwydded”, rhaid i'ch meddyg esbonio'n glir i chi y risgiau a'r manteision o gymryd y feddyginiaeth. Dylai eich meddyg roi gwybodaeth glir i chi, siarad â chi am eich opsiynau a gwrando'n ofalus ar eich barn a'ch pryderon. Darllenwch ein taflen wybodaeth i gleifion am ddefnydd di-drwydded ac all-drwydded o feddyginiaethau.

Mae Grŵp Asesu Meddyginiaethau Cymru'n Un ac AWTTC yn adolygu'r penderfyniad hwn yn rheolaidd i weld a oes unrhyw dystiolaeth newydd a allai effeithio ar y penderfyniad hwn.

Am ragor o wybodaeth, ewch i: Leukaemia Care (Saesneg yn unig)

 

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What did the One Wales Medicines Assessment Group decide?

Venetoclax can be given in combination with azacitidine to treat acute myeloid leukaemia (AML) that has not responded to chemotherapy or has relapsed afterwards. Treatment is only recommended for adults with AML who have had at least one course of intensive chemotherapy before or after having a bone marrow transplant. 

Venetoclax plus azacitidine will be available to eligible patients who are registered with a GP practice in Wales, even if they need to receive their treatment outside Wales.

Venetoclax is not licensed to be used in combination with azacitidine to treat AML, so using it in this way is called “off-label” use. When a medicine is used “off-label”, your doctor must clearly explain to you the risks and benefits of taking the medicine. Your doctor should give you clear information, talk with you about your options and listen carefully to your views and concerns. Read our patient information leaflet about unlicensed and off-label use of medicines.

The One Wales Medicines Assessment Group and AWTTC review this decision regularly to see if there is any new evidence that may affect this decision.

For more information about AML visit: Leukaemia Care

Medicine: venetoclax (Venclyxto^®) with azacitidine

Indication: For the treatment of relapsed/refractory acute myeloid leukaemia in adults following at least one line of intensive chemotherapy before or following allogenic haematopoietic stem cell transplant (HSCT) as an alternative to intensive chemotherapy.

Meeting date: 03 November 2025

Criterion: Clinical effectiveness and safety

OWMAG were presented with the Evidence Status Report (ESR) and noted the rationale for use of venetoclax with azacitidine for treatment of relapsed or refractory (R/R) acute myeloid leukaemia (AML) as an alternative to intensive chemotherapy. The group noted the current treatments for patients with R/R AML who are ineligible for intensive chemotherapy typically involves low-intensity regimens such as low-dose cytarabine, palliative therapies, or off-label venetoclax in combination with azacitidine. The group acknowledged that there was a risk balance for older or less fit patients where the potential gains with receiving FLAG-Ida may be lower and the toxicity greater. So, whilst FLAG-Ida would be a treatment option, venetoclax with azacitidine would offer a less demanding and less toxic treatment option with the potential to offer curative intent (bridge to hematopoietic stem cell transplant [HSCT]) in some patients. The group also acknowledged that the proposed place of venetoclax with azacitidine would not include patients with targetable FLT3 mutations for whom gilteritinib would be a licensed and NICE-approved treatment option. OWMAG considered the available real-world evidence, including UK-based observational studies by Wood et al. (2022, 2025) and a multicentre Canadian retrospective study by Pelland et al. (2024). Across these studies, venetoclax-based therapy achieved overall response rates of 52–55% and median overall survival of 6.8–8.9 months, with higher responses observed in patients with molecular relapse or minimal residual disease. Bridging to HSCT was achieved in 30-38% of patients and the group recognised that for those unsuitable for HSCT a sustained response may be achieved. The group noted that outcomes with venetoclax and azacitidine were generally less favourable than those achieved with intensive salvage chemotherapy. However, indirect comparisons between venetoclax with azacitidine and FLAG-Ida were not possible due to heterogeneity in study designs and patient characteristics. In particular, patients receiving venetoclax were typically older, had higher-risk disease, and were less fit for intensive therapy, making direct comparison problematic. Input from the clinical expert supported the rationale for considering venetoclax with azacitidine as a less intensive alternative for patients less suitable for FLAG-Ida. The group noted the poor adverse event profile associated with intensive chemotherapy compared with the less intensive venetoclax and azacitidine regimen. OWMAG considers that, while direct clinical evidence for venetoclax with azacitidine in R/R AML is limited, the available real-world data suggest potential clinical benefit for selected patients ineligible for intensive therapy.

Criterion: Cost-effectiveness

OWMAG opinion There is no published cost effectiveness evidence available for this treatment. Therefore, OWMAG considered the cost consequence analysis (CCA) and an exploratory cost utility analysis (CUA) presented in the ESR. The CCA compared venetoclax with azacitidine versus FLAG-Ida. Costs included in the CCA were medicine acquisition, administration, inpatient stay, adverse events, and subsequent treatment (HSCT). Clinical outcomes focussed on median overall survival and response rate. The incremental cost indicated that venetoclax and azacitidine were cost saving but the incremental median overall survival and incremental median response rate was negative when compared to FLAG-Ida. Sensitivity analyses indicated that the cost results were most sensitive to rate of HSCT between treatments. An additional scenario analysis was conducted by AWTTC to offer further contextualisation of incremental cost and clinical outcomes, applying the cost-utility methodology. The same UK-based utility value was applied to both groups. Utility estimates for adverse events were calculated based on NICE TA765. Results were presented with and without a severity multiplier of 1.7. The results indicated that the treatment was cost effective. The group acknowledged the limitations of the analyses in terms of uncertainty due to heterogeneity of patients both within studies and between studies for both venetoclax with azacitidine and for the FLAG-Ida comparator studies. The costing approach was limited as it excluded palliative care ongoing resource use, donor lymphocyte infusion (DLI) and additional monitoring costs. The group acknowledged that HSCT rates had the most impact on incremental costs. However, the group considered that patients suitable for treatment with venetoclax and azacitidine were less likely to be eligible for HSCT than patients who would be suitable for FLAG-Ida and therefore this assumption in difference in uptake rates of HSCT was reasonable. On consideration of these factors OWMAG were unable to definitively conclude a cost effectiveness position for venetoclax with azacitidine. However, the health economic evidence suggested that the incremental cost implication of delivering venetoclax with azacitidine is reasonable in the context of the potential health impact.

Criterion: Budget impact

OWMAG opinion OWMAG considers the clinical estimate of patient numbers to be reasonable. The group considers that the clinical assumptions underlying the budget impact estimates are generally reasonable. Differences in baseline patient characteristics between venetoclax with azacitidine and FLAG-Ida cohorts, including prior allogeneic HSCT, number of previous treatments, and overall fitness, have been taken into account. The main driver of the budget impact is the cost of HSCT, with lower rates expected in the venetoclax-treated population. OWMAG notes that variation in treatment cycles, adverse event rates, and additional care needs, including palliative care or hospitalisation for monitoring, introduces uncertainty. Administration costs for venetoclax with azacitidine may be higher in some patients who may be monitored in hospital for tumour lysis syndrome during initiation of therapy. FLAG-Ida costs may be underestimated if G-CSF is required beyond seven days or if patients require more prolonged hospital stay. Costs for further treatments beyond HSCT, consolidation therapies such as DLI, or palliative care have not been fully included. OWMAG considers that, based on the estimated number of eligible patients and the expected treatment pathway, the overall budget impact is likely to be low. The use of venetoclax with azacitidine is expected to provide a bridge to HSCT for some patients ineligible for intensive salvage therapy. The group also noted that venetoclax with azacitidine is currently being accessed for patients in Wales via Individual Patient Funding Requests. OWMAG consider the budget impact to be reasonable value for money for NHS Wales.

Criterion: Resource use

OWMAG opinion OWMAG note that treatment with venetoclax with azacitidine typically involves more treatment cycles than intensive salvage chemotherapy such as FLAG-Ida. However, as venetoclax with azacitidine is largely outpatient and lower intensity, the overall resource use for administration and supportive care is likely lower than for intensive chemotherapy. The group note that monitoring for patients on venetoclax with azacitidine may be less intensive overall, although hospitalisation may be required during initiation of therapy to monitor for tumour lysis syndrome in some patients, whereas intensive chemotherapy requires substantial inpatient stay for administration and supportive care. The group considers that any potential additional resource use with venetoclax with azacitidine is acceptable, as it may be offset by lower inpatient requirements and reduced management needs for serious treatment-related adverse events. Venetoclax with azacitidine is likely to be associated with lower resource use for adverse event management than intensive chemotherapy, reflecting lower rates of grade ≥3 toxicities and reduced need for hospital-based interventions.

Criterion: Other factors

OWMAG opinion The group understand that the prognosis for patients with relapsed or refractory AML who are ineligible for intensive chemotherapy and lack targetable mutations is poor, and that treatment in this setting is generally expected to be palliative or focused on disease control rather than cure. Patients should be informed of the potential options and that venetoclax with azacitidine may provide lower response rates when compared to FLAG-Ida. The group considered the lay perspective, highlighting the treatment’s potential to improve quality of life and reduce travel burden for patients accessing tertiary centres. These factors were acknowledged as important in understanding the broader impact of the recommendation.

Final recommendation

OWMAG recommends the use of venetoclax with azacitidine for the treatment of relapsed/refractory acute myeloid leukaemia in adults following at least one line of intensive chemotherapy before or following allogenic haematopoietic stem cell transplant (HSCT) as an alternative to intensive chemotherapy. This recommendation is subject to the development of appropriate start/stop criteria.

Summary of rationale

Despite limited clinical evidence, OWMAG considers that venetoclax with azacitidine may provide meaningful clinical benefit for selected patients with R/R AML who are ineligible for intensive salvage therapy. The associated cost is viewed as a reasonable use of NHS resources in this context. Real-world data will continue to be captured to further assess the effectiveness and value of this treatment in the NHS Wales setting.

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Key findings

Licence status: Venetoclax (Venclyxto^®) with azacitidine is not licensed for the treatment of relapsed/refractory acute myeloid leukaemia in adults following at least one line of intensive chemotherapy before or following allogenic haematopoietic stem cell transplant (HSCT) as an alternative to intensive chemotherapy; its use for this indication is off-label.

Clinical evidence: The clinical evidence for venetoclax in combination with azacitidine comes from real-world, multicentre, and single-arm studies. Wood et al. (2022, 2025) and Pelland et al. (2024) reported that 40–46% of patients achieved complete remission or complete remission with incomplete count recovery rate, with higher responses in those treated for molecular relapse. Median overall survival ranged from 7 to 20 months. Up to a quarter of patients were subsequently bridged to allogeneic HSCT, with generally favourable post-transplant outcomes. These findings suggest that venetoclax-based lower-intensity regimens can provide meaningful disease control in heavily pretreated, high-risk patients. Studies are presented for the medicine most likely to be displaced which is Flag-Ida (fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor).   However, there are considerable limitations with the comparison of the patients treated with FLAG-Ida and those treated with venetoclax and azacitidine due to heterogeneity between baseline characteristics of patients in the respective studies.

Safety: No new safety signals emerged with venetoclax in combination with azacitidine in R/R AML compared with its use in other indications.

Patient factors: Patients with R/R AML have few treatment options and generally poor outcomes. A stem cell transplant can potentially cure the disease, but it is only an option if patients reach remission and have a suitable donor. Intensive chemotherapy has limited efficacy and is associated with significant toxicity, particularly in older patients or those with poor overall health. Venetoclax with azacitidine provides a lower-intensity option, administered in an outpatient setting.

Cost effectiveness: An All Wales Therapeutics and Toxicology Centre (AWTTC) literature review did not identify any published studies reporting the cost-effectiveness of venetoclax with azacitidine for the indication under consideration.  

An AWTTC cost consequence analysis (CCA) compares the costs and outcomes of venetoclax with azacitidine versus FLAG-Ida. The base case analysis finds venetoclax with azacitidine to be associated with cost savings [commercial in confidence text removed] a shorter median overall survival (8.9 months versus 10.2 months) and a lower response rate (52% versus 71%) when compared with FLAG-Ida. A range of sensitivity and scenario analyses assess the influence of parameters and characterise uncertainty.

The analysis includes a number of limitations. Notably, the clinical comparisons are based on separate studies of different patient populations. Caution should be applied when drawing conclusions from the economic analysis.

Budget impact: Use of venetoclax with azacitidine in place of FLAG-Ida has been estimated to result in cost savings of [commercial in confidence text removed] per year. Results are subject to the same limitations as outlined in the clinical and cost-effectiveness sections of the report. In practice the budget impact is expected to be largely neutral as patients in Wales are already accessing venetoclax with azacitidine via the Individual Patient Funding Request route.

Impact on health and social care services: Venetoclax with azacitidine is administered in an outpatient setting, potentially reducing healthcare resource use. In contrast, conventional salvage chemotherapy requires prolonged inpatient admission and is associated with higher needs for blood product support and intensive management of neutropenia-related infections.

Innovation and/or advantages: Clinical experts indicate the main benefit of this treatment is that it is safer, easier, can be given locally mostly as an outpatient, and requires less hospital time and fewer blood transfusions.

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Background

Adults with relapsed or refractory acute myeloid leukaemia (R/R AML) following at least one line of intensive chemotherapy, with or without prior allogeneic haematopoietic stem cell transplant (HSCT), have poor prognosis and incurable disease¹. The therapeutic goals are to control disease progression, achieve remission (where possible), control symptoms, preserve quality of life, and minimise treatment-related adverse effects².

Current treatment options are limited and often poorly tolerated, typically involving intensive salvage chemotherapy or palliative care³. There is a recognised need for better-tolerated therapies that improve quality of life and reduce hospitalisation. Venetoclax combined with azacitidine may offer a less toxic alternative, potentially improving remission rates and survival, particularly in younger, fitter patients as a bridge to allogeneic HSCT.

Clinicians in Wales have identified a patient cohort likely to benefit from venetoclax with azacitidine which was considered suitable for assessment through the One Wales Medicines process.

Twelve applications for this indication have been submitted through the Individual Patient Funding Request (IPFR) process between January 2024 to March 2025, all of which were approved.

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Target group

Patients with R/R AML who have relapsed following, or are refractory to, at least one line of intensive chemotherapy before or following HSCT.

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Marketing authorisation date

Not applicable for this indication, off-label. 

Venetoclax (Venclyxto^®) with azacitidine is not licensed for the indication under consideration.

Venetoclax was first licensed in the UK in 2016, it is licensed for the treatment of newly diagnosed AML in adults ineligible for intensive chemotherapy, in combination with a hypomethylating agent (e.g. azacitidine) or low-dose cytarabine⁴. It is also licensed in chronic lymphocytic leukaemia (CLL) ⁴.

Azacitidine is licensed in the UK for the treatment of adult patients not eligible for HSCT with intermediate-2/high-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), and AML (≥20% blasts by WHO classification)⁵.

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Dosing information

Venetoclax and azacitidine are administered in 28-day cycles⁴. For most R/R AML patients, clinical experts recommend a lower venetoclax dose of 100 mg orally daily when given with an azole antifungal (posaconazole or voriconazole). Venetoclax is metabolised by enzyme cytochrome P450 3A4 (CYP3A4), therefore co-administration with strong CYP3A4 inhibitors such as azole antifungals necessitates a dose reduction to mitigate toxicity. Venetoclax 400 mg oraly daily is only used in  patients who cannot take azole antifungals  or who achieve remission with normal blood counts and no longer require antifungal prophylaxis⁴.

Venetoclax dosing begins with 100 mg orally on day 1, increasing to 200 mg on day 2, 400 mg on day 3, then reduced back down to 100 mg daily on day 4 and thereafter. Azole antifungals start on day 4. In cases of drug-induced cytopenia, treatment cycles may be shortened to 14–21 days. If neutrophil counts normalise, the azole antifungal is stopped and venetoclax increased to 400 mg daily. It should be noted that this dosing approach reflects local practice for treatment of R/R AML, rather than Summary of Product Characteristics (SmPC) recommendations, as confirmed by NHS Wales clinical experts. Patients should be adequately hydrated and receive anti‑hyperuricaemic agents to reduce the risk of tumour lysis syndrome before the first dose and during titration⁴.

Azacitidine is administered at 75 mg/m² via subcutaneous injection into the upper arm, thigh or abdomen on days 1–7, though in practice it is often given on days 1–5 and 8–9 to avoid weekend hospital visits.

Treatment typically continues until disease relapse. Patients who are medically fit and achieve remission may proceed to allogeneic HSCT, at which point venetoclax and azacitidine are stopped^6,7. Clinical experts suggest treatment is discontinued on disease progression or if there is no response after 3 cycles.

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Clinical background

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Incidence/prevalence

In 2021, Wales reported 85 new cases of AML, corresponding to an incidence of approximately 3 per 100,000 population¹⁵. Specific data on R/R AML in Wales are limited. International evidence provides context, a systematic review reported a median cumulative relapse incidence of 46.8% after induction chemotherapy and 29.4% following stem cell transplantation¹⁶, suggesting that roughly half of all patients experience relapse. Clinical experts in Wales estimate that approximately 9–10 R/R AML patients per year would be eligible for treatment with venetoclax in combination with azacitidine.

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Current treatment options and relevant guidance

Management of R/R AML is challenging due to limited treatment options, treatment-associated toxicity, and poor prognosis. For patients lacking targetable mutations, particularly those unable to tolerate intensive chemotherapy, there is no single standard of care¹⁷. Instead, regimens such as venetoclax with azacitidine, low-dose cytarabine, or other low-intensity therapies are selected based on individual patient suitability.

Salvage chemotherapy for R/R AML typically involves regimens such as FLAG-Ida (fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor), MACE (mitoxantrone, cytarabine, and etoposide), or MEC (mitoxantrone, etoposide, and cytarabine), with FLAG-Ida often preferred by clinicians in Wales. For patients where the focus is on controlling the disease rather than curing it, palliative regimens may be used. These can include IV low dose cytarabine, oral hydroxycarbamide, or oral etoposide for cytoreduction, alongside supportive measures such as transfusions and antibiotics.

Targeted therapy options for R/R AML are limited. Gilteritinib is recommended by National Institute for Health and Care Excellence (NICE) Technology Appraisal (TA) 642 (2020) for adults with FLT3 mutations, present in approximately 25% of cases, while no licensed targeted agents exist for the remaining 75% without these mutations³.

Venetoclax with azacitidine is licensed and recommended by NICE TA765 (2022) for patients with untreated AML where intensive chemotherapy is unsuitable¹⁸. Venetoclax with azacitidine is currently off-label for R/R AML and has not yet been appraised by NICE for this indication. The NICE appraisal ID6468, assessing venetoclax in combination with azacitidine for AML before and after HSCT, is currently under development, [commercial in confidence text removed]¹⁹.

Other therapies in the NICE development pipeline, both currently awaiting appraisal, include:

• Liposomal cytarabine–daunorubicin for treating R/R AML in people aged 1 to 21 years (ID4017)²⁰
• Iodine-131–apamistamab for relapsed or refractory AML prior to HSCT (ID6355)²¹

International guidance highlights broader use:

• The 2025 guidelines from the National Comprehensive Cancer Network (NCCN) in the United States recommend venetoclax combined with hypomethylating agents, such as azacitidine, for relapsed or refractory acute myeloid leukaemia, especially in patients who are unfit for intensive salvage therapy or as a bridge to HSCT²².
• European LeukemiaNet (ELN) 2022 and the British Society for Haematology (BSH) support the combination in older or unfit patients, with dose modifications advised when co-administered with strong CYP3A4 inhibitors such as azole antifungals⁸. The guidelines recommend a risk-adapted approach, including HSCT for eligible patients and low-intensity regimens for those unsuitable for intensive therapy⁸.

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Summary of evidence on clinical effectiveness

The All Wales Therapeutics and Toxicology Centre (AWTTC) conducted a literature search during August 2025 to look for evidence about the use of venetoclax with azacitidine for the treatment of R/R AML in adults. Searches were performed using the Cochrane library, Central Register of Controlled Trials, EMBASE, MEDLINE and TRIP database with the search terms venetoclax, venclyxto, azacitidine, vidaza, onureg, acute myeloid leukaemia, AML, relapsed or refractory, and adults.

The primary outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), adverse events (AE), health related quality of life (HRQoL) and resource use. A literature search identified 225 records which were assessed for eligibility, with 197 excluded following removal of duplicates and screening of title and abstracts. Following eligibility screening, 8 publications were included in the report, 5 were retrospective cohort studies and 3 were real-world observational data reports (2 studies and 1 update). Any remaining records were excluded due to small patient numbers, incorrect cohort or unsuitable study design (see Appendix 1). An additional 6 studies were identified by the company, 5 of which were considered eligible for inclusion.

Of the included studies, the real-world, UK-based, observational study by Wood et al.^6,7 and the multicentre retrospective analysis by Pelland et al.²³ were deemed the most relevant sources of evidence pertinent to the indication in this report and were therefore included in the main analysis. The remaining supplementary studies are summarised in Appendix 2.

Clinical efficacy of venetoclax with azacitidine

Safety

Discussion

Outcomes in R/R AML are influenced by patient selection, prior therapy, and transplant eligibility, with treatment completion generally high and chronological age alone appearing less predictive of response in certain cohorts. Wood and Pelland demonstrated that venetoclax combined with azacitidine achieved overall response rates of 44% to 52% and CR/CRi rates of 37% to 41% in relapsed or refractory AML, translating to a median overall survival of 8 to 9 months in real-world series. ^6,7,23. HSCT increased OS, with one study reporting an OS of 18.9 months following HSCT post salvage therapy²³. In contrast, intensive regimens such as FLAG-Ida, as reported by Westhus, Delia, and Doma, can achieve substantially longer survival (median OS reported ranging between 9.4 and16 months), particularly in transplanted patients, with some cohorts reporting an OS of up to 63 months^24-27. These differences likely reflect patient selection, since FLAG-Ida cohorts were typically younger, earlier in their relapse course, and less exposed to prior transplant compared with venetoclax-based studies.

Ye and Pelland both reported that more than half of patients receiving venetoclax plus azacitidine were refractory^23,28, whereas Ganzel²⁹, Tenold³⁰, and Wood^6,7 observed refractory rates of 26% to 48% in venetoclax plus HMA cohorts. FLAG-Ida studies, such as those by Westhus and Doma, generally captured patients at first relapse or refractory only to induction, representing a less heavily pretreated population^24,26.

Prior therapy exposure also differed across regimens, Garciaz, Pelland, and Wood showed that patients receiving venetoclax with azacitidine had one to three prior lines of therapy and 18% to 30% prior transplant exposure^7,23,31, whereas Ganzel and Tenold reported that venetoclax plus HMA patients had one to six prior lines and 20% to 42% transplant exposure^29,30. In contrast, FLAG-Ida cohorts studied by Westhus, Delia, and Doma mostly included first-relapse or induction-refractory patients, whist prior transplant exposure was lower than the venetoclax plus azacitidine studies, ranging from 0% to 8%^24,26,27.

Disease risk distributions were broadly similar, with most patients classified as intermediate or adverse, although some FLAG-Ida studies, such as those by Westhus and Delia, included higher proportions of intermediate-risk patients, potentially favouring outcomes^26,27. Importantly, heavily pretreated patients, defined as those with two or more prior lines of therapy and/or prior allogeneic transplant, were more frequent in venetoclax plus HMA cohorts, which likely contributed to inferior outcomes compared with FLAG-Ida populations.

Disease risk, as defined by the European LeukemiaNet (ELN)⁸, is used to stratify prognosis and broadly guide treatment decisions. Age, in turn, influences treatment primarily through its impact on functional status, which encompasses ECOG performance, frailty, and comorbidities. Patients over 60 years generally experience more frequent hospitalisations due to higher rates of cytopenias, infections, and reduced treatment tolerance, although a fit older patient with preserved functional status may tolerate intensive therapy similarly to younger adults³². Patients treated with venetoclax plus azacitidine in the studies by Garciaz, Ye, and Pelland were generally older, with median ages ranging from 50 to 73 years^23,28,31, whereas cohorts reported by Ganzel, Tenold, and Wood receiving venetoclax plus HMA tended to be slightly younger, with median ages in the mid-50s to 60s^7,29,30. In comparison, Westhus, Delia, and Doma reported median ages of 49 to 60 years in FLAG-Ida studies, and included fewer patients over 60 years and may partly explain differences in tolerability and transplant eligibility^24,26,27.

Outcomes with venetoclax-based regimens are significantly improved when used in molecular relapse (median OS 17.6–18.4 months) or when bridging to HSCT, underscoring the prognostic impact of disease burden and transplant eligibility^6,7. Overall, venetoclax plus azacitidine balances efficacy and tolerability, serving as a valuable salvage strategy in older or heavily pretreated patients, while still permitting consolidation with HSCT in a meaningful proportion (27–38%) of responders^6,7,23.

Safety findings from these studies are consistent with the profile described in the SmPC for venetoclax and azacitidine^4,5. Most AEs are manageable and do not typically result in permanent treatment discontinuation. Grade 3/4 hematologic toxicities, including neutropenia, thrombocytopenia, anaemia, and febrile neutropenia, were reported in 60–70% of patients. Infections such as pneumonia and sepsis occurred frequently, while TLS was rare (<5%) and manageable with standard prophylactic measures. Supportive interventions, including dose interruptions, growth factor administration, and transfusions, were commonly required. The consistency between trial findings and the SmPC reinforces that venetoclax and azacitidine is generally tolerable, although careful monitoring for cytopenias, TLS and infection is essential to ensure safe administration^4,5.

Overall, while venetoclax with azacitidine provides an alternative to intensive chemotherapy for patients with R/R AML, differences in trial design, small sample sizes, patient characteristics, and follow-up durations complicate direct comparisons with other salvage regimens. These limitations necessitate cautious interpretation of efficacy outcomes, and larger controlled studies are needed to better define long-term benefits, comparative effectiveness, and optimal patient selection.

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Cost-effectiveness evidence

Review of published evidence on cost-effectiveness

A literature review conducted by AWTTC did not identify any studies relevant to the cost-effectiveness of venetoclax (Venclyxto^®) in combination with azacitidine for the treatment of R/R AML in adults following at least one line of intensive chemotherapy before or following allogenic HSCT.

Context

An AWTTC cost-consequence analysis (CCA) compares selected resource use and clinical outcomes associated with venetoclax (Venclyxto^®) with azacitidine versus FLAG-Ida in the treatment of R/R AML. The analysis adopts a lifetime time horizon and an NHS Wales/Personal and Social Services perspective. As median overall survival is less than one year costs and outcomes are undiscounted.

The patient pathway for R/R AML consists of initial therapeutic interventions followed by potential HSCT, additional therapy cycles or palliative care.  In the analysis, clinical outcomes, the number of treatment cycles, and the clinical pathway are informed by a UK observational study for venetoclax with azacitidine and a European observational study for FLAG-Ida ^7,24. The model pathways are a simplification of those reported in the observational studies, defined by clinical experts to represent delivery within Wales.

Patients receiving venetoclax with azacitidine complete an initial two cycles followed by treatment according to their response status. Over half of patients (52%) respond to therapy, with 55% continuing treatment with three additional cycles. The remaining 45% of patients receive allogenic HSCT. Patients who do not respond (48%) receive palliative care, as informed by discussion with clinical experts in Wales. Patients receiving FLAG-Ida receive a single cycle, almost half receive HSCT (47%). The HSCT rate is derived from the whole cohort in the Doma et al. study which includes patients treated with both FLAG-Ida and FLAG without idarubicin (FLAG-only) regimens²⁴. Based on clinical expert opinion in Wales, 50% of patients receiving HSCT are assumed to have an additional bridging cycle of FLAG-only to minimise toxicity, particularly cardiac toxicity. The remainder (53%) are assumed to progress to palliative care.

Cost of intervention: medicine acquisition and administration costs 

The medicine acquisition costs and delivery schedule for venetoclax with azacitidine are displayed in Table 1. Hospital admission to receive this treatment is not routine, based on clinical expert opinion in Wales.

Table 1. Venetoclax with azacitidine: medicine acquisition costs, treatment schedule and medicine administration costs (opens image in new tab) 

Table 2 details medicine acquisition cost and administration cost of venetoclax with azacitidine, delineated by cycle number. It is assumed that vial wastage occurs, pack sharing is practiced and that patients fully adhere to treatment regimens. The differences in cycle costs are driven by the initial treatment titration of venetoclax. 

Table 2. Venetoclax with azacitidine: total medicine acquisition and administration costs by cycle (opens image in new tab) 

Cost of comparators: medicine acquisition and administration costs

Clinicians in Wales identify FLAG-Ida as the most appropriate comparator for venetoclax with azacitidine in the targeted patient group. FLAG-Ida medicine acquisition costs, administration costs and inpatient costs are reported in Table 3. More detailed costs are reported in Appendix 3.a – 3.c.

Table 3. Total cost of medicines, administration and inpatient stays for one FLAG-Ida cycle (opens image in new tab) 

Adverse events

A targeted literature review informed the adverse event rates for venetoclax with azacitidine and FLAG-Ida. Serious adverse events (grade 3 or higher) are included in the analysis if the associated incidence rate is ≥5% in either treatment arm. Adverse event rates for venetoclax with azacitidine are based on evidence from a phase 3 randomised controlled trial⁹, for FLAG-Ida they are sourced from NICE TA642³. These sources were selected based on their data granularity and relative compatibility. Included adverse events are either treatment emergent or treatment related (within 30 days of treatment). The total costs of adverse events per patient are detailed in Table 4. Further details are reported in Appendix 3.d.

HSCT and palliative care costs

The weighed cost of HSCT over a 3-month horizon reported by Wales Joint Commissioning Committee is [commercial in confidence text removed], details are included in appendix 3.e. Palliative care costs are not included in the analysis due to variability of delivery and uncertainty of duration.

Total costs  

Table 4 reports total costs for the treatment comparison.

Table 4. Total costs (opens image in new tab) 

Clinical outcomes

The clinical outcomes associated with the delivery of venetoclax with azacitidine and with FLAG-Ida are reported by Wood et al., 2025 and Doma et al., 2024^7,24. The median overall survival of patients receiving venetoclax with azacitidine is 8.9 months (95% CI: 5.9 to 11.9) with an overall response rate of 52%. FLAG-Ida is associated with a median overall survival of 10.2 months and an overall response rate of 71%.

Results

The results of the base case are detailed in Table 5.  When compared with FLAG-Ida, the incremental saving generated is [commercial in confidence text removed] per patient. The main cost difference can be attributed to fewer patients undergoing HSCT. Patients receiving venetoclax with azacitidine are also associated with an incremental overall survival loss of 1.3 months.

Table 5. Base case analysis (opens image in new tab) 

Sensitivity and scenario analysis

A range of sensitivity and scenario analyses, reported in table 6, were conducted to test the influence of parameters and to characterise uncertainty within the modelled costing approach.  Due to data limitations, these analyses do not include any variability in clinical and health outcomes.

Table 6. Sensitivity and scenario analysis (opens image in new tab) 

Sensitivity and scenario analysis are detailed in appendix 3.f – 3.i.

Threshold analysis

To characterise the scale of the differences in costs and overall survival a range of threshold analyses are undertaken applying cost-effectiveness thresholds of £20,000 and £30,000 per quality adjusted life year (QALY). In the base case, venetoclax with azacitidine is less costly but also less effective than FLAG-Ida. Therefore, the threshold analysis seeks to identify the number of QALYs it would be acceptable to forego given the projected cost saving. The threshold analyses suggest that it would be acceptable to forego [commercial in confidence text removed] QALYs at a threshold of £20,000 per QALY, and [commercial in confidence text removed] QALYs at a threshold of £30,000 per QALY, in the context of a 1.7 severity modifier (see Table 7 for severity modifier considerations).

Exploratory cost-utility analysis

Due to data and population limitations, it was considered inappropriate to undertake a cost-utility analysis as the AWTTC base case. However, an additional scenario analysis was conducted to offer further contextualisation of incremental cost and clinical outcomes, applying cost-utility methodology. Expanding on the threshold analysis to include an estimate of health-related quality of life (HRQoL) an AWTTC targeted literature review sought disease specific HRQoL data for adult patients with relapsed/refractory AML. A UK based utility analysis was selected to inform the analysis based on recency and patient matching³⁶. Accordingly, a utility value of 0.628 for adults with relapsed AML is used for both the venetoclax with azacitidine and the FLAG-Ida groups³⁶. Due to data limitations, the simplified model structure assumes a constant utility value over time. Therefore, the model does not capture variation in utility according to response status. Adverse events reduce the HRQoL of patients, the range of treatment emergent adverse events described in the costing section each have corresponding negative utility estimates reported in NICE TA765¹⁸. The utility decrements due to adverse events are calculated as 0.018 for venetoclax with azacitidine and 0.014 for FLAG-Ida (see Appendix 3.d for further details).

The results of the exploratory analysis are detailed in Table 7. Incremental-cost-effectiveness ratios (ICERs) are reported with and without application of the severity modifier. These ICERs are for contextualisation purposes only. There is a high degree of uncertainty around these estimates, and they should be interpreted with caution.

When compared with FLAG-Ida, the point estimate for the ICER falls within the southwest quadrant of the cost-effectiveness plane (i.e. venetoclax with azacitidine is less costly and less effective than comparator FLAG-Ida), producing an ICER of [commercial in confidence text removed] saved per QALY forgone. When the severity modifier is applied the saving per QALY foregone is [commercial in confidence text removed]. In the southwest quadrant, an ICER > £20,000 saved per QALY forgone is generally desirable.

Table 7. Exploratory cost-utility analysis (opens image in new tab) 

Analysis limitations

• The clinical comparison is subject to uncertainty and potential bias due to the variability in trial characteristics and the potential for selection bias.
• It is uncertain whether the populations in the intervention and comparator arms are sufficiently comparable to support direct comparison. This uncertainty increases the risk of bias and reduces the potential for analysis validity. If the populations are not comparable, differences in outcomes and costs may reflect underlying population characteristics rather than true treatment effects.
• The prior HSCT rate of the population informing venetoclax with azacitidine clinical effectiveness was 32% compared to 8% for FLAG-Ida. The difference in pretreated status of the populations may influence clinical outcomes. Therefore comparisons of the populations may be inappropriate.
• The average age at diagnosis for the AML population in England is 72 years¹⁰. The cohorts used to inform the analysis had average ages of 58 and 60 for patients receiving venetoclax with azacitidine and FLAG-Ida respectively. Survival is reported as having a strongly negative correlation with age¹⁰. If the population in Wales is older than that of the clinical evidence cohorts, the analysis may overestimate overall survival.  
• Age is also related to HSCT rate. Younger patients are associated with a higher rate of HSCT²⁴. If the rate of HSCT in the Welsh population is lower than the modelled rate, the overall survival and associated costs may be lower than reported.
• Incremental cost is highly sensitive to changes in HSCT rates. HSCT rates and pre-treated HSCT rates vary between the study arms, this uncertainty reduces the comparability between the two populations and any subsequent conclusions.
• The use of median OS, due to data limitations, has associated limitations. A Kaplan-Meier survival curve or a parameterised long-term survival would be preferential. The use of median OS effectively ignores longer-term outcomes, treatment benefits and costs. The impact of this limitation is uncertain.
• Adverse events are reported as treatment emergent adverse events. Venetoclax with azacitidine is delivered over a longer period than FLAG-Ida. Therefore, adverse events may reflect a higher proportion of condition emergent events compared to treatment related events. Due to the frailty of the patient cohort, this approach may overestimate the adverse events related to venetoclax with azacitidine.
• The incremental cost of venetoclax with azacitidine is sensitive to the base case assumptions relating to inpatient stay. These inputs are informed by expert clinicians in the absence of observed data, which introduces uncertainty. Variation in inpatient stay could have a significant impact on the costs associated with venetoclax and azacitidine.
• Adverse event costs are calculated according to the additional treatment required, this may lead to double counting in the FLAG-Ida arm as the estimate of inpatient stay duration includes consideration of additional care. This may bias the analysis in favour of venetoclax with azacitidine.
• Clinical experts report that patients not responding to treatment would not proceed directly to HSCT. The evidence informing HSCT rates for the venetoclax with azacitidine include only patients who have responded to treatment. In contrast, the FLAG-Ida rates are not delineated by response status. This lack of data granularity may bias in favour of venetoclax and azacitidine.
• The FLAG-Ida HSCT rate incorporates the complete study cohort, including both FLAG-Ida and FLAG only. It is unknown what impact this may have on associated costs and outcomes.
• The analysis adopts a limited costing approach which does not include palliative care or ongoing resource use, including additional monitoring, subsequent HSCT (beyond the initial HSCT included) or donor lymphocyte infusion. It is unknown what impact this has on the analysis aside from an increase in uncertainty.

AWMSG’s policy for medicines for severe conditions

AWTTC believes that the use of venetoclax with azacitidine in the given patient population meets the QALY shortfall criteria set by the AWMSG policy on appraising medicines for severe conditions.

The AWMSG QALY shortfall criteria for appraising medicines for severe conditions, and a discussion of the extent to which the medicine may meet these criteria, are provided in Table 8.

Table 8. Severity modifier considerations for One Wales medicines assessment group (OWMAG) (opens image in new tab) 

If the One Wales Medicines Assessment Group (OWMAG) conclude that venetoclax with azacitidine should be considered under the AWMSG policy for appraising medicines for severe conditions, OWMAG usually need to consider:

• the effect of the severity QALY weight applied, and whether the weighted QALY benefits in this patient group result in a most plausible ICER that falls within the current cost-effectiveness threshold range.

In addition, OWMAG usually need to be satisfied that:

• The estimates of the expected life years and total QALYs for the general population and for patients being treated with the comparator medicines(s) are sourced from recent and robust data sources.
• The assumptions used in the economic modelling are plausible, objective and robust.

However, as previously noted, there is a considerable uncertainty around the ICER estimates in the exploratory cost-utility analysis, and they should therefore be interpreted with caution. In this assessment, consideration of the severity modifier enables an explicit evaluation of whether the condition qualifies as severe under AWMSGs criteria and provides additional context to inform the threshold analysis.

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Budget impact

The Patient Access Scheme (PAS) price of venetoclax is [commercial in confidence text removed] per 100 mg tablet. The All Wales Drug Contract (AWDC) price for azacitidine is [commercial in confidence text removed] per subcutaneous (SC) 1 ml vial (100 mg) and for posaconazole is [commercial in confidence text removed] per 100 mg tablet. All costs exclude VAT. The dose of azacitidine is as per the SPC, 75 mg per m² of BSA by SC injection daily for the first 7 days of a 28-day cycle. In practice azacitidine is administered on days 1 to 5 and 8 to 9 to avoid weekend hospital attendance. The SC and oral formulations allow for patients to be typically treated at haematology day units on an outpatient basis. Venetoclax is an oral tablet taken daily, with an initial ramping of dose on days 1,2 and 3 of a cycle with 100 mg, 200 mg and 400 mg taken daily. From day 4 onwards and for subsequent cycles the venetoclax dose is reduced to 100 mg daily to coincide with the start of taking the posaconazole. Clinical experts consider that fewer than 10% of patients would have contra-indication to posaconazole and that the majority of patients will require antifungal prophylaxis for the duration of treatment. The daily dose of venetoclax therefore remains at 100 mg daily from day 4 until treatment discontinues. Monitoring costs have not been included in the budget impact, clinical experts report that no additional monitoring is required for patients treated with venetoclax with azacitidine. Table 9 shows the estimated medicine acquisition costs and drug administration costs for venetoclax with azacitidine for one patient per cycle.

Table 9. Estimated cost of venetoclax with azacitidine in Wales (per patient, per cycle) (opens image in new tab) 

The comparator treatment is salvage chemotherapy; clinical experts consider the most appropriate regimen to be FLAG-Ida although others such as MEC (mitoxantrone, etoposide and cytarabine) or MACE (amsacrine, cytarabine and etoposide) may also be used depending upon patient characteristics. For the purposes of the budget impact calculations FLAG-Ida has been used as the comparator treatment. One 28-day cycle of FLAG-Ida comprises fludarabine and cytarabine on days 1 to 5, idarubicin on days 3-5 and granulocyte-colony stimulating factor (G-CSF) on days 1-7. Administration requires central venous access, and patients will be in-patients for the duration of the drug administration, clinical experts estimate that patients will require in-patient care for a total of 20 days, administration costs include an additional 13 days of in-patient care. The estimated cost for one cycle of FLAG-Ida for one patient, including medicine acquisition costs and drug administration costs is shown in Table 10. Clinical experts advise that idarubicin is usually omitted from an additional cycle, cost of a cycle of FLAG is included.

Monitoring costs are not included as clinical experts advise that monitoring will not differ between treatment regimens.

The cost of HSCT is [commercial in confidence text removed] as reported by Wales Joint Commissioning Committee and detailed in the cost effectiveness section and appendix 3.e.

Table 10. Estimated cost for 1 cycle of FLAG+/-Ida per patient (opens image in new tab) 

Treatment response and duration for venetoclax with azacitidine has been estimated from the results of the Wood et al (2025) study; 48% of patients are non-responders and discontinue treatment after a median of 2 cycles⁷. Of patients who respond to treatment; 45% receive HSCT after a median of 2 cycles (as per Wood et al, 2025). In those patients not receiving cellular therapy in Wood et al, 2025, treatment continued for a median of 5 cycles.  It is assumed that the remaining 55% receive a median of 5 cycles before disease progression or discontinuation. Clinical experts estimate that 10 patients per year would be eligible for treatment. The flow diagram below (Figure 1) shows the distribution of treatment with venetoclax with azacitidine for these 10 patients based on results of the Wood et al study, patient numbers have been rounded.

Figure 1. Patient flow for treatment with venetoclax with azacitidine (opens image in new tab) 

Clinical experts estimate that patients would usually receive up to 2 cycles of salvage chemotherapy. The second cycle may be required if response is partial following the first cycle or if remission is achieved but there is a delay in HSCT, for example whilst a suitable donor is found. The study by Doma et al (2024) has been used to inform the duration and response to treatment with FLAG-Ida as this was the best matched for patient age and detail on number of cycles²⁴. In the study 36 (28%) patients received a second cycle of FLAG+/-Ida and 61 (47%) patients proceeded to receive HSCT. The flow diagram below shows the distribution of treatment with FLAG-Ida based on the results of the Doma et al study, patient numbers have been rounded. Patients receiving a second cycle are assumed to receive FLAG only.

Figure 2. Patient flow for treatment with FLAG-Ida (opens image in new tab) 

In the absence of clinical trial data adverse event rates for venetoclax with azacitidine have been taken from the results of the VIALE-A trial which evaluated efficacy and safety in newly diagnosed AML patients ineligible for intensive chemotherapy⁹. Adverse event rates for FLAG-Ida have been taken from the comparator arm for the NICE TA765 which evaluated gilteritinib versus chemotherapy in patients with FLT3-mutated R/R AML³. Clinical experts have confirmed that the adverse events would not expected to be different in patients with FLT3 mutated AML. Costs of adverse events have been taken from NICE TA765 (venetoclax with azacitidine for untreated acute myeloid leukaemia). Mean adverse event treatment costs are estimated to be £967 per patient for venetoclax with azacitidine and £1,146 for FLAG-Ida. For more detail refer to the cost-effectiveness section above and Appendix 3. d. 

Table 11 provides the estimated budget impact for treatment of 10 patients with venetoclax with azacitidine in Wales including medicines acquisition costs, administration and adverse event costs.

Table 11. Estimated annual costs in Wales (opens image in new tab) 

Budget impact issues

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Equality and health impact assessment

AWTTC have completed an Equality and Health Impact Assessment in parallel with each development stage of the project. This follows the five ways of working for public bodies, and work to achieving the wellbeing goals, outlined in the Well‑Being of Future Generations (Wales) Act 2015. It is not expected that venetoclax with azacitidine will have significant potential negative impact on people based on the protected characteristics of the Equality Act 2010.

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Additional factors

Prescribing unlicensed medicines

Venetoclax with azacitidine is not licensed to treat this indication and is therefore ‘off label’. Providers should consult the relevant guidance on prescribing unlicensed medicines before any off-label medicines are prescribed.

Care has been taken to ensure the information is accurate and complete at the time of publication. However, the All Wales Therapeutics and Toxicology Centre (AWTTC) do not make any guarantees to that effect. The information in this document is subject to review and may be updated or withdrawn at any time. AWTTC accept no liability in association with the use of its content. An Equality and Health Impact Assessment (EHIA) has been completed in relation to the medicine and has been published on the AWTTC website.

Information presented in this document can be reproduced using the following citation: All Wales Therapeutics & Toxicology Centre. Evidence Status Report. Venetoclax (Venclyxto^®) with azacitidine for the treatment of relapsed/refractory acute myeloid leukaemia. Reference number: OW32. 2025.

Copyright AWTTC 2025. All rights reserved.

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• Original assessment: OWMAG recommendation with starting and stopping criteria December 2025 PDF 74KB
• Original assessment: OWMAG decision rationale December 2025 PDF 55KB
• Original assessment: Evidence Status Report December 2025 PDF 417KB
• Original assessment: Equality and Health Impact Assessment December 2025 PDF 144KB