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Beth benderfynodd Grŵp Asesu Meddyginiaethau Cymru’n Un?

Gellir rhoi sorafenib fel triniaeth (gynhaliol) barhaus ar gyfer lewcemia myeloid acíwt (AML) mewn pobl ar ôl iddynt gael trawsblaniad bôn-gelloedd alogenëig – triniaeth sy'n cynnwys cymryd bôn-gelloedd iach o waed neu mêr esgyrn un person, yn ddelfrydol aelod agos o'r teulu sydd â’r un math o feinwe neu debyg, a'u trosglwyddo i'r claf. Mae sorafenib ond yn addas ar gyfer pobl y mae eu lewcemia wedi'i achosi gan fath penodol o fwtaniad mewn genyn o'r enw FLT3.

Bydd sorafenib 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 sorafenib wedi'i drwyddedu i drin AML, felly os caiff ei ddefnyddio i drin AML fe’i gelwir 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 am ganser thyroid anaplastig ewch i: Leukaemia Care

What did the One Wales Medicines Assessment Group decide?

Sorafenib can be given as ongoing (maintenance) treatment for acute myeloid leukaemia (AML) in people after they have had an allogeneic stem cell transplant – a treatment that involves taking healthy stem cells from the blood or bone marrow of one person, ideally a close family member with the same or similar tissue type, and transferring them to the patient. Sorafenib is only suitable for people whose leukaemia was caused by a specific type of mutation in a gene called FLT3.

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

Sorafenib is not licensed to treat AML, so using it to treat AML 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 visit: Leukaemia Care

This treatment is not to be used as a bridge to transplant or as an alternative option to haematopoietic cell transplantation.

Starting criteria: Patients who have received an allogenic haematopoietic cell transplantation for acute myeloid leukaemia and where:

• There was presence of the FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutation at the time of diagnosis or AML relapse.
• There is no evidence of graft versus host disease (GvHD).
• There are no contraindications to the use of sorafenib.
• The patient is not eligible for entry into a clinical trial.

Patients who satisfy the eligibility criteria will be prescribed sorafenib following consultation with the patient and/or carer after consideration of potential adverse effects, cautions and contraindications. This consultation should be recorded in the patient’s notes.

The recommended dose is 800 mg/day in two divided doses to be adapted according to tolerance. Treatment should start 30-60 days post-transplant and may continue up to a maximum of two years.

Monitoring: 

• Full blood count
• Urea and electrolytes
• Liver function tests
• Phosphate and calcium
• Blood glucose

The above tests should be done weekly for month 1 then monthly for 2 months, extended to every two months if the patient is well.

• Blood pressure every 1-2 months
• Thyroid function test (if clinical signs of hypo/hyperthyroidism)
• Electrocardiogram every 1-2 months
• Bone marrow monitoring (morphology, MRD, chimerism) at month 1, 2, 3, 6, 12,18 and 24 post-transplant, but monitoring can be increased as required.
• Clinical symptoms of GvHD
• Clinical evaluation of side effects, refer to Summary of Product Characteristics

Any other monitoring should be in accordance with the Summary of Product Characteristics for sorafenib. Sorafenib should be transiently discontinued in the case of GvHD requiring systemic treatment with corticosteroids, but may be cautiously resumed once remission of GvHD is documented.

Stopping criteria: 

• evidence of morphological relapse on bone marrow examination
• toxicity; a dose reduction may be considered, follow the guidance in the Summary of Product Characteristics
• patient request
• after two years of sorafenib

Only one course of treatment may be issued in accordance with this advice. Requests for repeat courses or continuing treatment beyond two years should be explored through funding mechanisms such as the individual patient funding request process. 

Health boards will take responsibility for implementing One Wales Medicines Assessment Group decisions and ensuring that a process is in place for monitoring clinical outcomes. 

Background: Acute myeloid leukaemia (AML) is a cancer of the blood and bone marrow characterised by clonal proliferation derived from primitive haematopoietic stem cells or progenitor cells. Abnormal differentiation of myeloid cells results in a high level of immature malignant cells and fewer differentiated red blood cells, platelets and white blood cells. Anaemia, bleeding problems and serious infections are common symptoms of AML. FMS-like tyrosine kinase-3 (FLT3) is a transmembrane ligand-activated receptor tyrosine kinase that plays a role in the proliferation, differentiation and apoptosis of hematopoietic cells through various signalling pathways. An FLT3-internal tandem duplication (ITD) mutation occurs in approximately 25% of all AML cases and is associated with relatively poor prognosis so patients are usually referred for allogenic haematopoietic cell transplantation (HCT) in first complete remission. AML relapse is the most frequent type of treatment failure after HCT, especially in patients with FLT3-ITD AML. Based on its mechanism of action tyrosine-kinase inhibitors (TKIs) such as sorafenib have been used in FLT3-ITD mutated AML to reduce the risk of relapse and improve survival.

This use of sorafenib for maintenance treatment following allogenic HCT is currently off-label. Clinicians in Wales consider there is an unmet need and have identified a cohort of people who could benefit from this treatment. This medicine was therefore considered suitable for assessment via the One Wales process.

Current One Wales Decision: Supported for maintenance treatment.

Licence status: Off-label use for this licensed medicine.

Guidelines: There have been no relevant updates to existing guidelines identified.

Licensed alternative medicines or Health Technology Assessment advice for alternative medicines: No new medicines or Health Technology Assessment advice reported.

Effectiveness: A repeat literature search conducted by AWTTC identified two papers which analysed the clinical effectiveness of sorafenib pertinent to the recommendation (See Appendix 1). These included a retrospective study published in August 2022 and a follow up study of the randomised control trial (RCT) NCT02474290 summarised in the original evidence status report. The primary objective of the follow up study was to report on viral infections (see safety section); clinical effectiveness data were reported as secondary endpoints. Overall results are comparable to those seen in the original evidence report with an indication that benefits with sorafenib are sustained.

The retrospective study by Aydin et al (2022) compared a cohort of 21 FLT3-ITD positive AML patients receiving sorafenib maintenance therapy with a control group of 22 patients without maintenance. The cumulative incidence of relapse for the sorafenib group compared to the control group at one (14.6% versus 42.4%), two (14.6% versus 42.4%) or three (14.6% versus 47.3%) years was significantly lower (p = 0.028). At 1 year, the pivotal study NCT02474290 reported a cumulative incidence of relapse (primary endpoint) of 7.0% (95% Confidence Interval [CI] 3.1 to 13.1) for patients assigned to sorafenib and 24.5% (95% CI:16.6 to 33.2) for those allocated to placebo (hazard ratio [HR] 0.25, 95% CI 0.11 to 0.57; p = 0.0010). Rates of relapse reported by Aydin et al were slightly higher when compared to the cohort in RCT NCT02474290 for both the sorafenib and control groups, this may in part be due to differences in study design and patient characteristics. The mean age of patients was markedly higher in this study (55 years) compared with the NCT02474290 cohort (35 years). The 3-year culminative incidence of relapse reported as a secondary endpoint in the follow up study of NCT02474290 (Xin et al, 2022) was 13.0% (95% CI: 7.3 to 20.4%) and 34.8% (95% CI: 25.5 to 44.2%), in the sorafenib and control groups respectively (hazard ratio= 0.306, 95% CI:0.162 to 0.579, p < 0.001). This indicates a sustained reduction in relapse rates with sorafenib compared with no maintenance treatment.

Similar to the RCTs included in the original evidence report the median overall survival (OS) had not been reached for the sorafenib group in the retrospective study after a median follow up of 34.7 months. This was compared with 31.4 months in the control group suggesting survival benefits when sorafenib is added as maintenance therapy, however median follow up was longer in the control group (67.9 months). Median OS was not reported in the NCT02474290 follow up study but OS rates for the sorafenib group at 3 years was 79% down slightly from 82.1% reported at two years in the original paper. The corresponding placebo group OS rates were lower than sorafenib at two years (68%) and three (61.4%) years. Overall there is an indication of prolonged survival advantage in the sorafenib group compared with no maintenance treatment.

Safety: A repeat literature search conducted by AWTTC identified one paper which analysed the safety of sorafenib pertinent to the recommendation. This was the follow-up of NCT02474290 (See Appendix 1).

The open-label, randomised phase III trial (n = 202) was followed up by investigating the effect of sorafenib maintenance post-transplantation on Epstein–Barr virus (EBV) and cytomegalovirus (CMV) infections. The primary endpoint was EBV and CMV infections within 3 years post-transplantation. The study had a median extended follow-up post-transplantation of 36.8 months (range: 2.5–67.1) and concluded that sorafenib maintenance post-transplantation did not increase the incidence and mortality of EBV and CMV-associated diseases compared with no maintenance post-transplantation.

Cost-effectiveness: No relevant cost-effectiveness analyses were identified in the repeat literature search.

Budget impact: In the original evidence summary it was estimated that four patients per year would be eligible for two years of treatment with sorafenib maintenance therapy. [CONFIDENTIAL DATA REMOVED] in Wales have been treated with sorafenib for FLT3-ITD mutated AML following the One Wales decision.

Impact on health and social care services: Minimal.

Patient outcome data: Outcome data were provided for six patients, [CONFIDENTIAL DATA REMOVED]

Next review date: June 2026

References: a full reference list is available on request.

Disclaimer: This document includes evidence published since the last review or full assessment of this medicine for the indication under consideration. It does not replace the original full evidence status report. Any previous reviews and the original full evidence status report are available from this webpage in the document history section.

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 One Wales policy and this found there to be a positive impact. Key actions have been identified and these can be found in the One Wales Policy EHIA document.

Information presented in this document can be reproduced using the following citation: All Wales Therapeutics & Toxicology Centre. Evidence Review. Sorafenib for acute myeloid leukaemia maintenance. Reference number: OW18. 2023.

Copyright AWTTC 2023. All rights reserved. References: a full reference list is available on request.

Appendix

• First review: One Wales Interim Decision and review report April 2023 PDF 84KB
• Original assessment: One Wales Interim Decision with decision rationale February 2022 PDF 69KB
• Original assessment: Evidence Status Report February 2022 PDF 208KB