Molecular Pathology Evaluation Panel and Molecular Pathology Consortium Advice Note

Transcription

1 Molecular Pathology Evaluation Panel and Molecular Pathology Consortium Advice Note MPEP/MPC Advice Note June 2016 Test evaluated: Tumour Protein p53 (TP53) Molecular Pathology Evaluation Panel and Molecular Pathology Consortium The Molecular Pathology Evaluation Panel (MPEP) assesses and evaluates molecular pathology tests for the NHS in Scotland against set criteria and makes recommendations to the Molecular Pathology Consortium (MPC) on the clinical validity, analytical validity and clinical utility of tests. Status of Advice The status of MPEP/MPC Advice Notes is advisory. This advice represents the views of MPEP/MPC and was arrived at after careful consideration and evaluation of the available evidence. It is provided to assist health professionals within NHS Boards in Scotland with clinical decision making. It is the expectation that should a clinician consider that the molecular pathology test would assist in a decision on case management for a patient within the indication specified then the test should be undertaken. This advice does not override the individual responsibility of health professionals to make decisions in the exercise of their clinical judgement in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. No part of this advice may be used or reproduced without the whole of the advice being quoted in full. ADVICE: TP53 analysis testing is accepted for use in NHS Scotland for patients who have: Chronic Lymphocytic Leukaemia (CLL) Del-5q- Myelodysplasia (del-5q- MDS) Testing of all CLL patients, in whom treatment is planned and also, prior to each line of therapy, is recommended. Testing of del 5q- MDS patients (ie at identification of isolated 5q- abnormality) at diagnosis is recommended. MPEP/MPC Advice Note

2 What is Tp53 analysis? TP53 analysis will detect all known variants in the coding sequence of the TP53 gene including single nucleotide variants, small insertions/deletions and larger insertions/deletions or other structural abnormalities. Proposed patient cohort who will be tested TP53 mutation analysis is recommended for the following patient cohort: CLL patients in whom treatment is planned, prior to each line of therapy 5q- MDS patients at diagnosis (i.e. at identification of isolated 5q- abnormality) Disease / Condition affected patient cohort and prognosis of patient cohort CLL is a chronic, malignant proliferation of mature B lymphocytes involving marrow, blood and lymphoid tissues. The presence of a 17p deletion (representing loss of the TP53 gene) is the single most important prognostic factor. Loss of TP53 (via deletions or mutations) predicts rapid disease progression, poor response to chemotherapy and poor overall survival. TP53 deleted / mutated subclones, being chemotherapy resistant, are enriched by successive lines of conventional chemotherapy such that their frequency of detection rises from 10% of patients at diagnosis to 40% or so in fludarabine refractory CLL. Treating these patients with chemotherapy regimens is regarded as futile and likely to result in significant toxicity. Del 5q- MDS: Myelodysplastic syndromes (MDS), is a group of diseases that affect the marrow. Del 5q MDS- is where part of chromosome 5 is missing. There are effective treatments for a particular subgroup of Myelodysplasia (MDS), characterised by transfusion dependence and a particular chromosome abnormality (5q-). The presence of a TP53 deletion / mutation predicts for a poor response however, as highlighted by the British Committee for Standards in Haematology (BCSH): The MDS BCSH Guidelines (December 2013) state that Lenalidomide is not currently recommended for patients with del(5q) and bone marrow blasts >5%, multiple (complex) cytogenetic abnormalities in addition to del(5q), patients with IPSS intermediate-2/high or with a known mutated TP53 gene. Relevance of test CLL: the identification of TP53 mutations in CLL patients combats the historically poor prognosis of this cohort and will allows precicing of specific treatment, which work independently of TP53, and have been shown to be highly effective. 5q- MDS: the identification of TP53 mutations in 5q- MDS would suggest against certain treatments agents which have been shown to be ineffective when a TP53 mutation is detected. MPEP/MPC Advice Note

3 Estimated incidence / prevalence of test CLL: UK data ( estimates 4,100 new cases per annum equating to approximately 400 patients per annum in Scotland. The prevalence of CLL in Scotland is 0.03% of the population of 5.5 million and as approximately 33% require treatment in any given year this equates to 577 patients. 10% of patients with CLL at diagnosis will have a 17p deletion / TP53 mutation; this rises to over 40% in relapsed / refractory disease. MDS: UK data ( indicates 50 new cases per annum equating to approx. 5 per annum in Scotland. TP53 aberrations are identified in approx 20% of 5q- MDS cases. Clinical Validity TP53 analysis is used to support treatment stratification. Test results will advice of the likely response to available therapies. CLL: Specific, effective, SMC-approved treatment (Idelalisib) will be offered, where appropriate, to patients with a 17p deletion or a TP53 mutation. Toxic chemoimmunotherapy based treatments will not be utilised. Del 5q- MDS: Lenalidomide is considerably less effective in 17p deleted / TP53 mutated disease and an alternative approach might be encouraged e.g. supportive care with blood transfusion or even consideration of marrow transplantation in younger fitter cases. Analytical Validity It is estimated that the combination of Sanger sequencing and MLPA will detect greater than 99% of TP53 variants, where the mutant population is greater than 20% in a population of wild-type TP53. CLL: FISH for 17p will be carried out (plus other routinely tested targets) as per current practice, in patients eligible for treatment with a chemotherapy based regime and in whom the current prognostic / predictive testing procedure (by FISH) is indicated. TP53 mutation analysis will be carried out on non-17p-deleted cases. Del 5q- MDS: Conventional karyotyping detects the 5q- abnormality in virtually all cases. For those patients exhibiting an isolated 5q-, TP53 sequencing will be performed. MPEP/MPC Advice Note

4 Clinical Utility This test detects TP53 variants that predict a poor response to conventional or approved therapies. This is an example of a Personalised Medicine approach to therapy, as it represents a powerful predictive tool. Selection of more effective approved treatments, with a high likelihood of response, is the objective for this testing - as well as the cost-saving from not utilising expensive therapies where it can be determined beforehand that the treatment will be ineffective. CLL: Comprehensive identification of a TP53 lesion will allow avoidance of costly, toxic chemotherapy and allow appropriate use of the SMC approved standard-of-care drugs (currently Idelalisib, with Ibrutinib being considered by SMC later this year). These drugs have proven benefit in this group of patients. Del 5q- MDS: The presence of a TP53 mutation predicts for a relatively poor response to lenalidomide. Rates of transformation to AML are approximately 2-3 x those of p53 Wild Type cases, and median survival is greatly reduced. Equally, the absence of a TP53 mutation predicts for a good response, allowing selection of patients who will benefit the most. Lenalidomide is a costly drug with not insignificant toxicity (predominantly myelosuppression in this setting). Patients in whom a TP53 mutation is identified, may be offered alternative treatments (e.g. allogeneic stem cell transplant for younger patients, transfusion and other supportive care for older less fit patients). Cost Effectiveness CLL: Cost savings will be made with regard to avoidance of chemoimmunotherapy in TP53 mutated CLL patients. (Cost of 6 cycles FCR approx 10,000, cost of 6 cycles BR approx 12,000, cost of 6 cycles CR approx 6,000) Choice of therapy is stratified according to age and fitness. It is anticipated that approx 51 TP53 mutated CLL patients per annum in Scotland and of these 15 patients would be identified prior to first line therapy (normally either FCR, BR or CR) assuming one third of patients would be treated with each of these regimens the potential saving in avoidance of chemoimmunotherapy is (5x 10,000) + (5 x 12,000) + (5 x 6,000) totalling 140,000. The avoidance of chemoimmunotherapy in second and third line therapy in TP53 mutated patients will be an additional cost saving but is more difficult to calculate precisely. 5q- MDS: avoidance of lenalidomide in a single patient will save approx. 40,000 per annumtp53 testing would be an additional cost. It is predicted that around one 5q- MDS patient per annumwould be identified with a TP53 mutation and therefore would not undergo lenalidomide treatment. MPEP/MPC Advice Note

5 Mechanism of funding for test TP53 Analysis will be carried out by the four nationally designated Molecular Pathology laboratories in Scotland. Contact details for the laboratories can be found at Contact details: Molecular Pathology Evaluation Panel & Molecular Pathology Consortium Area 062, 1 South Gyle Crescent, Edinburgh, EH12 9EB T: E: nss.mpep@nhs.net MPEP/MPC Advice Note