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Duvelisib for Relapsed Chronic Lymphocytic Leukaemia – Second and Subsequent Line

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Horizon Scanning Research April 2016 & Intelligence Centre Duvelisib for relapsed chronic lymphocytic leukaemia – second and subsequent line LAY SUMMARY Chronic lymphocytic leukaemia is a type of cancer which usually develops very slowly. In people with chronic lymphocytic leukaemia, the body makes too many white blood cells called lymphocytes. These This briefing is based on lymphocytes are abnormal and do not work properly so build up in the information lymph nodes (glands), spleen, bone marrow and blood. Many patients available at the time who have chronic lymphocytic leukaemia are diagnosed when having of research and a a routine blood test and if well, usually do not need to start treatment limited literature straight away. However, if the disease starts to cause symptoms, search. It is not treatment is then required. intended to be a definitive statement Duvelisib is a new type of drug for patients with chronic lymphocytic on the safety, leukaemia given as a tablet twice a day. Some studies have efficacy or suggested duvelisib may be helpful for people whose first treatment effectiveness of the has failed and whose disease has continued to spread. More studies health technology are now aiming to show how well it works and that it is safe to use. covered and should not be used for If duvelisib is licensed for use in the UK, it could be a new treatment commercial option for patients with chronic lymphocytic leukaemia that may reduce purposes or symptoms of the disease and increase survival. commissioning without additional information. NIHR HSRIC ID: 9609 This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre TARGET GROUP • Chronic Lymphocytic Leukaemia (CLL): relapsed – second or subsequent line. TECHNOLOGY DESCRIPTION Duvelisib (NK1197; IPI145) is a small-molecule, selective dual inhibitor of phosphatidylinositol 3 kinase (PI3K) δ and γ isoforms. The PI3K pathway promotes cell proliferation, growth, motility, metabolism and survival. The PI3Kδ/γ isoforms play an important role in immune-receptor signal transduction. Treating cancer cells with a PI3Kδ/γ inhibitor has been shown to block growth and induce cell death. Activity of PI3Kδ (p110δ) is needed for BCR-induced DNA synthesis and phosphorylation of Akt/protein kinase B, forkhead transcription factor/forkhead box O3a (FOXO3a), and p70 S6 kinase. PI3Kδ is also needed for interleukin 4-induced phosphorylation of Akt/PKB and FOXO3a and protection from apoptosis. As such, selective inhibition of PI3Kδ/γ may provide a treatment for various haematological malignancies. Early phase trials have suggested that duvelisib appears safe and has some activity in patients with relapsed CLL. In the phase III clinical trial, duvelisib is administered orally at 25mg twice daily for the first 21-day cycle, and then at 25mg twice daily for subsequent 28-day cycles, for up to 18 cycles1. Duvelisib does not currently have Marketing Authorisation in the EU for any indication. Duvelisib is also currently in phase III development for previously treated, indolent, non- Hodgkin lymphoma (as combination therapy with bendamustine and rituximab). It is in phase II development for previously treated indolent non-Hodgkin lymphoma (as monotherapy), previously untreated follicular lymphoma (as combination therapy with rituximab or obinutuzumab), relapsed follicular lymphoma (monotherapy) and relapsed or refractory indolent non-Hodgkin lymphoma (as combination therapy with rituximab). INNOVATION and/or ADVANTAGES If licensed, duvelisib will offer an additional oral treatment option for patients with relapsed CLL. DEVELOPER AbbVie; in collaboration with Infinity. AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. PATIENT GROUP BACKGROUND CLL is a disease affecting the growth and development of B-lymphocytes2. Patients with CLL have abnormal B-cells in their blood as well as in lymph nodes at diagnosis3. The 2 Horizon Scanning Research & Intelligence Centre disease can also be characterised by abnormal lymphocyte morphology and the accumulation of resting malignant B-cells in the spleen and bone marrow4,5. The progressive accumulation of monoclonal B-lymphocytes leads to leucocytosis, lymphadenopathy, hepatosplenomegaly, anaemia, thrombocytopenia, neutropenia, bone marrow failure, recurrent infections, and systemic symptoms (fatigue, weight loss, and night sweats)6,7. In contrast to most other leukaemias, patients with CLL are not necessarily treated at diagnosis, but rather after the development of symptomatic or progressive diseasea,6. Whilst around 40% of patients are asymptomatic at diagnosis, the majority will require treatment at some point and as no current treatment option is curative, most patients who are treated will eventually relapse8,9. Expert opinion also notes that in their experience around 50% of patients who have early stage disease at diagnosis eventually require treatment, but this is difficult to measure as early CLL can go undetecteda. An expert estimates that around 80% of patients are asymptomatic at diagnosisa. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: • Improving Outcomes: A Strategy for Cancer (2011). • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages). B01/S/a. CLINICAL NEED and BURDEN OF DISEASE CLL is the most common leukaemia in adults4, accounting for around 37% of all leukaemia diagnoses in the UK and 1% of all new cancer cases10. In 2013, 2,982 patients were newly diagnosed with CLL (ICD-10 C91.1) in England11. The risk of developing CLL increases progressively with age8, with around 60% of cases in 2013 diagnosed in people aged 70 and over11. Incidence in men is almost twice that of women8; in 2013, 1,884 males and 1,098 females were diagnosed with CLL in England11. Between 2008 and 2010, relative survival at five years for patients aged 15-64 years was estimated to be around 84%12. However, for patients aged 65 years and over relative survival at five years was approximately 62%12. In 2014-15, there were 26,918 hospital admissions due to CLL (ICD-10 C91.1) in England, accounting for 27,712 finished consultant episodes and 14,415 bed days13. In 2014, there were 920 deaths from CLL registered in England and Wales14. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance • NICE technology appraisal in development. Leukaemia (chronic lymphocytic) – ibrutinib [ID749]. Expected June 2016. • NICE technology appraisal in development. Leukaemia (chronic lymphocytic, relapsed) – ofatumumab (maintenance) [ID732]. Expected September 2016. a Expert personal communication. 3 Horizon Scanning Research & Intelligence Centre • NICE technology appraisal. Idelalisib for previously treated chronic lymphocytic leukaemia (TA359). October 2015. • NICE technology appraisal. Obinutuzumab in combination with chlorambucil for untreated chronic lymphocytic leukaemia (TA343). June 2015. • NICE technology appraisal. Ofatumumab in combination with chlorambucil or bendamustine for untreated chronic lymphocytic leukaemia (TA344). June 2015. • NICE technology appraisal. Bendamustine for the first line treatment of chronic lymphocytic leukaemia (TA216). February 2011. • NICE technology appraisal. Ofatumumab for the treatment of chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab (TA202). October 2010. • NICE technology appraisal. Rituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia (TA193). July 2010. • NICE technology appraisal. Rituximab for the first line treatment of chronic lymphocytic leukaemia (TA174). July 2009. • NICE technology appraisal. Fludarabine monotherapy for the first line treatment of chronic lymphocytic leukaemia (TA119). February 2007. • NICE technology appraisal. Guidance on the use of fludarabine for B-cell chronic lymphocytic leukaemia (TA29). September 2001. Other Guidance • British Committee for Standard in Haematology. Inerim statement from the BCSH CLL guidelines panel. 201515. • European Society for Medical Oncology. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 201516. • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology – non-Hodgkin’s lymphoma. 201517. • British Committee for Standards in Haematology. Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia. 20125. • National Cancer Institute Working Group. Guidelines on the treatment of chronic lymphocytic leukaemia. 1996 (revised 2008)18. CURRENT TREATMENT OPTIONS Treatment strategies for CLL, as a disease of the elderly, are highly individualised7. Factors influencing the choice of treatment include an assessment of fitness to tolerate chemotherapy and/or immunotherapy, co-morbidities, TP53 status, previous or current immune cytopenias, and evidence of lymphomatous transformation5. Guidelines recommend the use of chemoimmunotherapy with FCR (fludarabine, cyclophosphamide and rituximab) for the first line treatment of physically fit patients with CLL5,16, provided that their disease does not exhibit a TP53 deletionb. In frailer patients and those
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