ATA129 for Epstein-Barr virusassociated. lymphoproliferative disorder

Transcription

1 March 2017 Horizon Scanning Research & Intelligence Centre ATA129 for Epstein-Barr virusassociated post-transplant lymphoproliferative disorder NIHR HSRIC ID: Lay summary ATA129 is a new treatment for Epstein-Barr virus-associated posttransplant lymphoproliferative disorder (EBV-PTLD). EBV-PTLD is a common complication of both organ and stem cell ( bone marrow ) transplant. After a transplant, the body s immune system is weakened so that it is unable to respond effectively to infections, leaving the patient very vulnerable to developing PTLD. Some studies have suggested that ATA129 can cells infected by Epstein- Barr virus and kill them. ATA129 is given directly into the bloodstream via intravenous infusion. This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information. 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. Horizon Scanning Research & Intelligence Centre University of Birmingham nihrhsric@contacts.bham.ac.uk

2 TARGET GROUP Epstein-Barr virus-associated post-transplant lymphoproliferative disorder (EBV-PTLD) second line in rituximab refractory patients following hematopoietic stem cell transplantation. TECHNOLOGY DESCRIPTION ATA129 (EBV-CTLs; Epstein-Barr virus T-cell therapy) is an EBV-virus specific T-cell therapy that targets EBV proteins. Volunteer donor-derived T-cells are stimulated with EBV antigen presenting cells, resulting in expansion of T-cells active against EBV-infected targets. The allogeneic product is characterised and stored for potential therapeutic use in an appropriate partially human leukocyte antigen (HLA)-matched patient. ATA129 is designed to recognise and target EBV-infected cells in immunocompromised individuals. In clinical trials 1, ATA129 was administered via intravenous (IV) infusion in a 5 week cycle consisting of 3 weekly infusions of 2 x 10 6 T-cells/kg. Patients may receive more than one cycle of therapy as required to achieve the maximal response. ATA129 does not currently have Marketing Authorisation in the EU for any indication. INNOVATION and/or ADVANTAGES If licensed, ATA129 will offer the only licensed treatment option for patients with rituximab refractory EBV-PTLD. DEVELOPER Atara Biotherapeutics, Inc. and Atara Biotherapeutics Ireland Limited. AVAILABILITY, LAUNCH OR MARKETING ATA129 was awarded PRIME status for EBV-PTLD by the EMA in October 2016 and is in phase III clinical trials. PATIENT GROUP BACKGROUND EBV is a human gamma herpesvirus, which asymptomatically infects over 95% of adults by the age of 30. Initial infection with EBV typically occurs in childhood, and can be clinically silent or difficult to distinguish from other mild viral infections 2. Following primary infection, EBV establishes a latent infection with memory B-cells at low levels that the immune system cannot clear 2. Allogeneic hematopoietic cell transplantation (allohct) is used to treat selected patients with a range of malignant and non-malignant haematological disorders and other specific disorders of the immune system 3. It involves high-dose chemo- and/or radiotherapy to destroy the patient s immune system followed by replacement of bone marrow stem cells

3 with stem cells from a tissue-type matched or unmatched donor 3. In the period following transplantation, the immune system is compromised allowing opportunistic pathogens to thrive and the reactivation of latent infections such as EBV. EBV reactivation can cause significant morbidity and mortality in immunocompromised patients, including induction of lymphoproliferation and EBV-positive B-cell tumours 4,5,6. PTLD presents as general or discrete lymphadenopathy. Symptoms are often non-specific and include pyrexia, sweats and weight loss, and extra-nodal involvement is common, including the gastrointestinal tract, lungs, skin, bone marrow and central nervous system 7. Its presentation can mimic fulminant sepsis syndrome 6. CLINICAL NEED and BURDEN OF DISEASE The incidence of EBV-PTLD is low and it occurs in diverse patient groups 8. Following allohct, EBV-PTLD incidence ranges from <1% to 11%, depending on the type of transplant and degree of immune suppression 9. Incidence also varies between transplant centres and whether donors are matched, mismatched, family or unrelated 10. The risk of developing EBV-PTLD is elevated during the first year following allohct, with the highest occurrence during the first six months 8. In 2012, there were 3,616 allohcts in England, an increase of 7.7% on the previous year 3. EBV-PTLD significantly impacts survival; a 3-year survival rate of 20% in patients with PTLD has been reported, as opposed to 62% among patients without PTLD 4. For patients who have either not responded to, or relapsed following first line therapy with rituximab, studies suggest a median overall survival of days 4,11,12 EBV-PTLD causes high mortality, from both refractory disease and complications of treatment. In addition, as it often occurs in the context of otherwise successful transplants, it may cause donated organs to be wasted 13. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal in development. Nivolumab for treating relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant (ID1103). Expected April NHS England Policies and Guidance NHS England. 2013/14 NHS Standard Contract for haematopoietic stem cell transplantation (Adult). B04/S/a. NHS England. 2013/14 NHS Standard Contract for haematopoietic stem cell transplantation (children). B04/S/b NHS England. Clinical Commissioning Policy: second allogeneic haematopoietic stem cell transplant for relapsed disease /P. NHS England. Clinical Commissioning Policy: haematopoietic stem cell transplantation (HSCT) for lymphoplasmacytic lymphoma (Adults) /P. NHS England. Clinical Commissioning Policy: haematopoietic stem cell transplantation (HSCT) (All ages): revised. B04/P/a. NHS England. Clinical Commissioning Policy: Use of Plerixafor for stem cell mobilisation (update). B04/P/b.

4 Other Guidance European Hematology Association. Management of Epstein-Barr virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: sixth European Conference on Infections in Leukemia (ECIL-6) guidelines European Group for Blood and Marrow Transplantation. Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation CURRENT TREATMENT OPTIONS Due to the heterogeneity of EBV-PTLD and patients, there is no one treatment approach. The aim of treatment is to cure the condition whilst preserving the transplant 7. Off-label monotherapy with rituximab is the first line treatment of choice with a positive outcome reported in almost 70% of patients 10. However, around 60-70% of patients treated with rituximab either fail to respond or relapse 15,16,17. Second line options for EBV-PTLD include 9,10,18 : Chemotherapy most commonly CHOP (cyclophosphamide, doxorubicin, oncovin, prednisone) with or without rituximab. Cellular therapy donor lymphocyte infusion (DLI) or EBV-specific cytotoxic T lymphocytes (CTLs). Surgery or radiotherapy may be used for select, localised cases of EBV-PTLD. In the allohct setting, chemotherapy has limitations as a therapeutic option as it is frequently associated with high rates of adverse events, including toxic deaths 19. Similarly, although DLI has been shown to produce responses in patients with EBV-PTLD, it is associated with a significant risk for induction of graft versus host disease (GvHD) 20. EFFICACY and SAFETY Trial NCT , ; ATA129; phase II. NCT , , P30CA008748, MSKCC-95024, NCI-V ; ATA129; phase I/II. Sponsor Atara Biotherapeutics, Inc. Atara Biotherapeutics, Inc. Status Ongoing. Ongoing. Source of Trial registry 1, manufacturer. Trial registry 21, manufacturer. information Location USA. USA. Design Non-randomised, uncontrolled. Non-randomised, uncontrolled. Participants Schedule Follow-up n=112 (planned); children and adults, any age; EBV-PTLD, lymphoma or other EBVassociated malignancy. All participants receive ATA129, IV, at 2x10 6 cells/kg on days 1, 8, and 15 of a 5 week cycle. Participants may receive more than one cycle of therapy as required. Follow-up per protocol is 12 months, however additional follow-up data is available. n=84 (planned); children and adults, any age; EBV-PTLD, lymphoma or other EBVassociated malignancy. All participants receive ATA129, IV, at 1 or 2x10 6 cells/kg on days 1, 8, and 15 of a 4-6 week cycle. Participants may receive more than one cycle of therapy as required. Follow-up per protocol is 6 months. Participants achieving complete remission are evaluated at 6 month intervals for one year, or more frequently as clinically

5 Primary outcome/s Secondary outcome/s Expected reporting date Efficacy; overall survival (OS); disease free survival, probability of EBV disease relapse. In vivo expansion and persistence of EBV CTLs; incidence, kinetics and durability of clinical response. No quality of life measures included in trial outcomes. Results expected in indicated. Additional follow-up date is available. Efficacy; safety; in vivo expansion and persistence of EBV CTLs; incidence, kinetics and durability of clinical response; OS. No quality of life measures included in trial outcomes. Interim results have been presented at various scientific conferences. The trial is expected to remain open. In 2017, Atara Biotherapeutics expect to initiate two phase III trials for the treatment of patients with rituximab refractory EBV-PTLD. ESTIMATED COST and IMPACT COST The cost of ATA129 is not yet known. IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Other: Reduced symptoms or disability No impact identified Impact on Health and Social Care Services Increased use of existing services: long term, due to increased survival. Re-organisation of existing services Other: Decreased use of existing services: short term. Need for new services None identified Impact on Costs and Other Resource Use Increased drug treatment costs Other increase in costs: additional treatment option. Reduced drug treatment costs Other reduction in costs: reduction in costs due to avoidance of toxicity associated with use of alternative treatments such as chemotherapy or radiation therapy. Other Issues Clinical uncertainty or other research question identified None identified REFERENCES

6 1 ClinicalTrials.gov. Therapeutic effects of Epstein-Barr virus immune T-lymphocytes derived from a normal HLA-compatible or partially-matched third party donor in the treatment of EBV lymphoproliferative disorders and EBV-associated malignancies. Accessed 10 February Houldcroft CJ and Kellam P. Host genetics of Epstein-Barr virus infection, latency and disease. Reviews in Medical Virology 2015;25: NHS England. Clinical commissioning policy: haematopoietic stem cell transplantation (HSCT)(all ages): revised. NHS England B04/)/a. London: January Uhlin M, Wikell H, Sundin M et al. Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. Haematologica 2014;99(2): Vockerodt M, Yap LF, Shannon-Low C et al. The Epstein-Bar virus and the pathogenesis of lymphoma. Journal of Pathology 2015;235: Rouce RH, Louis CU and Heslop HE. EBV lymphoproliferative disease after hematopoietic stem cell transplant. Current Opinion in Hematology 2014;21(6): Al-Mansour Z, Nelson BP and Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Current Hematologic Malignancy Reports 2013;8(3): Rasche L, Kapp, M, Einsele et al. EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic STC. Bone Marrow Transplantation 2014;49: Taylor GS, Long HM, Brooks JM et al. The immunology of Epstein-Barr virus-induced disease. Annual Review of Immunology 2015;33: Styczynski J, van der Velden W, Fox CP et al. Management of Epstein-Barr virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: sixth European Conference on Infections in Leukemia (ECIL-6) guidelines. Haematologica 2016;101(7): Ocheni S, Kroeger N Zabelina T et al. EBV reactivation and post transplant lymphoproliferative disorders following allogeneic SCT. Bone Marrow Transplantation 2008;42(3): Fox CP, Burns D, Parker AN et al. EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era. Bone Marrow Transplantation 2014;49(2): Vickers MA, Wilkie GM, Robinson N et al. Establishment and operation of a good manufacturing practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease. British Journal of Haematology 2014;167: Snowden JA, Saccardi R, Allez M et al. Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplantation 2012;47(6): Choquet S, Leblond V, Herbrecht R et al. Efficacy and safety of rituximab in B-cell posttransplantation lymphoproliferative disorders: results of a prospective multicentre phase 2 study. Blood 2006;107(8): Choquet S, Oertel S, LeBlond V et al. Rituximab in the management of post-transplantation lymphoproliferative disorder after solid organ transplantation: proceed with caution. Annals of Hematology 2007;86(8): Oertel SH, Verschuuren E, Reinke P et al. Effect of anti-cd 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder. PTLD. American Journal of Transplantation 2005;5(12): Kanacry JA and Ambinder RF. EBV-related lymphomas: new approaches to treatment. Current Treatment Options in Oncology 2013;14(2): Trappe RU, Dierickx D, Zimmerman H et al. Response to rituximab is a predictive biomarker in post-transplant lymphoproliferative disorder (PTLD) and allows successful treatment stratification in an international phase II trial including 152 patients. Blood 2015;126(23): Doubrovina E, Oflaz-Sozmen b, Prockop SE et al. Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation. Blood 2012;119(11):

7 21 ClinicalTrials.gov. Biological therapy in treating patients at high-risk or with lymphoma, lymphoproliferative disease, or malignancies. Accessed 17 February 2017.