The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 18 July 2012

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 18 July 2012 ANTILYMPHOCYTE GLOBULINS FRESENIUS 20 mg/ml, solution to dilute for infusion 10 glass bottle(s) of 5 ml (CIP code: ) Applicant: FRESENIUS MEDICAL CARE FRANCE Rabbit anti-human T lymphocyte immunoglobulin Date of Marketing Authorisation: 6 May 1998 (national procedure) Date of last amendment (extension to indication): 9 February 2012 Reason for request: Inclusion for hospital use in the extension of indication: "-Conditioning before HSC (Haemopoietic Stem Cell) transplantation -Prevention of graft versus host disease after allogenic HSC transplant. This medicinal product is indicated for use particularly in stem cell transplantation from unrelated volunteer donors in combination with standard treatments for malignant haematological disorders. Medical Economic and Public Health Assessment Division 1/8

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Rabbit anti human T lymphocyte immunoglobulin 1.2. Indication "Antilymphocyte Globulins Fresenius are used in combination with other immunosuppressant medicinal products in the following indications: - Prophylaxis of acute rejection after allogenic solid organ transplantation. Antilymphocyte Globulins Fresenius are indicated for use in association with other immunosuppressant medicinal products (e.g. glucocorticoids, purine antagonists, calcineurin inhibitors or mtor inhibitors). - Treatment of corticosteroid-resistant rejection after allogenic solid organ transplantation if the effect of treatment with methyl-prednisolone is insufficient. - Conditioning before HSC (Haemopoietic Stem Cell) transplantation. - Prevention of graft versus host disease following allogenic HSC transplantation. This medicine is indicated particularly in stem cell transplantation from unrelated volunteer donors in combination with standard treatments for malignant haematological disorders" Dosage " Antilymphocyte Globulins Fresenius must only be prescribed by a doctor with experience in immunosuppressant therapies for organ transplantations or immunosuppressant therapies for conditioning before stem cell transplantation. Treatment must be initiated and monitored only by qualified doctors. Recommended dose The dose of Antilymphocyte Globulins Fresenius depends on the indication and is determined according to body weight. [ ] Conditioning before stem cell transplantation: Antilymphocyte Globulins Fresenius in myeloablative conditioning for HSC allotransplantation. The standard dose is 10 to 30 mg/kg/day of Antilymphocyte Globulins Fresenius, generally administered from day -3 to day -1 before the stem cell transplantation» No dosage adjustment required in children or patients 65 years old [ ]".. 2/8

3 2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2012) L: Antineoplastic agents and immunomodulators L04: Immunosuppressants L04A: Immunosuppressants L04AA: Selective immunosuppressants L04AA04: Antilymphocyte globulins (rabbit) 2.2. Medicines in the same therapeutic category THYMOGLOBULIN 5 mg/ml (Rabbit anti-human thymocyte immunoglobulins), powder for injectable solution or infusion, GENZYME, which has the following indications: Immunosuppression in transplantation: prevention and treatment of transplant rejection. Prevention of acute and chronic graft versus host reaction in haemopoietic stem cell transplantation. Treatment of acute corticosteroid-resistant graft versus host reaction. Haematology: treatment of bone marrow aplasia. THYMOGLOBULIN has a high actual benefit and a grade V improvement in actual benefit (opinion of 17 January 2007) Medicines with a similar therapeutic aim Ciclosporin (NEORAL, SANDIMMUN) is indicated for "Preventative or curative treatment of graft versus host disease". 3/8

4 3 ANALYSIS OF AVAILABLE DATA 3.1. Efficacy The presentation of ANTILYMPHOCYTE GLOBULINS FRESENIUS (ATG-F) in its new indication is based on an open, randomised, phase III study comparing the efficacy and safety of a treatment regimen of ATG-F + ciclosporin A (CsA) + Methotrexate (MTX) with the conventional regimen of CsA and MTX in patients suffering from acute myeloblastic leukaemia, acute lymphoblastic leukaemia, myelodysplastic syndrome or chronic myeloid leukaemia who may undergo allogenic HSC transplantation: study AP-AS-21-DE_CSR.05. Aim of the study: to compare the efficacy and safety of a treatment regimen to ATG-F + ciclosporin A (CsA) + Methotrexate (MTX) to the conventional regimen of CsA and MTX in patients undergoing allogenic HSC transplantation for acute myeloblastic leukaemia, acute lymphoblastic leukaemia, myelodysplastic syndrome or chronic myeloid leukaemia. Primary endpoint: efficacy, both in terms of the incidence of severe acute graft versus host disease (grade III-IV) (GvHDa) and in terms of the mortality rate during the first 100 days after transplantation. The main secondary endpoints involved an analysis of each of the following criteria: development of chronic GvHD, time to the transplant taking defined as the time between the transplant being performed and the first occasion when the neutrophil count was over 1/nL and the platelet count over 50/nL during three consecutive days, disease-free survival, overall survival, development of relapse or progression, and safety. Inclusion/non-inclusion criteria: - Adult patients suffering from: acute myeloblastic leukaemia, or acute lymphoblastic leukaemia: first complete remission or beyond the first remission, relapse, no remission (refractory from the outset, failure of induction); myelodysplastic syndrome or myelofibrosis when HSC transplantation is indicated; chronic myeloid leukaemia: beyond the first chronic phase, accelerated phase, blast phase, chronic phase. patients who may receive an HSC transplantation from an unrelated compatible donor (8/8 alleles) HLA A, -B (based on DNA), HLA-DRB1, -DQB1 Results: A total of 103 patients were randomised to the ATG-F group and 98 patients to the non-atg-f group. Median follow up was three years. Early failure, (i.e. death or GvHDa) occurred in 21% of patients in the group treated with ATG-F combined with the reference treatment compared to 35% of patients receiving the conventional treatment regimen. There was no significant difference in the logistic regression model adjusted for stratified randomisation factors. Separate analysis of the two components of the primary endpoint showed the regimen with ATG-F in combination with the reference treatment to be superior to reference treatment alone in terms of incidence of acute GVHD during the first 100 days after transplantation, with an incidence of 12% [95% CI 6.8%; 19.8%] in the ATG-F group compared to 26% [18.2%; 35.8%] in the non ATG-F group (p<0.05). Mortality rates before GvHDa during the 100 days following transplantation were similar in the two groups: 9.7% in the ATG-F group and 9.2% in the comparator group (cf.table 1). 4/8

5 Table 1: Incidence of early failures ATG F n=103 Conventional regimen n=98 n % n % No treatment failure NS Early failure NS GvHDa p=0.03 death NS Secondary endpoints Significantly fewer patients treated with ATG-F developed any stage of GvHDa (56.3% compared to 74.5%, p<0.05), and there were significantly fewer cases of chronic GvHD over the three years of follow-up (30% compared to 60%; p<0.05). The three-year disease-free survival rate was 48% in patients treated with ATG-F compared to 38% in patients not treated with ATG-F (not significant difference). Overall three-year survival was 55% in patients treated with ATG-F compared to 43% in patients not treated with ATG-F (not significant difference). Finally, the relapse/progression percentage was 33% in patients treated with ATG-F compared to 28% in patients not treated with ATG-F (not significant. difference) Safety All patients whatever the treatment group they were, have had at least one adverse effect during the study. The main results are shown in table 2. Table 2: Overall safety assessment ATG-F Conventional regimen Number of patients with at least one AE 106 (100%) 95 (100%) Average number of AE per patient Number of patients with at least one SAE 82 (77.4%) 68 (71.6%) Mean number of SAE patients Number of SAE per year of follow-up Number of patients with at least one fatal SAE. 32 (30.2%) 28 (29.5%) Number of patients who dropped out because of AE 0 0 AE: adverse event; SAE: serious adverse event The profile of adverse events in each group is shown in table 3. 5/8

6 Table 3: Adverse events reported by at least 20% of patients in each group. ATG-F Conventional regimen Infection 103 (97.2%) 91 (95.8%) Mucosal inflammation 73 (68.9%) 69 (72.6%) Fever 67 (63.2%) 50 (52.6%) Hypertension 59 (55.7%) 49 (51.6%) Diarrhoea 51 (48.1%) 44 (46.3%) Headaches 44 (41.5%) 29 (30.5%) Rigors 33 (31.1%) 13 (13.7%) Epistaxis 23 (21.7%) 11 (11.6%) Renal impairment 23 (21.7%) 17 (17.9%) Abdominal pain 21 (19.8%) 24 (25.3%) Concerning the most common adverse events, infections, the incidence of CMV infection was 54% in patients treated with ATG-F compared to 30% in the comparator group. The incidence of oral herpes infections was 17% in the ATG-F group compared to 6% in the comparator group. 9.4% of patients died due to infection in the ATG-F group compared to 8.4% in the comparator group. The main adverse effects in the ATG-F group which occurred during study AP-AS-21- DE_CSR.05, were mainly infection (47.2%), fever (31.1%), and rigors (21.7%). Pharmacovigilance data from the last five years of use of ATG-Fresenius have not shown any change in the safety profile Conclusion The assessment of the efficacy of ANTILYMPHOCYTE GLOBULINS FRESENIUS (ATG-F) in its new indication is based on an open, randomised phase III study comparing the efficacy and safety of a treatment regimen including ATG-F + ciclosporin A (CsA) + Methotrexate (MTX) to the conventional regimen of CsA and MTX in patients suffering from acute myeloblastic leukaemia, acute lymphoblastic leukaemia, myelodysplastic syndrome or chronic myeloid leukaemia who may undergo an allogenic HSC transplantation: study AP- AS-21-DE_CSR.05. Twelve patients in study AP-AS-21-DE_CSR.05 in the ATG-F group developed acute grade III-IV graft versus host disease (GVHDa) before D100 after transplantation. Ten patients died, i.e. the early failure rate (primary endpoint) was 21.4%, 95% CI [ ]. Twenty-four patients developed GVHDa and nine died in the control group, i.e. an early failure rate of 35% 95% CI [24.3 to 43], adjusted odds ratio: 0.59, 95% CI [0.30 to 1.17], (p = 0.13). No difference was seen in relapse rates, overall survival or disease-free survival between the treatment groups (secondary endpoints). No comparison was shown between ANTILYMPHOCYTE GLOBULINS FRESENIUS and THYMOGLOBULIN. 6/8

7 Most adverse events were infectious. 9.4% of patients died from an infection in the ATG-F group compared to 8.4% in the group treated with ciclosporin A (CsA) + Methotrexate (MTX) alone. 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Both the diseases for which conventional haemopoietic stem cell transplantation is used and the transplantation itself are life-threatening. ANTILYMPHOCYTE GLOBULINS FRESENIUS is a preparatory treatment (conditioning) for the haemopoietic stem cell transplantation and is intended to prevent graft versus host disease. There are treatment alternatives (THYMOGLOBULIN). The efficacy safety ratio for ANTILYMPHOCYTE GLOBULINS FRESENIUS in combination with other chemotherapies is high. This is a first line therapy. Public health benefit: The burden from the clinical situations involved (conditioning for HSC transplantation, prevention of graft versus host disease after allogenic HSC transplantation), which are serious and life-threatening but relatively uncommon diseases, is low. Development of organ and haemopoietic stem cell transplantation is a public health priority listed in the second national transplant plan, In view of the findings of the open, randomised placebo-controlled study and the lack of comparative data against THYMOGLOBULIN, the additional impact of ANTILYMPHOCYTE GLOBULINS FRESENIUS compared to conventional treatment on the morbidity and mortality of patients who are treated cannot be quantified. The impact of this treatment on quality of life is not documented. ANTILYMPHOCYTE GLOBULINS FRESENIUS is an alternative additional treatment in the management of patients, although its response to the public health need cannot be quantified. The actual benefit of the proprietary medicinal product is substantial Improvement in actual benefit In the absence of a comparison with THYMOGLOBULIN, a rabbit anti-thymocyte immunoglobulin and the comparison medicinal product, ANTILYMPHOCYTE GLOBULINS FRESENIUS does not offer an improvement in actual benefit (IAB V) when used for conditioning for haemopoietic stem cell transplantation or to prevent graft versus host disease after allogenic haemopoietic stem cell transplantation Therapeutic use Conditioning before bone marrow or stem cell transplantation is intended to eradicate the malignant clone (or tumour proliferation) (dose effect). In allogenic transplantation it also has an immunological effect (graft versus leukaemia or GVL) which contributes to eradicating the malignant proliferation. Haemopoietic stem cell allotransplantation is currently the treatment of choice for many malignant blood dyscrasias (leukaemias, lymphomas) and also for benign haematological 7/8

8 diseases such as bone marrow aplasia. 1 In particular, autologous transplantation is used for the treatment of myeloma (in patients who are eligible for intensive treatment following induction chemotherapy) and in the treatment of non-hodgkin's lymphomas. 2 Recent findings suggest that intensive polychemotherapy before haemopoietic stem cell transplantation is useful in the management of patients under 65 years old with a primary central nervous system lymphoma. 3,4 Pre-transplantation conditioning uses various chemotherapy protocols, which may include alkylating agents and can possibly be combined with whole body irradiation (in malignant blood dyscrasias). Standard conditioning protocols are associated with important toxicity. Socalled low intensity conditioning (non-myeloablative) reduces the toxicity using the immunological effects of the graft. The choice of conditioning protocol depends on many factors, particularly the patient's general health and age, co-morbidities and type of blood dyscrasia. Currently, there is little standardisation in terms of HSC transplantation. The place of ATG-F in this treatment regimen has been validated in the clinical study described above. It must be used in combination with existing treatment regimens during the three days before transplantation Target population The target population for ANTILYMPHOCYTE GLOBULINS FRESENIUS is children and adults undergoing haemopoietic stem cell transplantation. According to epidemiological findings from the Annual Biomedicine Agency s 2010 report, HSC allotransplantation was reported in 1,644 patients in 2010 (including 246 children) mostly for malignant blood dyscrasias: acute myeloblastic leukaemia (31.2%), acute lymphoblastic leukaemia (14.5%) and myelodysplasias (9.5%). The target population for ANTILYMPHOCYTE GLOBULINS FRESENIUS is difficult to define but may be in the region of 1600 patients considering that all patients who may receive an HSC allotransplant are potential candidates for conditioning treatment with ANTILYMPHOCYTE GLOBULINS FRESENIUS Transparency Committee recommendations The transparency Committee recommends inclusion on the list of medicines approved for hospital use and various public services in this extension to indication. 1 Evolution des conditionnements des greffes allogéniques de cellules souches hématopoïétiques chez l adulte depuis 10 ans Bulletin du cancer 95 (1): January SFH Reference standards 2009, NCCN 2011 Non-Hodgkin s Lymphomas 3 Gonzalez-Aguilar A, Houillier C, Soussain C, Hoang-Xuan K Prise en charge des lymphomes primitifs du système nerveux central Rev Neurol (Paris) Oct; 167(10): Epub 2011 Sep 8. 4 del Rio MS, Choquet S, Hoang-Xuan K, Glaisner S, Fourme E, Janvier M, Soussain C. Platin and cytarabinebased salvage treatment for primary central nervous system lymphoma. J Neuro-oncol Nov; 105(2): Epub 2011 Jun 9. 8/8