Indikation Patients with CML. Wirkstoff Imatinib. Marke/Handelsname Glivec. Anzahl der vorgesehenen Studienzentren/Praxen in Deutschland 50

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1 Titel der Studie Non-interventional study (NIS) to assess the molecular monitoring of patients with chronic myelogenous leukemia (CML) in chronic phase (CP) under treatment and correlation with patient compliance Zielsetzung/Fragestellung of quantitative polymerase-chain-reacion (PCR) tests from peripheral blood and to assess the correlation of response with patient compliance of the patients treated for CML at the medical facility with regard to regular intake of the prescribed Glivec dose. Indikation Patients with CML Wirkstoff Imatinib Marke/Handelsname Glivec Anzahl der vorgesehenen Studienzentren/Praxen in Deutschland 50 Angestrebte Fallzahl beteiligter Patienten 500 Beginn der Studie Geplante Dauer der Studie Recruitment till 2010; observational period 2 years Studiennummer CSTI571ADE73 Studienleiter Prof. Dr. Hans Tesch Tagesklinik und Belegstation im Krankenhaus Bethanien Im Prüfling Frankfurt/Main Hammer,Ilka Manager Patient Oriented Programs Novartis Pharma GmbH Roonstr Nürnberg Deutschland ilka.hammer@novartis.com Telefon: 0911/ Unternehmen Novartis Pharma GmbH Roonstr Nürnberg

2 Deutschland Stand der Information Status der Studie Study completed Zusammenfassung der Ergebnisse Methodologie This is a non-interventiona study (NIS) in patients with CML in CP who are treated with Glivec according to the facility s regular treatment protocols and in accordance with the product information. Glivec may not be prescribed for the purpose of including the patient in the NIS. Assessment intervals per patient are not fixed but should be scheduled according to facility procedure and each patient s clinical symptoms. The medical decision about therapeutic or diagnostic measures is made solely by the treating physician. No further tests are required apart from routine clinical examinations. Analysierte Anzahl der Patienten 484 Diagnose und Einschlußkriterium Patients suffering from BCR-ABL positive (Ph+) CML in chronic phase who are prescribed Glivec.Glivec may not be prescribed for the purpose of including the patient in the NIS. Wirkliche Dauer der Studie 6 years Wirksamkeit unter Alltagsbedingungen The objective of this non-interventional study (NIS) was to document the clinical response to medical treatment by means of quantitative polymerase-chain-reacion (PCR) tests from peripheral blood and to assess the correlation of response with patient compliance of the patients treated for CML at the medical facility with regard to regular intake of the prescribed Glivec dose. This comprised the following points: Determination of hematologic, cytogenetic and molecular response: BCR-ABL expression before and during treatment with Glivec, cytogenetic profile at the start of treatment, type of BCR-ABL transcript (if these parameters were routinely tested at the facility and documented for the NIS). Determination of the number of prescribed Glivec tablets per prescription and the correlation with the time between prescriptions in days. If the result indicated insufficient compliance, additional measurement of Glivec serum level. In order to assess hematologic, cytogenetic (conventional bone marrow cytogenetic assess-ment) and molecular response, adequate tests were performed in accordance with routine procedures at the facility. Sicherheit

3 An "adverse event (AE) was defined as every untoward medical condition occurring in a patient after the administration of a drug or treatment, irrespective of whether or not a causal relationship with the drug or treatment was suspected (4th Announcement on the Reporting of Adverse Events and Drug Abuse according to Section 63b(1-8) of the German Drug Law). All AEs occurring in patients had to be documented on the "Adverse Event Report", including the type of the event, its first occurrence and its duration. Furthermore, the doctor had to document whether or not he suspected a relationship to any of the drugs or treatments the patient had received. Additionally, he was required to report countermeasures taken as well as the outcome of the event. Serious Adverse Events (SAE) Using the definitions denoted in 3 Par. 8 of the Guidelines for Good Clinical Practice, GCP, (dated August 9th, 2004), a serious adverse event (SAE) is any untoward medical occurrence which Is fatal or life-threatening, Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability or incapacity Results in a congenital anomaly or a birth defect. Hospitalization was not regarded as a SAE, if one of the following conditions applied: Hospitalizations which had already been scheduled prior to inclusion in the NIS. Elective hospitalization for the treatment of pre-existing conditions which were not related to the disease investigated in the NIS or the drug applied during the NIS. Outpatient hospital treatment which did not result in hospitalization (unless one of the other criteria is met, e. g., the event is life-threatening). Hospitalizations which were part of the regular treatment or monitoring of the disease investigated in the NIS and have not been caused by a deterioration of the patient s condition. Methoden Section 3(1) and Section 4 was guaranteed. All patients provided written informed consent/data protection consent before any data were collected and assessed. The NIS was conducted by self-employed hemato-oncologists in Germany. Recruitment of study centers was performed by CHOP GmbH, Frankfurt/M., Germany. Male and female patients with diagnosed Ph-pos or BCR-ABL-pos CML in chronic phase, who were being treated with Glivec and for whom treatment with Glivec was medically indica ted, were allowed to be included in the study. It was not allowed to prescribe Glivec only for the purpose of the NIS but not for clinical necessity. According to the recommendations of the summary of product charac teristics (SmPC), Glivec is to be administered orally at dosages of 400 to 800 mg/day. Data collection visits were scheduled at the beginning of the study and subsequently after 3, 6, 9, 12, 15, 18, 21 and 24 months. With Addendum 1 the observational period was extended to 24 months. Ergebnisse zur Wirksamkeit unter Alltagsbedingungen

4 Table 5 3 presents the hematologic response to therapy at the patient s last documented visit. The vast majority of patients (413/484, 85.3%) were in CHR at their last documented visit Molecular response In 453/484 patients (93.6%), a quantitative RT-PCR analysis was performed (Table 6). Table 5 4 presents the molecular response to therapy at patient s most recent visit. Under the analyses have 74,4% of patients with tumor reduction (s. Tab.5-4). At the end of the study 52,5% of the patients had a negative PCR and 21,8% had a reduction of tumor burden about 3 log. (Figure ). Different numbers of examinations were performed per patient. Six PCR analysies were performed by more than a half of the participate patients. In respectively 17% cases 8 or 9 PCR determinations were documented. Determination/Patient Number of patients Percent Cytogenetic response Table 5 5 presents the cytogenetic response to therapy at patient s last documented visit. In 212/484 patients (43.8%) cytogenetic response was determined. The majority of these patient achieved CCR (151/212 patients in whom cytogenetic response was determined [71.2%] percentage calculated by the author) (Table 10). Table 5-4-3: Number of cytogenetic examination/patients Number of tablets administered All patients took at least 1 Glivec tablet. The distribution of the intake by number of tablets is shown in Table 5 6. The most frequent total number of tablets taken was 810 (in 216 patients); this corresponds to a treatment duration of approximately 27 months at a dosage of 400 mg imatinib per day in these patients, which corresponds with the number of visits documented (cf. Table 5 2). Sixty-six patients took >810 tablets (up to 3150 tablets), and 202 patients took <810 tab lets, thereof, 174 patients with <740 tablets. Ergebnisse zur Sicherheit The safety of the treatment with Glivec was primarily based on the incidence and types of AEs/SAEs including their relationship to the Glivec treatment (see Table 5 8). Overall, 216 (44.6%) of the 484 patients in total experienced at least 1 AE or SAE. In most of these patients (42.4% in total), the at least 1 AE was non-serious. However, in 181 patients (37.4%), at least 1 non-serious AE was rated as drugrelated. SAEs occurred in 30 patients, corresponding to 6.2% of the total population. In 9 patients (1.9%), at least 1 SAE was rated as drug-related. Eight patients (1.7%) died, but none of the deaths were related to the treatment with Glivec. Schlussfolgerungen

5 patients with CML. Moreover, the correlation between the clinical response and the patients treatment compliance should be assessed. The data of 484 patients of either sex at an average age of approximately 70 years were documented at 56 hematooncological sites. The planned observation period was about 2 years. Upon enrollment, most of the patients were in a chronic phase and at low or intermediate risk according to the prognostic Hasford score. The patient population is representative for patients within clinical routine The population included all age groups and demonstrated, through the number of comorbidities, there was no selection to the healthy and younger patients. The age spectrum correlates approximately to the age group distribution under the patients in Germany, so that the study is realistic representative for the patients treated in practice. According to the non-interventional character of this study, RT-PCR evaluations were only to be done, if part of the routine activities at the respective site. Actually, this was done in 93.6% of the patients, indicating that this test is already an established procedure in clinical practice. The different dosage data showed clearly, that the main of patients got 400mg Imatinb per day. In exceptional cases dosing of 300mg and 600mg Imatinib was given in practice. An increase of dosage till 1000mg were documented in single cases. On the basis of cytogenetic and molecular results, the response to first-line imatinib was very good. RT-PCR showed a complete molecular response (CMR) to treatment with Glivec in 52,5% of the tested patients, as defined by absence of detectable BCR-ABL1 mrna. 21.9% of the patients had achieved a major molecular response (MMR), as defined by a 3 log reduction in BCR-Abl transcripts vs. BCR. This was also reflected in the results for hematologic response (85.3% CHR and 3.1% PHR), and in the results for cytogenetic response (71.2% CCR and 14.2% PCR). The latter one, however, was done in only 212 of the 484 patients (43.8%). The cytogenetic response is less commonly used than molecular response evaluation. The cytogenetic examination of the bone marrow was documented by half of the patients and showed with nearly 40% a good result. The extensive and painful puncture of the bone marrow is not necessary for patients with complete molecular response and the local physicians do not perform this on a regular basis Based on the number of site visits, the number of tablets taken per patient, the planned observation period of approximately 2 years and the prescribed Glivec dosage were adhered to in the majority of patients (approximately 76%). However no formal analysis of these data could be performed. The compliance was roughly estimated by correlation of the number of the tablets prescribed and the intervall between the prescriptions. Measurement of compliance in cases of patients with 400mg Imatinib through the comparison between intervall of prescription and number

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