Imatinib Generics in Treatment of Chronic Myeloid Leukemia
Imatinib Generics in Treatment of Chronic Myeloid Leukemia; A Prospective Observation in Large Cohort of Patients from Polish (PALG) Imatinib Generics Registry Sacha T, Góra-Tybor J, Szarejko M, Bober G, Grzybowska-Izydorczyk O, Niesiobędzka-Krężel J, Dudziński M, Wasilewska E, Myśliwiec K, Gil J, Gniot M, Pietkun I, Mędraś E, Hołojda J, Wącław J and Giannopoulos K Tomasz Sacha Dept of Hematology, Jagiellonian University Hospital Kraków, Poland
Imatinib generics in Poland – economical considerations Regulation (Pharma Law): the cost should not exceed 50% of original medicament price 12 generics registered ( 01 June 2014), currently > 20 No. Generic’s Name Pharma Company 1 Imakrebin Alvogen 2 Imatenil Biofarm 3 Imatinib Accord Healthcare 4 Imatinib Actavis Polska 5 Imatinib Apothex 6 Imatinib medac Medac 7 Imatinib Polfa S. A. 8 Imatinib Teva Pharmaceuticals 9 Imatinib Zentiva 10 Meaxin Krka 11 Nibix Adamed 12 Telux Nobilus Ent Initial price in many hospitals (result of a tender): app. 2%-5% of original imatinib Current price in majority of hospitals (result of a tender): app. 5%-10% of original
Polish Imatinib Generics Registry The aims of one-year prospective, web-based observation registry of 726 CML-CP pts in 16 Centers: 1. To assess the efficacy of imatinib generics at the dose 400 mg/d A. In the group of newly diagnosed patients with completed 12 mo observation (available RQ-PCR result at 12 mo): - the rate of optimal response acc. to ELN / Polish guidelines - the rate of failure acc. To ELN / Polish guidelines - the rate of pts with BCR/ABL reduction to < 10% at 3 mo. - the rate of pts with BCR/ABL reduction to < 1% at 6 mo. - the rate of pts with MMR/MR 4/ MR 4. 5 achieved at 12 mo. - to follow the dynamics of the molecular response - the rate of pts with CCy. R achieved at 12 mo. - the rate of pts switched to II GTKI due to a failure / resistance B. In the group of patients switched from Glivec to Imatinib generics with MMR achieved before generic start, and treated with generics for more than 12 months: - the rate of sustained response - the rate of response improvement - the rate of MMR / MR 4. 5 loss - the rate of CCy. R loss
Polish Imatinib Generics Registry The aims of one-year observation in 726 CML-CP pts in 16 Centers: 2. To assess the safety of imatinib generics at the dose 400 mg/d In the group of newly diagnosed and switched patients: - the rate of hematologic advers e events in 3 rd / 4 th grade acc. to CTCAE criteria - the rate of non-hematologic advers e event s in all grades acc. to CTCAE criteria
Polish Imatinib Generics Registry Current report (criteria): 1. Patients with completed 12 mo observation (available RQ-PCR result at 12 mo) 2. Patients with MMR achieved before generic start (switched patients) 3. Patients who were switched to generic > 12 mo ago Number of records: 726 99 patients de novo treated with generics Nibix: 62, Meaxin: 24 (87%), other: 13 (7 excluded from efficacy analysis) 627 patients switched from Glivec to generics Nibix – 445 (70. 9%) 94% Meaxin – 146 (23. 3%) Imakrebin – 3 (0. 4%) Imatinib Polfa – 1 (0. 01%) Imatinib Teva – 31 (4. 3%) Nibix then Telux since 26. 01. 15 r – 1 (0. 01%) Telux – 2 (0. 02%) Telux since 28. 04. 2015 r – 1 (0. 01%) Imatinib Zentiva – 2 (0. 02%)
Frequency of RQ-PCR Tests in Polish Patients (2012 survey) CML pts PCR – Lab Number of Expected number of frequency of RQ-PCR tests (2012 survey) number RQ-PCR / mo RQ-PCR tests Bydgoszcz 69 Bydgoszcz 19 23 Gdańsk 119 Gdańsk 30 39 Katowice 162 Katowice 26 54 Kielce 81 Kielce 17 27 Kraków UJCM 183 Kraków UJCM 98 61(+31) 92 31% of 1165 less than recommended Kraków Szp. im pts. 37 monitored Kraków Jag. frequently Univ Rydygiera Łódź 101 Warszawa IHi. T 33 Poznań 122 Poznań 42 41 Rzeszów 58 Kraków 16 19 Warszawa IHi. T 110 Warszawa IHi. T 76 70 Warszawa Klinika 72 Warszawa Klinika 30 24 Wrocław 120 Wrocław 37 40
Molecular monitoring frequency in pts. treated with imatinib generics. Polish Imatinib Generics Registry Frequency of RQ-PCR monitoring in 726 pts. treated with imatinib generics who completed 1 year observation 53% 60% 50% 40% 25% 30% 16% 20% 6% 10% 0% 4 tests 3 tests 2 tests 1 tests
Polish Imatinib Generics Registry 1. The efficacy of imatinib generics at one-year A. newly diagnosed patients; n = 92, (Nibix: 62, Meaxin: 24 , other: 6) Early molecular response RQ < 10% at 3 mo 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 79% 63% 65. 7% 65/99 All Gen 19/24 Meaxin 39/62 Nbix Reduction of BCR/ABL to <1% at 6 mo 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 58% 53. 4% 54/99 All Gen 14/24 Meaxin 33/62 Nbix
Polish Imatinib Generics Registry The efficacy and safety of imatinib generics at one-year A. newly diagnosed patients; n = 92, (Meaxin: 24, Nibix: 62, Other 6) Optimal response acc to ELN / PALG (MMR at 12 mo) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 66% 56% 49. 5% 26. 3% of pts switched to 2 GTKI Resistance: 13. 1% Progression to AP/BC: 1% Intolerance: 12% Safety: Haematologic tox. (3/4): 3%, 1 switched to 2 GTKI All Gen Meaxin Nibix Non-haematologic tox. : 40. 4%, 12. 1% pts switched to 2 GTKI
Polish Imatinib Generics Registry 1. The efficacy of imatinib generics at one-year B. switched patients; n = 627, (Nibix: 445, Meaxin: 146, IMA Teva: 28, Imakrebin: 1, IMA Polfa: 1, Telux: 1) Molecular response under generics therapy 64. 8 70% 60% 50% 40% 30% 20% 19 15% 10% 0% Response worsened Response sustained Response improved
Polish Imatinib Generics Registry 1. The efficacy of imatinib generics at one-year B. switched patients; n = 627, (Nibix: 445, Meaxin: 146, IMA Teva: 28, Imakrebin: 1, IMA Polfa: 1, Telux: 1) Loss of responses under generics therapy 10. 3% CCy. R loss 10. 9% 1. 3% MMR loss MR 4, 5 loss MR fluctuations
Polish Imatinib Generics Registry Safety of imatinib generics in an annual follow-up – complete cohort (n=892) 19. 3 20. 00% 18. 00% 16. 00% 14. 00% 12. 00% 172 10. 00% 8. 00% 6. 00% 4. 00% 0. 5 2. 00% 5 0. 00% 3/4 Gr Haematol tox All Non haematol tox
Polish Imatinib Generics Registry – Adverse Events (non – hematologic, all grades) Meaxin and Nibix Ø Most frequent adverse events Ø No of pts: 598 Lp. Adverse Event Meaxin [%] Nibix [%] 1. Bone pain / arthralgia 7. 4 4. 0 2. Nausea / dyspepsia 6. 7 7. 3 3. Abdominal pain 5. 2 5. 9 4. Muscle cramps / myalgia 5. 2 3. 8 5. Fatigue 4. 5 2. 7 6. Edema localised 4. 5 3. 8 7. Diarrhea 2. 9 6. 5 8. Vomiting 2. 9 4. 6 9. Skin rash / pruritus 1. 5 4. 3 10. Palpebral / face edema 1. 5 5. 7
Polish Imatinib Generics Registry The efficacy and safety of imatinib generics in an annual follow-up – complete cohort (n=892); switch to 2 GTKI 4. 50% 3. 8% 4. 00% 3. 50% 41 3. 00% 34 2. 50% 7 2. 00% 7 5 5 1. 50% 0. 78 1. 00% 0. 56% 0. 50% 0. 00% Switch to 2 GTKI Intolerance Resistance Intolerance+Resistance
Polish Imatinib Generics Registry Efficacy of Imatinib Generics vs Glivec Newly diagnosed pts N=92 EMR (BCR/ABL<10% at 3 mo) achieved by 65% of „newly diagnosed” pts % Pts Trial ENESTnd* Dasision& BELA§ PFS TKI ≤ 10% >10% ≤ 10% Imatinib 66% 34% 98% Nilotinib 1 90% 10% 95% Imatinib 65% 35% 96% Dasatinib 84% 16% 93% Imatinib 65% 35% 94% Bosutinib 86% 14% 93% P value > 10% 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 83% 75% 68% 64% Overall Survival P value ≤ 10% >10% <. 001 99% 79% 86% <. 001 . 006 97% 63% 87% . 01 . 001 96% 88% . 003 96% 39/62 86% . 03 . 003 99% 95% . 09 99% Nbix 88% . 004 65. 7% 65/99 83%All Gen. 004 Meaxin * ENESTnd, PFS = TFS, PFS and OS at 4 years 1 Nilotinib, 300 mg BID arm & DASISION, PFS = TFS + Loss CHR, loss MCy. R, doubling of WBC count to > 20 x 10^9/L PFS and OS at 3 yrs §BELA, PFS = TFS + Loss CHR, loss CCy. R, doubling of WBC count to > 20 x 10^9/L PFS and OS at 2 yrs Hughes TP et al. Blood 2014, 123 (9): 1353 -60; Jabbour E et al. Blood 2014, 123 (4): 494 -500; Brummendorf TH et al. Blood 2012; 120(21): Abstract 69.
Polish Imatinib Generics Registry Efficacy of Imatinib Generics vs Glivec Newly diagnosed pts N=99 BCR/ABL reduction to <1% at 6 mo achieved by 53% of newly diagnosed pts EUTOS registry Time to first CCy. R could be calculated for 1491 patients Median time to first CCy. R was 10 months. After 12 months 57% (95% CI 54%-60%) V. Hoffmann et al. MMR at 12 mo achieved by 49, 5% of pts in newly diagnosed pts EUTOS registry Time to first MMR could be calculated for 1259 patients. Median time to first MMR was 15 months. Cumulative incidence of MMR after 12 months was 41% (80% of pts on IMA, 13% on Nilo, 7% on Dasa. V. Hoffmann et al.
Polish Imatinib Generics Registry Summary Switched pts N=627 Molecular response under therapy with generics was: • Sustained in 65% of pts. • Improved in 19% of pts. • Worsened in 15% of pts. • CCy. R lost 0. 3% of pts. • MMR lost 1. 3% of pts. • MR 4, 5 lost 10. 3% of pts. 4. 5% of pts. switched to 2 GTKI • 3. 8% for intolerance (non-haematologic toxicity) • 0. 8% for resistance • 0. 6% for intolerance + resistance
Polish Imatinib Generics Registry Conclusion Tested generics of imatinib seem to be as effective as Glivec Safety profile of all generics is acceptable – no increased switching rate from 1 st to 2 GTKI Common analysis of bigger cohort of patients is limited due to a different generics used Problem: frequent change of generic imatinib in a single patient
Polish Imatinib Generics Registry Ackonwledgments 1. Ewa Wasilewska ; Klinika Hematologii UM, Białystok 2. Justyna Gil; Oddział Hematologii Onkologicznej Podkarpacki Ośrodek Onkologiczny, Brzozów 3. Monika Szarejko; Klinika Hematologii GUM, Gdańsk 4. Grażyna Bober; Klinika Hematologii ŚAM, Katowice 5. Zofia Kubala; Klinika Hematologii UJCM, Kraków 6. Iwona Pietkun; Oddział Hematologii WSS im. Rydygiera, Kraków 7. Olga Grzybowska – Izydorczyk; Klinika Hematologii UM, Łódź 8. Michał Gniot; Klinika Hematologii i Chorób Rozrostowych Układu Krwiotwórczego, Poznań 9. Katarzyna Kościów; Oddział Hematologii i Onkologii Hematologicznej SW, Opole 10. Marek Dudziński; Klinika Hematologii KSW, Rzeszów 11. Joanna Góra – Tybor; Instytut Hematologii i Transfuzjologii, Warszawa 12. Joanna Niesiobędzka – Krężel; Klinika Hematologii, Onkologii i Chorób Wewnętrznych, Warszawa 13. Krzysztof Myśliwiec; Oddział Hematologii SW, Zielona Góra 14. Ewa Mędraś; Klinika Hematologii, Wrocław 15. Bartosz Garus; Klinika Hematologii, Świętokrzyskie Centrum Onkologii, Kielce 16. Jadwiga Hołojda; Oddział Hematologii, Legnica Patients with CML treated in Polish Centers
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