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CML: What's New at EHA? Tim Brümmendorf, EHA Capacity Building Session, EHA congress June 2017


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"CML: What's New at EHA?", presented by Prof Tim Brümmendorf, EHA Patient Advocacy Capacity Building Session, EHA congress June 2017

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CML: What's New at EHA? Tim Brümmendorf, EHA Capacity Building Session, EHA congress June 2017

  1. 1. Chronic myeloid leukemia (CML) 2017: What’s new at EHA ? Prof. Dr. med. Tim H Brümmendorf Klinik für Hämatologie und Onkologie Universitätsklinikum Aachen
  2. 2. Challenges in Treatment of CML in 2017 Background: Most patients with newly diagnosed CML are assumed to have a normal life-expectancy ! The challenges in CML treatment are focussed on 1.Offer the perspective of a treatment-free remission (cure ?) to as many as possible patients 2.Prevention of and (in case it happens) improved treatment of – disease progression to AP/BC and – development of resistance to TKI 1.Improvement of tolerability and adherence to TKI 2.Eradiaction of leukemic stem cells as a continued source of relapse/disease progression
  3. 3. Evolution of targeted therapy of CML: A simplified view reviewed in: Balabanov, Braig and Brümmendorf Drug Discovery Today 2014; 11:89-99 Inhibition: +++ (+) – (bcr-)abl c-KIT PDGF-R Resistance Imatinib 1 x Proof-of-principle, Role model of TKIs 2nd Generation Nilotinib 30 x T315I Modulation of resistance src Dasatinib 325 x T315I Escalation to synergistic pathways Bosutinib 100 x T315I De-escalation of “off-target“ kinases Rationale behind compound Ponatinib 250 x “3rd Generation” T315I Coverage of T315I FGFR RET
  4. 4. 4 Imatinib (retrospective) N=252 Nilotinib (prospective) N=408 Dasatinib (prospective) N=418 Imatinib (prospective) N=416 Primary Objective •Better understand use of TKIs in 1st -line treatment of CP-CML in routine clinical practice Secondary Objectives •Evaluate patient benefit of CML treatment •Determine healthcare resource utilization SIMPLICITY: An Ongoing Observational Study1,2 Eligibility: •Newly-diagnosed CP-CML pts •Receiving 1st -line imatinib, dasatinib or nilotinib •≥18 years at time of diagnosis •Not participating in CML clinical trial CP-CML, chronic phase chronic myeloid leukemia; TKI, tyrosine kinase inhibitor 1.Clinical Study record: NCT01244750 2.Zyczynski T et al. Presented at ISPOR 7th Asia-Pacific Conference (Singapore), Poster PCN63. SIMPLICITY Recruitment targets: 200 patients (retrospective imatinib cohort) 400 patients (each prospective cohort)
  5. 5. 5 SIMPLICITY TKI, tyrosine kinase inhibitor
  6. 6. 6 Reason to Switch TKI Early vs. Late Dasatinib Nilotinib Imatinib SIMPLICITY *† *Reasons for discontinuation according to clinician judgement; chosen from electronic case report form or entered manually † Includes insurance/financial reasons, unrelated medical conditions, pt and/or physician choice * * * Across TKIs, intolerance is most common reason for switching, both early and late TKI, tyrosine kinase inhibitor
  7. 7. BOSUTINIB VS IMATINIB FOR NEWLY DIAGNOSED CHRONIC MYELOID LEUKEMIA: INITIAL RESULTS FROM THE BFORE TRIAL Author(s): Tim H. Brümmendorf Abstract: S425 Type: Oral Presentation Presentation during EHA22: On Saturday, June 24, 2017 from 12:15 - 12:30
  8. 8. Bosutinib: A Dual Inhibitor of SrcBosutinib: A Dual Inhibitor of Src and Abl Kinasesand Abl Kinases Src enzyme (ELISA) IC50 = 1.2 nM Src enzyme (Lance) IC50 = 3.8 nM Abl enzyme IC50 = 1.4 nM K562 cell IC50 = 20 nM KU812 cell IC50 = 4.3 nM Once daily oral application ! independent of food ! Boschelli DH, et al. J Med Chem. 2005;48(11):3891-3902. Golas JM, et al. Cancer Res. 2003;63(2):375-381. Golas JM, et al. Cancer Res. 2005;65(12):5358-5364. Puttini M, et al. Cancer Res. 2006;66(23):11314-11322. Courtesy of Scapozza L and Shaheen A, University of Geneva, Switzerland. N C N H N C l C l O O ON N
  9. 9. 9 Bosutinib Efficacy and Safely in NewlyBosutinib Efficacy and Safely in Newly Diagnosed CML (BELA): Study DesignDiagnosed CML (BELA): Study Design ● Primary endpoint: complete cytogenetic response (CCyR) rate at 12 mo ● Secondary endpoints: – Major molecular response (MMR) rate at 12 mo – Time to CCyR and MMR – Time to and rate of transformation to accelerated phase (AP) or blast phase (BP) CML – Safety and tolerability Phase 3 open-lapel trial in newly diagnosed chronic phase CML N = 502 139 sites 31 countries Bosutinib 500 mg/day n = 250 Imatinib 400 mg/day n = 252 5-year follow-up 5-year follow-up R A N D O M I Z E 1-year analysis
  10. 10. BELA Study (3000): CCyR and MCyR Jorge E. Cortes et al. J. Clin. Oncol. 2012;30:3486-3492 Primary study endpoint
  11. 11. AV001 Study Design • Key eligibility criteria: Chronic Phase - CP CML ≤6 months prior, no prior therapy (other than hydroxyurea or anagrelide) • Primary endpoint: Major molecular response at 12 months (48 weeks) • Key secondary endpoints − MMR by 18 months, duration of MMR, CCyR by 12 months, duration of CCyR, event-free survival (EFS), and overall survival (OS) R A N D O M I Z E Randomization is stratified based on Sokal risk score and geographical regions Bosutinib 400 mg/day n = 250 Imatinib 400 mg/day n = 250 5-year study Phase 3 open-label trial in newly diagnosed CP CML N = 500 Ph+ (approx. 530Ph+ and Ph-) 195 sites up to 28 countries Phase 3 open-label trial in newly diagnosed CP CML N = 500 Ph+ (approx. 530Ph+ and Ph-) 195 sites up to 28 countries 4-year follow-up 1-year core Treatment Phase Lead investigators: Jorge Cortes, Houston (North America) Tim Brümmendorf, Aachen (Europe) first presentation of the data at ASCO (Chicago) and EHA (Madrid) in June 2017
  12. 12. BFORE: BOS vs IM in Frontline CML Introduction • Bosutinib (BOS): dual SRC/ABL TKI approved for adults with Ph+ CML resistant or intolerant to prior TKIs • Potent activity and manageable toxicity in all phases of CML – Ph+ leukemias resistant/intolerant to previous TKIs (phase 1/2)1-4 – Newly diagnosed CP CML (phase 3; BELA)5-7 • CCyR rate at 12 mo (primary objective) higher with BOS vs imatinib (IM) but not statistically significant • Improved 12-mo MMR rate and shorter time to response with bosutinib • Objective: further assess the efficacy and safety of BOS vs IM for first-line treatment of CP CML 1. Cortes JE, et al. Blood. 2011;118:4567-76. 2. Khoury HJ, et al. Blood. 2012;119:3403-12. 3. Kantarjian HM, et al. Blood. 2014;123:1309-18. 4. Gambacorti-Passerini C, et al. Am J Hematol. 2014;89:732-42. 5. Cortes JE, et al. J Clin Oncol. 2012;30:3486-92. 6. Brümmendorf TH, et al. Br J Haematol. 2015;168:69-81. 7. Gambacorti-Passerini C, et al. Am J Hematol. 2014;89(10):947-53. Cortes et al. ASCO 2017
  13. 13. BFORE: BOS vs IM In Frontline CML Molecular Response Over Time (mITT) BOS IM (n=246) (n=241) P=0.02 P=0.01 P=0.02 MR4 MR4.5 MMR MR4 MR4.5 MMR MR4 MR4.5 MMR MR4 MR4.5 MMR P=0.12 P<0.0001 P<0.01 Cortes et al. ASCO 2017
  14. 14. BFORE: BOS vs IM in Frontline CML Cumulative Incidence of CCyR (mITT) Results are subject to change after 12 mo due to incomplete follow-up. HR=1.38 (95% CI: 1.13‒1.69); P<0.001 Cortes et al. ASCO 2017
  15. 15. BFORE: BOS vs IM in Frontline CML Transformation to AP/BP (mITT) • 4 (1.6%) BOS and 6 (2.5%) IM patients progressed to AP/BP during treatment • 5 of these patients (3 BOS and 2 IM) met AP criteria within 2 weeks based on basophil count ─ All 5 continued on study drug, and 4 achieved MMR Cortes et al. ASCO 2017
  16. 16. BFORE: BOS vs IM in Frontline CML Conclusions • BFORE met its primary endpoint with a significantly higher rate of MMR at 12 mo with BOS vs IM (47% vs 37%; P=0.02) ─ Rate of CCyR by 12 months significantly higher with BOS (77% vs 66%; P<0.01) • Responses occurred earlier with BOS • Results suggest lower dose (400 mg) is associated with better tolerability and improved outcomes • Safety data consistent with known profiles; no new safety signals ─ BOS associated with higher incidence of GI events and transaminase elevations; rarely leading to discontinuation ─ Lower incidence of musculoskeletal events • BOS could become a welcome new frontline treatment option Cortes et al. ASCO 2017
  17. 17. ASSESSMENT OF IMATINIB 400MG AS FIRST LINE TREATMENT OF CHRONIC MYELOID LEUKEMIA: 10 -YEAR SURVIVAL RESULTS OF THE RANDOMIZED CML STUDY IV Author(s): Ruediger Hehlmann Abstract: S424 Type: Oral Presentation Presentation during EHA22: On Saturday, June 24, 2017 from 12:00 - 12:15
  18. 18. Methods •1551 newly diagnosed patients in chronic phase (CP) were randomized into a 5-arm study. •1536 patients were evaluable: • 400 for IM400mg, • 430 for IM + IFN, • 420 for IM800mg, • 158 for IM + cytarabine* and • 128 for IM-after-IFN-failure* *recruitment to the latter two arms was stopped after a pilot-phase.
  19. 19. Results •10-year overall survival (OS) was 82%, •10-year progression free survival (PFS) was 80% •In the treatment arms, 10-year OS was • 80% with IM400mg, • 84% with IM + IFN, • 79% with IM800mg, • 84% with IM + cytarabine and • 79% with IM after IFN •In a multivariate analysis, risk factors for survival were: • Clinical risk group, • comorbidities, • major route chromosomal aberrations, • smoking and • type of treatment center (academic vs other) !
  20. 20. Results
  21. 21. CONCLUSION • Monotherapy with IM400mg provides a close to normal life expectancy. • Faster response does not necessarily translate into better survival. • Outcome of CML is currently more determined by disease biology and demographics than by treatment optimization.
  23. 23. Methods •Trial entry required first chronic phase of CML, TKI treatment for ≥ 3 years, and either the same TKI (imatinib, dasatinib or nilotinib) since diagnosis or only one switch for intolerance. •All PCR tests (minimum of 3) in the 12 months before trial entry must have been ≤0.1% (i.e. MMR), each with ≥ 10,000 ABL1 control transcripts; •those with all results ≤ 0.01% were allocated to the ‘stable MR4’ group; the remainder to the ‘MMR but not MR4’ group. •TKI treatment was reduced to half the standard dose (imatinib 200mg daily, dasatinib 50mg daily or nilotinib 200mg twice daily) for the first 12 months, then stopped completely. •Molecular recurrence was timed as the first of 2 consecutive samples with loss of MMR (>0.1%) and mandated resumption of full TKI dose.
  24. 24. BRITISH DESTINY STUDY - design 174 Patienten mit CML, TKI-Behandlung ≥ 3 Jahre mit dem gleichen TKI (oder Tausch bei Intoleranz), PCR-Tests in den letzten 12 Monaten ≤0,1% Stable MR4 PCR-Tests in den letzten 12 Monaten ≤ 0,01% MMR, aber nicht MR4 PCR-Tests in den letzten 12 Monaten 0,01% ≤ x ≤ 0,1% Behandlung 1.Reduktion auf Hälfte der jeweiligen TKI-Standarddosis in den ersten 12 Monaten 2.Danach komplettes Absetzen 3. Monatliches PCR-Monitoring 4.TKI-Re-Therapie im Falle eines molekularen Rückfalles (MMR >0,1% in zwei aufeinander folgenden Proben)
  25. 25. Results •174 patients (male 98; female 76) were recruited after giving informed consent from 20 UK centres. •At entry, 148 patients were receiving imatinib, 16 nilotinib and 10 dasatinib, for a median duration of 6.8 years. •after 12 months of half-dose therapy, molecular recurrence was lower in patients with stable MR4 at entry (3 of 125 patients; 2.4%) than in those in “MMR but not MR4” (9 of 49 patients; 18.4%) (p < 0.001). •during the subsequent 12 months of complete treatment cessation in 117 stable MR4 patients, only 26 further recurrences and 4 withdrawals occurred, giving a recurrence free survival (RFS) of 77% (90% CI: 71-83%) for the overall 24 months for this patient group. •The recurrence rate on cessation is higher in the “MMR but not MR4 group” (20 recurrences and 4 withdrawals among 36 patients during cessation; 39% RFS overall (90% CI: 29-52%); p = < 0.001). •duration of TKI treatment was an additional predictive factor (p = 0.058; HR 0.93), in line with recent data from EUROSKI. •The probability of RFS remains unrelated to age, gender, performance status or prior TKI (imatinib vs second generation). No progression to advanced phase was seen; one case lost haematological response.
  26. 26. Sex Imatinib Nilotinib Dasatinib Median duration 98 m, 76 w 148 16 10 6,8 Jahre MR4 (n=117) 90% CI- Intervall MMR, but no MR4 (n=57) 90% CI- Intervall relapse 26 - 20 - withdrawal 4 - 4 - 24-Months- RFS 77% 71-83% 39% 29-52% Results
  27. 27. Results
  28. 28. CONCLUSION • The present 24 month RFS of 77% for the overall 24 months in patients in stable MR4 appears better than in any comparable study to date ! • This implies that the initial 12 months of dose reduction may be responsible, perhaps via improved compliance in the few months prior to stopping or through an as yet undefined mechanism.
  29. 29. DURABLE TREATMENT-FREE REMISSION (TFR) FOLLOWING FRONTLINE NILOTINIB (NIL) IN PATIENTS (PTS) WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP): ENESTFREEDOM 96-WK UPDATE Author(s): David Ross Abstract: P601 Type: Poster Presentation Presentation during EHA22: On Saturday, June 24, 2017 from 17:30 - 19:00
  30. 30. Methods •ENESTfreedom (NCT01784068) is evaluating the ability to stop NIL and remain in TFR in pts with a sustained deep molecular response (DMR) on frontline NIL. •Previous results from ENESTfreedom showed that 51.6% of pts (98/190) who attempted TFR remained off treatment and in major MR (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [IS]) at 48 wk. Aims To analyze updated TFR data and predictive factors for remaining in TFR in ENESTfreedom.
  31. 31. Study layout Hochhaus et al. Leukemia 2017;1-7
  32. 32. Results Hochhaus et al. Leukemia 2017;1-7
  33. 33. CONCLUSION • The majority of pts in TFR at 48 wk remained in TFR at 96 wk, and they reported fewer AEs during the second 48 wk of TFR than in the first 48 wks • No strong predictors for remaining in TFR were identified. • the biological explanation for an association between Sokal risk score at diagnosis and a subsequent ability to remain in TFR is unknown. These results support TFR as a valuable option for pts in sustained DMR on frontline NIL.
  34. 34. LONG-TERM FOLLOW-UP IN VERY ELDERLY PATIENTS WITH CHRONIC MYELOID LEUKEMIA TREATED WITH IMATINIB FRONTLINE Author(s): Monica Crugnola Abstract: P604 Type: Poster Presentation Presentation during EHA22: On Saturday, June 24, 2017 from 17:30 - 19:00
  35. 35. Background Very elderly (>75 yrs) people are a substantial proportion of chronic myeloid leukemia (CML) patients that sometimes receive Imatinib (IM) at reduced doses based on physicians’ judgment. However, data on long-term follow-up of these patients are still lacking. Aims To investigate the treatment response and outcome in a cohort of very elderly patients with newly diagnosed CML in chronic phase. Method We revised in a retrospective database 263 CML patients aged ≥ 75 years and diagnosed from 2/2002 to 1/2016 and treated with IM frontline; among these, 121 patients (46%) were older than 80 yrs.
  36. 36. Results I •Median age at diagnosis was 78.5 yrs •Sokal Risk at diagnosis was • low in 1 patient (0.4%), • intermediate in 171 (68.4%), • high in 78 (31.2%) and • not evaluable in 13 patients. •As regards comorbidities, • 63 patients had no or 1 concomitant disease, • 147 patients 2 or 3 and • 53 patients (20.1%) 4 or more. •initial IM dose was • 400 mg/day in 180 (68.4%), • 300 mg/day in 67 (25.5%) and • <300 mg/day in 16 (6.1%) patients.
  37. 37. Results II •250 patients (92.8%) achieved a complete haematological response (CHR). •Among these, 208 (79% of all 263 patients) achieved a cytogenetic response (CyR), which was partial in 18 patients and complete (CCyR) in 190 (72.2% ) •Among the 190 patients in CCyR, 148 (56.2%) achieved a molecular response (MMolR) (ratio < 0.1). •Eleven patients (4.2%) developed a blastic phase (myeloid in 8 and lymphoid in 3 cases). After a median follow-up of 45.0 months from IM start (IQR 22.3– 72.0), • 93 patients have died (9 from disease progression and 84 from unrelated causes), • 144 are alive and 104 of them are still in treatment with IM, while 8 discontinued for prolonged deep molecular response and 22 switched to 2nd generation TKI. • Five-years event-free survival (EFS) and overall survival (OS) were 51.2% (CI95% 44.8-57.6) and 70.9% (CI95% 64.6-77.2), respectively.
  38. 38. Results III Multivariate analysis for OS OR 95% CI P MMolR achievement 0.363 0.236 - 0.560 <0,001 Age < 80 years 0.622 0.397 - 0.975 0.038 Male gender 1.589 1.048 - 2.410 0.029 Multivariate analysis for EFS OR 95% CI P 400 mg IM initial dose 0.656 0.459 - 0.938 0,021 PLTS < 500 x 109 /l 1.517 1.064 - 2.161 0.021 Concomitant diseases ≤ 3 0.597 0.398 - 0.896 0.013
  39. 39. CONCLUSION • The long term follow-up of very elderly CML patients treated with IM suggests that any effort to treat these patients with standard doses should be made, in order to achieve cytogenetic and molecular responses as in younger subjects.
  40. 40. 40 Thanks for your attention Aachen Imperial Cathedral UNESCO world heritage site since 1978