History of CML Treatment

Transcription

1 History of CML Treatment Eduardo Olavarria No conflict of interest Lisbon, 20th March 2018 #EBMT18

2 What is CML?

3 The mystery of chronic myeloid leukaemia

4 Chronic myeloid leukaemia Often diagnosed by chance e.g. routine blood test Symptoms typically are fatigue, lethargy, abdominal swelling/bloating, night sweats Characterised by high white cell count, sometimes anaemia, increased or decreased platelets, enlarged spleen Examination of blood shows primitive cells, range of white cells, e.g. neutrophils, eosinophils, basophils

5 Blood film from CML in CP

6 Chronic myeloid leukaemia Incidence 10-15:1,000,000 population 700 new cases per annum in UK Median age of onset years Bi or triphasic disease, chronic phase, acceleration and blast crisis

7 Clinical course: phases of CML Before TKIs Chronic phase Median duration 5 6 years Advanced phases Accelerated phase Blast crisis Median duration 6 12 months Median survival 3 6 months

8 Clinical course: phases of CML After TKIs Chronic phase GLIVEC Stable and durable chronic phase? Advanced phases Accelerat ed phase Blast crisis Median duration 6 24 months Median surviva l 3 6 month s

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10 Estimated Prevalence of CML in Europe until 2050

11 Biology of CML

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13 A normal set of chromosomes

14 The Philadelphia chromosome Normal CML

15 produces the Philadelphia (Ph) chromosome q11.2 q q + 9 9q(+) 22 Ph 22q- (Ph) 22 bc r abl abl-bcr bcrabl expresses a fusion oncoprotein with tyrosine kinase activity

16 Classical t(9;22)(q34.1;q11.2) Dual Fusion (D-FISH) Signal Pattern der(9) Ph 22 der( 9) Ph 9 BCR ABL Vysis EN

17 What s a cytogenetic response and why does it matter? Major response Type of response % of Philadelphiapositive cells Minor/minim al More than 35% Partial Less than 35% Complete 0% Test performed on a sample of bone marrow every 6 months or so WITH INTERFERON If you have a major response you probably live longer If you have a complete response you probably live even longer If you sustain a complete response for several years -???cure.

18 Survival Without AP/BC by Level of CyR at 18 Months on First-line Imatinib % w it h o u t A P / B C Response at 18 months 30 CCyR PCyR No MCyR Estimated rate at 60 n= 358 months 99% n= 66 n= % 83% M o n th s s i n c e r a n d o m i z a ti o n p< p<

19 Molecular Abnormality Chromosome 22 5 BCR Chromosome 9 3 ABL BCR-ABL gene 11 mrna BCR ABL 210 KD protein

20 ATP Ia SH2 SH3 Ib Bcr SH1 SH1 F-Actin BD NES G-Actin BD DNA BD NLS DNA BD NLS DNA BD PxxP NLS Pxx P PxxP SH1 ATP p145 Abl Proliferation Adherence Apoptosis Abl p210 Bcr-Abl

21 Real time quantitative RT-PCR I. Hydrolysis Probes II. Hybridization Probes Release from quenching by hydrolysis Increased resonance energy transfer by hybridization h h X 106 X 105 x 104 BCR-ABL plasmid molecules h x = 40,000 h X X TaqManTM LightCyclerTM

22 What s a molecular response and why does it matter? Type of response Suboptimal Major Complete Test performed on a sample of peripheral blood every 3 months or so More than 0.1% WITH TKIs Less than 0.1% If you have a major response you probably live longer If you have a complete response you have a 40% chance of stopping Imatinib If you sustain a complete response for several years -???cure. % of bcr-abl compared to (normal) abl Less than 0.003%

23 What s a molecular response and why does it matter? % w it h o u t p r o g r e s s io n % 80 85% Log reduction at 12 months versus time to progression - Imatinib N o C C y R w i th i n 1 2 m o n th s ( n = ) < 3 lo g r e d u c ti o n ( n = ) > = 3 lo g r e d u c ti o n ( n = ) = C e n s o r e d o b s e r va t io n s M o n th s s i n c e r a n d o m i z a ti o n

24 Tyrosine Kinase Inhibitors in CML

25 BCRABL P P Cytoskel etal proteins P STAT1 +5 GRB- SHC DOK RAS- CRKL CBL CRK 2 SO GAP PI3K S RASRASGDP GTP RAF-1? P SAP K P ERK MYC AKT P MEK1 /2 BCLX L P P P BCL XL Mitochon dria BA D BA D 143-3

26 ATP-binding competitors B L B -A CR ATP P P R C B tr s b Su ate Y Y T ed t a iv t Ac L B A I K Y r st b Su ate

27 What a difference a pointmutation made... Wild type T315I mutant (Gorre et al., Science, June 2001)

28 Treatment challenges in CML

29 Current Aim of TKI Therapy in CML Molecular response CP-CML at Diagnosis PFS Lifelong maintenance EFSNear-normal life expectancy Leukemic burden <10% <1% CCyR MMR M3 M6 M12 Stable or improving MMR M18 > M18 Treatment change upon lack or loss of response, progression or unacceptable Baccarani et al. JCO 2009; 27: Björkholm et al. JCO 2011: Gambacorti-Passerini et al. JNCI 2011; 103: Time on TKI therapy an optimal side effects

30 0106/IRIS study: design R A N D O M I Z Imatinib N=553 Crossover IFN-a + Ara-C Crossover for: N=553 Lack of response Loss of response E 1106 patients total Intolerance of treatment

31 Complete Cytogenetic Responses 100 I m a ti n i b IF N +A ra -C 90 % r e s p o n d in g 80 63% % 69% 51% 50 p< % % 0 3 3% 6 14% 9% 12% M o n th s s i n c e r a n d o m i z a ti o n 21 24

32 Estimated Response to First-line Imatinib % responding Estimated rate at 30 months 40 CHR 97% MCyR 90% CCyR 82% Months since randomization

33 CML-Study IV Cumulative incidence of molecular response to imatinib 92% 89% 81% 72% 59% MR2 MMR MR4 MR4.5 MR5 n n n n n = = = = = Patients at risk MR2 MMR MR4 MR MR Hehlmann et al, JCO 2014

34 ENESTnd: Cumulative Incidence of MMR Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Patients With MMR, % 100 By 1 Yeara By 4 Yearsa By 5 Yearsa 77%, P < %, P < %, P < %, P < %, P <.0001 Δ 17% Δ 17% to 20% % 56% 51%, P <.0001 Δ 24% to 28% % Time Since Randomization, Calendar Years MMR, major molecular response (BCR-ABLIS 0.1%). a Cumulative response rates reported consider each year to consist of twelve 28-day cycles. 34 Saglio G, et al. Blood. 2013:[abstract 92].

35 Molecular Responses at 5 Years a Achieved response Not evaluated for molecular response at 5 years Did not achieve response [off treatment: dasatinib n=95 (37%), imatinib n=94 (36%); not evaluated: b dasatinib and imatinib n=11 each (4%)] MMR 52% MMR 49% MMR Dasatinib n=259 Imatinib n=260 MR 39% MR4 28% MR4 Dasatinib n=259 Imatinib n=260 25% MR4.5 18% MR4.5 Dasatinib n=259 Imatinib n=260 5 years ± 3 months. Patients on treatment with no sample analyzed at 5 years ± 3 months. MR4, BCR-ABL (IS) 0.01%. a b MR

36 MR4.5 by 5 Yearsa According to Sokal Risk Score P =.0004 P =.0082 P =.0148 P <.0001 P =.0105 P =.0041 (n = 283) a By cycle 60 (28 days per cycle). (n = 282) 36 (n = 281) Saglio G, et al. Blood. 2013:[abstract 92].

37 Achievement of <10% BCR ABL Transcripts at 3 Months: Evaluable Patients Evaluable: patients with an assessment at 3 months or later. Data as of 1 April

38 Achievement of <10% BCR ABL Transcript Levels at 3 Months by Sokal Risk Score: Evaluable Patients Data as of 1 April

39 OS: BCR-ABL (IS) at 3 months 1% vs. 1-10% vs. >10% Hanfstein et al, 2012; Leukemia, 26: )

40 ENESTnd Progression to AP/BC on Studya According to Sokal Risk Score Intermediate Sokal Risk High Sokal Risk Patients With Progression to AP/BC, n Low Sokal Risk n= a % % % % % % 5.1 % % 78 New events reported since the 4-year Nilotinib analysis 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD 78 All 3 progressions to AP/BC on study reported since the 4-year analysis occurred in patients with high Sokal risk scores at baseline; all 3 patients also had BCR-ABLIS > 10% at 3 months All progressions in patients with low/intermediate Sokal risk scores occurred during the first 2 years on study Progression to AP/BC or death due to advanced CML on core treatment or during follow-up after discontinuation of core treatment. Hughes T, EHA 2014

41 Survival After Progression to AP/BC ENESTnd IRIS Median survival ~10.5 months % Alive Months Since Progression Clark RE, et al. Haematologica. 2012;97(s1):237 [abstract 0583].

42 First line therapy in CML in CP The main advantage of 2nd generation TKI as first line is the increase in the proportion of patients candidates for discontinuation

43 All pts but 1 who lost MMR restarted 2G-TKI treatment and regained MMR after a median time of 3 months (1-8). Molecular Relapse free survival 200 interim patients overtime, loss MMR=89 Relapses within 6 months, n=77 At 6 months : 63 % (95% CI : 55% - 69%) At 12 months: 56 % (95% CI : 49 % - 63 %) At 18 months : 55 % (95% CI : 47 % - 61 %) 63% remained without relapse the first 6 mo DR

44 250,000 patients x 40% discontinuation = 100,000 patients = 3.5 Billion per year

45 Possible role of SCT in CML Soon after diagnosis T D Good risk for transplant O N TE Low chancec ofa responding to TKI I Patient s INDpreference After failing TKIs Imatinib failure, suboptimal response, intolerance Failure to 2nd generation TKIs Resistance to TKIs associated with the T315I mutation Y R E V T NO USEFUL In accelerated phase or blast

46 Path to SCT in CML: First Line Imatinib

47 Allo-SCT for CML in Europe Updated from Gratwohl A et al. Haematologica 2009;91:

48 SCT for CML: the EBMT score Overall Survival after allo-bmt for 3211 patients with CML according to the EBMT Risk Score 1.0 Survival Years 5 Prognostic factors for survival (defined before SCT): Age Disease phase Disease duration Histocompatibility Patient/Donor gender

49 Outcome after allo-sct for CML in advanced phase Overall Survival of CML patients in AP/BC transplanted between ,00 0,80 HLA-id Sib (N=915) 0,60 0,40 MUD (N=740) MUD (N=168) 0,20 0, HLA-id Sib (N=232) Courtesy of CLWP-EBMT

50 Survival after SCT for early CML-CP Survival of patients in early first chronic phase according to the revised chronic phase risk score (N=2049) Risk score (0 2 points per category) Age, years: <30 (0); (1); >40 (2) Donor: sibling (0); unrelated (2) Interval diagnosis SCT: <1 year (0); >1 year (1) Sex match: female male (1); all other (0) Passweg JR, et al. Br J Haematol 2004;125:

51 Progress in allo-sct for CML Overall survival for allo SCT in German CMLIV study Overall survival among good risk patients (score=0 1) Imatinib failure Survival Probability Elective Advanced phase Elective, n = 19, 3-yr survival: 88% Imatinib failure in 1 CP, n = 37, 3-yr survival: 94% Advanced phase, n = 28, 3-yr survival: 59% Months After Transplantation Gratwohl A, et al. Haematologica 2006;91: Saussele S, et al. Blood. 2010;115:

52 Impact of previous Imatinib on SCT Lee et al. Blood. 2008; 112(8):

53 The Effect of Prior Therapy with Nilotinib or Dasatinib on the Outcome after Allo SCT for Patients with CML EBMT Non-Interventional Prospective Study

54 The Effect of Prior Therapy with Nilotinib or Dasatinib on the Outcome after Allo SCT for Patients with CML EBMT Non-Interventional Prospective Study No differences in outcomes between Nilotinib, Dasatinib and Sequential TKI

55 The Effect of Prior Therapy with Nilotinib or Dasatinib on the Outcome after Allo SCT for Patients with CML EBMT Non-Interventional Prospective Study

56 Response after Allogeneic SCT for CML 10-2 Cytogenetic RemissionCytogenetics positive negative Molecular Remission q-pcr positive q-pcr negative 0 Leukaemic cells Sensitivity of PCR Haematologic Remission FBC negative1012

57 Complications after SCT for CML 88% 21% 10% 68% 19% 2% D Heim (CLWP-EBMT) Unpublished data

58 Detection of Relapse Cytogenetics Cytogenetic Relapse Cytogenetic remission negative positive 10-2 Molecular Relapse q-pcr positive q-pcr negative High Medium Low No Disease Disease Disease Detectable Burden Burden Burden Disease 0 Leukaemic cells Sensitivity of Test Haematological Haematological remission Relapse positive FBC negative

59 Probability of survival Treatment of relapse 100 DLI (n=91) 2nd BMT (n=27) other (n=47) Months post relapse

60 Results of DLI in CML Overall No. patients 271 Early 188 GvHD Myelosuppression Cytogenetic Response Survival at 3y 67 Failure free survival DLI- related mortality Late

61 Molecular response to DLI Molecular remission (%) % 80Molecular/Cytogenetic relapse Overall 60 61% 47% 40 p = Haematological relapse Months post DLI 24 30

62 Cytogenetic remission (%) 100 Probability of molecular remission 91% 80 67% BDR (n=28) EDR (n=20) Months post first DLI 21 24

63 Probability of relapse (%) 20 Molecular relapse after remission with DLI % Months post achieving molecular remission

64 Incidence of GHVD after DLI (n=500) GvHD post DLI No Yes No 24% 8% Response* Yes 32% 36% *Molecular and/or cytogenetic remission

65 Imatinib in relapse: overall survival Probability of Survival CP (n=51) AP (n=31) BC (n=46).4.2 p = Months

66 Response after Relapse DLI or TKI 10-2 Cytogenetic RemissionCytogenetics positive negative Cytogenetic RemissionCytogenetics negative Molecular Remission q-pcr q-pcr positive positive q-pcr negative 0 Leukaemic cells Sensitivity of PCR FBC negative positive Haematologic No response Remission FBC negative1012

67 MUITO OBRIGADO!

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