History of CML Treatment

History of CML Treatment Eduardo Olavarria No conflict of interest Lisbon, 20th March 2018 #EBMT18 www.ebmt.or

What is CML?

The mystery of chronic myeloid leukaemia

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

Blood film from CML in CP

Chronic myeloid leukaemia Incidence 10-15:1,000,000 population 700 new cases per annum in UK Median age of onset 50-60 years Bi or triphasic disease, chronic phase, acceleration and blast crisis

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

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

Estimated Prevalence of CML in Europe until 2050

Biology of CML

A normal set of chromosomes

The Philadelphia chromosome Normal CML

produces the Philadelphia (Ph) chromosome q11.2 q34.1 9 9q + 9 9q(+) 22 Ph 22q- (Ph) 22 bc r abl abl-bcr bcrabl expresses a fusion oncoprotein with tyrosine kinase activity

Classical t(9;22)(q34.1;q11.2) Dual Fusion (D-FISH) Signal Pattern 2 2 9 der(9) Ph 22 der( 9) Ph 9 BCR ABL Vysis EN 01.2004

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.

Survival Without AP/BC by Level of CyR at 18 Months on First-line Imatinib 100 90 % w it h o u t A P / B C 80 70 60 50 40 Response at 18 months 30 CCyR PCyR No MCyR 20 10 0 Estimated rate at 60 n= 358 months 99% 0 6 12 18 n= 66 n= 56 24 30 36 90% 83% 42 48 M o n th s s i n c e r a n d o m i z a ti o n p<0.001 60 66 p<0.001 54

Molecular Abnormality Chromosome 22 5 BCR 1 1 1 1 Chromosome 9 3 ABL 2 11 2 11 BCR-ABL gene 11 mrna BCR ABL 210 KD protein

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

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

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%

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 100 90 95% 80 85% 70 60 Log reduction at 12 months versus time to progression - Imatinib 50 40 N o C C y R w i th i n 1 2 m o n th s ( n = 1 2 8 ) < 3 lo g r e d u c ti o n ( n = 1 0 3 ) > = 3 lo g r e d u c ti o n ( n = 1 3 7 ) 30 20 10 0 = C e n s o r e d o b s e r va t io n s 0 3 6 9 12 15 18 21 24 M o n th s s i n c e r a n d o m i z a ti o n 27 30 33

Tyrosine Kinase Inhibitors in CML

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 143-3 BA D 143-3

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

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

Treatment challenges in CML

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: 6041-6051 Björkholm et al. JCO 2011: 2514-2420 Gambacorti-Passerini et al. JNCI 2011; 103: 553-561 Time on TKI therapy an optimal side effects

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

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% 70 60 76% 69% 51% 50 p<0.001 40 25% 30 20 10 0 1% 0 3 3% 6 14% 9% 12% 9 12 15 18 M o n th s s i n c e r a n d o m i z a ti o n 21 24

Estimated Response to First-line Imatinib 100 90 % responding 80 70 60 50 Estimated rate at 30 months 40 CHR 97% MCyR 90% CCyR 82% 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months since randomization

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 = = = = = 1442 1442 1358 1331 1208 Patients at risk MR2 MMR MR4 MR4.5 0 1442 1442 1358 1331 2 143 349 668 839 5 35 66 197 316 8 11 20 56 89 10 2 5 12 21 MR5 1208 922 470 164 48 Hehlmann et al, JCO 2014

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 90 80 By 4 Yearsa By 5 Yearsa 77%, P <.0001 76%, P <.0001 55%, P <.0001 70 77%, P <.0001 73%, P <.0001 Δ 17% Δ 17% to 20% 60 50 60% 56% 51%, P <.0001 Δ 24% to 28% 40 30 27% 20 10 0 0 1 2 3 4 5 6 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].

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 4.5 (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

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].

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

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

OS: BCR-ABL (IS) at 3 months 1% vs. 1-10% vs. >10% Hanfstein et al, 2012; Leukemia, 26: 2096-2101)

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 103 1.0 % 103 1.0 % 104 2.0 % 101 1.0 % 100 9.9 % 101 9.0 % 5.1 % 78 14.1 % 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

Survival After Progression to AP/BC ENESTnd IRIS 100 90 80 Median survival ~10.5 months % Alive 70 60 50 40 30 20 10 0 0 6 12 18 24 30 36 42 48 Months Since Progression Clark RE, et al. Haematologica. 2012;97(s1):237 [abstract 0583].

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

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

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

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

Path to SCT in CML: First Line Imatinib

Allo-SCT for CML in Europe Updated from Gratwohl A et al. Haematologica 2009;91:513-21.

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.8.6 0-1 2.4 3 4.2 5-7 0.0 0 1 2 3 4 Years 5 Prognostic factors for survival (defined before SCT): Age Disease phase Disease duration Histocompatibility Patient/Donor gender

Outcome after allo-sct for CML in advanced phase Overall Survival of CML patients in AP/BC transplanted between 1995-2005 1,00 0,80 HLA-id Sib (N=915) 0,60 0,40 MUD (N=740) MUD (N=168) 0,20 0,00 0 24 HLA-id Sib (N=232) 48 72 96 120 Courtesy of CLWP-EBMT

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); 30 40 (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;125:613 620.

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 1.0 1991 1999 1980 1990 Survival Probability 2000 2003 0.9 Elective 0.8 0.7 0.6 Advanced phase 0.5 0.4 0.3 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% 0.2 0.1 0 0 6 12 18 24 30 36 Months After Transplantation Gratwohl A, et al. Haematologica 2006;91:513 521. Saussele S, et al. Blood. 2010;115:18801885. 42 48

Impact of previous Imatinib on SCT Lee et al. Blood. 2008; 112(8): 3500-7.

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

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

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

Response after Allogeneic SCT for CML 10-2 Cytogenetic RemissionCytogenetics positive negative Molecular Remission q-pcr positive 1010 108 10-6 106 10-8 104 q-pcr negative 0 Leukaemic cells Sensitivity of PCR Haematologic Remission FBC negative1012

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

Detection of Relapse Cytogenetics Cytogenetic Relapse Cytogenetic remission negative positive 10-2 Molecular Relapse q-pcr positive 1012 1010 108 10-6 106 10-8 104 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

Probability of survival Treatment of relapse 100 DLI (n=91) 2nd BMT (n=27) other (n=47) 80 60 40 20 0 0 24 48 72 96 120 144 168 Months post relapse

Results of DLI in CML Overall No. patients 271 Early 188 GvHD 45 47 Myelosuppression Cytogenetic Response Survival at 3y 67 Failure free survival DLI- related mortality 40 19 69 18 80 80 53 15 Late 83 21 43 38 66 12 25 21

Molecular response to DLI Molecular remission (%) 100 87% 80Molecular/Cytogenetic relapse Overall 60 61% 47% 40 p = 0.004 20 Haematological relapse 0 0 6 12 18 Months post DLI 24 30

Cytogenetic remission (%) 100 Probability of molecular remission 91% 80 67% BDR (n=28) 60 40 EDR (n=20) 20 0 0 3 6 9 12 15 18 Months post first DLI 21 24

Probability of relapse (%) 20 Molecular relapse after remission with DLI 15 10 6% 5 0 0 12 24 36 48 60 72 84 Months post achieving molecular remission

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

Imatinib in relapse: overall survival Probability of Survival 1.0.8.6 CP (n=51) AP (n=31) BC (n=46).4.2 p = 0.0001 0 3 6 9 12 15 18 21 24 27 30 33 36 Months

Response after Relapse DLI or TKI 10-2 Cytogenetic RemissionCytogenetics positive negative Cytogenetic RemissionCytogenetics negative Molecular Remission q-pcr q-pcr positive positive 1010 108 10-6 106 10-8 104 q-pcr negative 0 Leukaemic cells Sensitivity of PCR FBC negative positive Haematologic No response Remission FBC negative1012

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