Philadelphia-positive Acute Lymphoblastic Leukemia

Transcription

1 Philadelphia-positive Acute Lymphoblastic Leukemia Nicolas Boissel Service d Hématologie Unité Adolescents et Jeunes Adultes Hôpital Saint-Louis, Paris

2 Ph+ acute lymphoblastic leukemia DR+, CD19+, CD22+, CD10+, CD20+ CD34+, CD33+, TdT+, CD25+ t(9;22)(q34;q11)

3 BCR-ABL

4 Genetic alterations in Ph+ ALL Locus Géne Enfants n = 21 Adultes N = 22 Total (%) N = 43 7p12.2 IKZF (84) 9p21 CDKN2A (53) 9p13.3 PAX (51) 20p12.2 C20orf (23) 13q14.2 RB (19) 5q14.3 MEF2C (14) 5q34 EBF (14) 12q22 BTG (14) 13q14 DLEU* (9) 3p14.2 FHIT (9) 12p13 ETV (7) *mir16 and mir15 Mullighan et al., Nature 453:110, 2008

5 Ph-ALL among age Moorman, 2007

6 Pre and post-imatinib (IM) era Young adults Largest pre-im studies (>100 pts) Group Reference Pts (N) CR rate (2 cycles) LALA NCRI/ECOG Dombret, Blood 2002 Fielding, Blood 2009 Allo-SCT rate EFS OS Risk factors % 39% - Age, WBC MRD response Allo-SCT % 28%* Age, WBC Allo-SCT Largest IM-CTx combination studies (>100 pts) Group Reference Pts (N) CR rate (2 cycles) NCRI/ECOG Fielding, ASH 2010 Allo-SCT rate EFS OS Risk factors % 44%* - GRAALL Chalandon, ASH % 60% - *: per-protocol myeloablative SCT

7 GRAAPH-2003 vs LALA-94 Tanguy-Schmidt, BBMT 2013

8 Open issues 1. Which h TKI? 2. Which optimal chemotherapy? 3. Which place for SCT in this new context? Allo / auto / CTx-TKI TKI only RIC / MAC (median age > 40 ans) TKI maintenance after SCT 4. Which risk-stratification?

9 Open issues 1. Which h TKI? 2. Which optimal chemotherapy? 3. Which place for SCT in this new context? Allo / auto / CTx-TKI TKI only RIC / MAC (median age > 40 ans) Maintenance Tx after SCT 4. Which risk-stratification?

10 MDACC HyperCVAD Imatinib vs Dasatinib DFS OS Ravandi, Blood 2013

11 Considerations to compare TKI strategies Early response Complete remission MRD : BCR-ABL, MRD (MFC, IgH/TcR) Long-term outcome Relapse risk Survival Tolerance Combined with CT After allogeneic transplant Long term effects Mutation induction

12 Open issues 1. Whichh TKI? 2. Which optimal chemotherapy? Intensive / Less intensive 3. Which place for SCT in this new context? Allo / auto / CTx-TKI only RIC / MAC (median age > 40 ans) Maintenance Tx after SCT 4. Which risk-stratification?

13 GIMEMA TKI - Prednisone GIMEMA LAL0201-B Imatinib 800 mg + PDN 40 mg/m2 30 patients 60y+ (median age 69y) CR (D45) : 100% GIMEMA LAL1205 Dasatinib 70 mg BID + PDN 60 mg/m2 + IT MTX (D22, D43) 55 patients 18y+ (median age 54y) CR (D22) : 92,5%, CR (D85) : 100% Vignetti, Blood 2007 Foá, Blood 2011

14 GRAAPH-2005 Steroid prephase Ph+ and/or BCR-ABL diagnosis Cycle 1 First induction Cycle 2 Consolidation/2 nd induction Interphase Two cycles Randomization A B IM-based IM-HyperCVAD IM (800mg for 28d) IM (800mg for 14d) MRD1 HD-MTX + HD-AraC + IM (800mg for 14d) MRD2 PBSC collection if Auto-SCT 6MP+ MTX+ IM (600mg for 14d) SCT Donor no donor no donor sibling or 9-10/10 MUD MMolR at MRD2 no MMolR at MR2 Allo-SCT Auto-SCT further even and odd MAC:CY-TBI CY-TBI IM-HyperCVAD cycles RIC (>55 y) IM+6MP+MTX maintenance and maintenance Chalandon ASH 2012

15 First cycle arm A, IM-based D1-2 D8-9 D15-16 D22-23 D28 D29 VCR, 2 mg DXM, 40 mg Imatinib, 800 mg/d Triple IT G-CSF from D15 Marrow Assessment (MRD-1) Chalandon ASH 2012

16 First cycle arm B, IM/HyperCVAD D1-2-3 D4 D7 D11 D14 D29 VCR, 2 mg DXR, 50 mg/m 2 CI CPM, 300 mg/m 2 /12h DXM, 40 mg Imatinib, 800 mg/d Triple IT G-CSF from D15 Response Assessment (MRD-1) Chalandon ASH 2012

17 GRAAPH-2005 Hematological response IM-based (n= 135) IM-HyperCVAD (n=133) p Total (n=268) CR 133 (98.5%) 121 (91.7%) (94.8%) Courses to CR one two 132 (97.8%) 1 (0.7%) 118 (88.7%) 3 (2.2%) (93.2%) 4 (1.5%) Resistance after 2 cycles 1 (0.7%) 3 (2.2%) (1%) D60 mortality 1 (0.7%) 9 (6.7%) (3.7%) Chalandon ASH 2012

18 GRAAPH-2005 Molecular response (Bone marrow) IM-based (n= 135) IM-HyperCVAD (n= 133) p Total (n=268) MRD1 Tested 116 (86%) 102 (77%) (81%) - MMolR 50 (43%) 46 (45%) (44%) - Undetectable 11 (9%) 10 (10%) (10%) MRD2 Tested - MMolR - Undetectable 112 (83%) 94 (71%) (77%) 74 (66%) 60 (64%) (65%) 32 (29%) 21 (22%) (26%) MMolR= BCR-ABL/ABL < 0.1% in the bone marrow Chalandon ASH 2012

19 GRAAPH-2005 Overall survival and EFS Median OS, 3.2 years Median EFS, 1.8 years 3-y OS, 51.7% ( ) 3-y EFS, 41.1% ( )

20 EWALL-Ph01 Patients aged 55y+ Induction and Consolidation Therapy (1st year) Induction MDR IDMTX 1 HDACMDR 2 P VCR DEXA Cons. I Cons. II Cons. III Cons. IV IDMTX HDAC ASP ASP Cons. V IDMTX ASP Cons. IV HDAC VCR VCR VCR DEXA DEXA DEXA Dasa 140 QD MP/MTX Dasa 100 6MP/MTX Dasa 100 6MP/MTX > 70y Dasa 100mg/d ~ mo 8 ~ mo 10 ~ mo 12 and Dex 20mg weeks Maintenance Therapy (2nd year) VCR VCR VCR VCR DEXA DEXA DEXA DEXA Dasa100MP/MTXDasa100 MP/MTXDasa100MP/MTXDasa100MP/MTXDasa100 MP/MTX Dasa100 Continue with Dasatnib 100mg/d 13 MP/MTX months Rousselot, personal com.

21 EWALL-Ph01 Patients and early-response N=71 patients, t aged 58-83y 83 (median 69y) CR rate (ITT analysis) : 94% 67 out of 71 patients t (3 deaths, 1 patient t primary resistant) t) Molecular response se log reduction 100 CMR 4.5 log 80 Percent 60 54% 53% % 24% 0 After Induction MRD1 During consolidation MRD2 Rousselot, personal com.

22 EWALL-Ph01 Survival 100 survival % at 3 years Percent Months pts at risk patients switched to imatinib and 3 to nilotinib post induction/consolidation 5 patients transplanted (3 RIC and 2 MAC, survival 9, 31, 16+, 25+ and 30+ months)

23 Open issues 1. Whichh TKI? 2. Which optimal chemotherapy? Intensive / Less intensive 3. Which place for SCT in this new context? Allo / auto / CTx-TKI only RIC / MAC (median age > 40 ans) Maintenance Tx after SCT 4. Which risk-stratification?

24 GRAAPH-2005 SCT in CR1 patients Arm A Arm B p Total (133 CR1) (121 CR1) (254 CR1) All CR1 patients Allo-SCT (63%) Auto-SCT (13.4%) MMolR patients Allo-SCT Auto-SCT CR to SCT time Allo-SCT 4.6 mths 4.5 mths mths Auto-SCT 53mths mths mths 5.1

25 GRAAPH-2005 Autologous versus allogeneic SCT Patients in MMolR

26 MDACC HyperCVAD-IM (N=52) N= 52 pts DFS OS Thomas, Hematology 2006

27 COG AALL0031 Impact of ITK exposure Schultz K, JCO 2009

28 GMALL IM post-allogeneic HSCT Up front timatinib ib Imatinib Ph + ALL in CR R eg i SCT R MRD monitoring 4 6 wks s t e r If MRD+ Imatinib MRD triggered Imatinib Ottmann, Leukemia 2013

29 GMALL IM post-allogeneic HSCT Ottmann, Leukemia 2013

30 Open issues 1. Whichh TKI? 2. Which optimal chemotherapy? Intensive / Less intensive 3. Which place for SCT in this new context? Allo / auto / CTx-TKI only RIC / MAC (median age > 40 ans) TKI maintenance after SCT 4. Which risk-stratification?

31 Proposed risk-factors Patient-related predictors Age Performans status ALL-related predictors WBC count Additional Cytogenetic Abnormality (?) IKZF1 deletion, PAX5 mutation Response-related predictors Poor prednisone-response, Poor bone-marrow response MRD (Ig/TcR, FCM, BCR-ABL)

32 EWALL-PH-01 Additional Cytogenetic Abnormality EWALL PH 01 trial in pts 55 ans 100 RFS Percent survival 75 Ph+ only 50 Ph+ and ACA days Courtesy of P.Rousselot

33 GIMEMA IKZF1 deletion 83 Adult Ph+ ALL (CT+ IM) Martinelli, J Clin Oncol 2009

34 MDACC Impact of MRD (M3, MFC) Ravandi, Blood 2013

35 EWALL-Ph01 Impact of MRD2 (BCR-ABL) 100 MRD2 Perc cent rela apse CMR 4.5 log no CMR 4.5 log p= Months from inclusion Rousselot, personal com.

36 Pre-TKI mutations Frequence and impact Pfeifer, Leukemia 2012

37 EWALL-Ph01 Mutations at relapse T315I 60% n=17 Rousselot, personal com.

38 Pediatric EsPhALL trial risk-stratification Risk-stratification Poor-risk : PPR, D15 M3-BM, D21 M2/3-BM, induction failure Goor-risk : (GPR or D15 M1/2-BM or D21 M1-BM) and CR after 1 course AlloSCT indication MRD1 > 0.05% or (MRD1 > 0.005% and MRD2>0)

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40 Conclusions TKI may be combined to low-dose CT or PDN to achieve high rates of CR. There is no evidence to recommend one specific TKI for front-line therapy. 50% of young patients are cured by current TKI+CT combinations. Allogeneic transplantation should be considered in young adults but : Autologous transplantation may challenge allogeneic transplantation (especially in low-mrd patients). Risk-stratification may help to identify low-risk patients that could be cured by TKI+CT alone and high-risk patients in whom alternative transplant could be proposed.

41 Ak Acknowledgments ld Hervé Dombret, Yves Chalendon and all the GRAALL PIs Philippe Rousselot and all the EWALL PIs

42 NCCN guidelines (National Comprehensive Cancer Network) Clinical trial recommended!!! Induction Consolidation / Maintenance Relapsed/ Refractory yrs CT + TKI Allo HSCT CT+TKI +/- TKI post HSCT (CT+TKI) or HSCT or DLI yrs CT + TKI Allo HSCT CT+TKI TKI +/- TKI post HSCT (CT+TKI) or CS+TKI or HSCT > 65 yrs CT+TKI or CS + TKI CT + TKI or CS+TKI CT+TKI or CS+TKI