Philadelphia-positive Acute Lymphoblastic Leukemia Nicolas Boissel Service d Hématologie Unité Adolescents et Jeunes Adultes Hôpital Saint-Louis, Paris
Ph+ acute lymphoblastic leukemia DR+, CD19+, CD22+, CD10+, CD20+ CD34+, CD33+, TdT+, CD25+ t(9;22)(q34;q11)
BCR-ABL
Genetic alterations in Ph+ ALL Locus Géne Enfants n = 21 Adultes N = 22 Total (%) N = 43 7p12.2 IKZF1 16 20 36 (84) 9p21 CDKN2A 10 13 23 (53) 9p13.3 PAX5 10 12 22 (51) 20p12.2 C20orf94 7 3 10 (23) 13q14.2 RB1 4 4 8 (19) 5q14.3 MEF2C 2 4 6 (14) 5q34 EBF1 3 3 6 (14) 12q22 BTG1 4 2 6 (14) 13q14 DLEU* 1 3 4 (9) 3p14.2 FHIT 2 2 4 (9) 12p13 ETV6 2 1 3 (7) *mir16 and mir15 Mullighan et al., Nature 453:110, 2008
Ph-ALL among age Moorman, 2007
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 154 67% 39% - 19% @3y Age, WBC MRD response Allo-SCT 267 67% 28%* 17% @5y 22% @5y 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 145 95% 44%* 36% @3y@ 43% @3y@ - GRAALL Chalandon, ASH 2012 268 95% 60% 41% @3y 52% @3y - *: per-protocol myeloablative SCT
GRAAPH-2003 vs LALA-94 Tanguy-Schmidt, BBMT 2013
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?
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?
MDACC HyperCVAD Imatinib vs Dasatinib DFS OS Ravandi, Blood 2013
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
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?
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
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
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
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
GRAAPH-2005 Hematological response IM-based (n= 135) IM-HyperCVAD (n=133) p Total (n=268) CR 133 (98.5%) 121 (91.7%) 0.006 254 (94.8%) Courses to CR one two 132 (97.8%) 1 (0.7%) 118 (88.7%) 3 (2.2%) 0.003-250 (93.2%) 4 (1.5%) Resistance after 2 cycles 1 (0.7%) 3 (2.2%) 0.35 3 (1%) D60 mortality 1 (0.7%) 9 (6.7%) 0.01 10 (3.7%) Chalandon ASH 2012
GRAAPH-2005 Molecular response (Bone marrow) IM-based (n= 135) IM-HyperCVAD (n= 133) p Total (n=268) MRD1 Tested 116 (86%) 102 (77%) 0.06 218 (81%) - MMolR 50 (43%) 46 (45%) 0.79 96 (44%) - Undetectable 11 (9%) 10 (10%) 0.99 21 (10%) MRD2 Tested - MMolR - Undetectable 112 (83%) 94 (71%) 0.02 206 (77%) 74 (66%) 60 (64%) 0.77 134 (65%) 32 (29%) 21 (22%) 0.34 53 (26%) MMolR= BCR-ABL/ABL < 0.1% in the bone marrow Chalandon ASH 2012
GRAAPH-2005 Overall survival and EFS Median OS, 3.2 years Median EFS, 1.8 years 3-y OS, 51.7% (44.8-58.2) 3-y EFS, 41.1% (34.6-47.5)
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 100 100 100 100 100 100 6MP/MTX Dasa 100 6MP/MTX Dasa 100 6MP/MTX 1 3 5 7 9 10 12 14 17 19 21 24 26 28 30 32 34 36 38 41 43 48 > 70y Dasa 100mg/d ~ mo 8 ~ mo 10 ~ mo 12 and Dex 20mg 51 52 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 15 18 21 24 months Rousselot, personal com.
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 100 3 log reduction 100 CMR 4.5 log 80 Percent 60 54% 53% 40 20 23% 24% 0 After Induction MRD1 During consolidation MRD2 Rousselot, personal com.
EWALL-Ph01 Survival 100 survival 80 60 45% at 3 years Percent 40 20 0 0 12 24 36 48 60 Months pts at risk 71 43 31 10 4. 6 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)
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?
GRAAPH-2005 SCT in CR1 patients Arm A Arm B p Total (133 CR1) (121 CR1) (254 CR1) All CR1 patients Allo-SCT 82 78 0.93 160 (63%) Auto-SCT 17 17 34 (13.4%) MMolR patients Allo-SCT 51 39 0.39 90 Auto-SCT 13 15 28 CR to SCT time Allo-SCT 4.6 mths 4.5 mths 0.8 4.6 mths Auto-SCT 53mths 5.3 45mths 4.5 014 0.14 51mths 5.1
GRAAPH-2005 Autologous versus allogeneic SCT Patients in MMolR
MDACC HyperCVAD-IM (N=52) N= 52 pts DFS OS Thomas, Hematology 2006
COG AALL0031 Impact of ITK exposure Schultz K, JCO 2009
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
GMALL IM post-allogeneic HSCT Ottmann, Leukemia 2013
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?
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)
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 25 0 0 180 360 540 720 900 1080 days Courtesy of P.Rousselot
GIMEMA IKZF1 deletion 83 Adult Ph+ ALL (CT+ IM) Martinelli, J Clin Oncol 2009
MDACC Impact of MRD (M3, MFC) Ravandi, Blood 2013
EWALL-Ph01 Impact of MRD2 (BCR-ABL) 100 MRD2 Perc cent rela apse 75 50 25 CMR 4.5 log no CMR 4.5 log p=0.01 0 0 12 24 36 48 60 Months from inclusion Rousselot, personal com.
Pre-TKI mutations Frequence and impact Pfeifer, Leukemia 2012
EWALL-Ph01 Mutations at relapse T315I 60% n=17 Rousselot, personal com.
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)
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.
Ak Acknowledgments ld Hervé Dombret, Yves Chalendon and all the GRAALL PIs Philippe Rousselot and all the EWALL PIs
NCCN guidelines 1.2012 (National Comprehensive Cancer Network) Clinical trial recommended!!! Induction Consolidation / Maintenance Relapsed/ Refractory 15-39 yrs CT + TKI Allo HSCT CT+TKI +/- TKI post HSCT (CT+TKI) or HSCT or DLI 40-65 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