Acute Lymphoblastic Leukemia in AYAs

Transcription

1 Lugano, 11 May 2018 Acute Lymphoblastic Leukemia in AYAs Nicolas Boissel Hematology Department, AYA Unit Saint-Louis Hospital, Paris, France

2 Discolures of commercial support Name of Company Research support Employee Consultant Stockholder Speaker s Bureau Advisory Board AMGEN X X X Other PFIZER X NOVARTIS X X SANOFI X SERVIER X X

3 Incidence per 100,000 US population ALL Incidence by age AYA Age-Specific SEER Incidence Rates,

4 ALL - Survival by age SEER registry Year of diagnosis : AYA Keegan TH, Cancer Apr 1;122(7):

5 ALL in AYA : specificity & issues A specific biology of ALL in AYA Treatment heterogeneity Maintenance therapy and adherence Specific short- and long-term toxicities Suboptimal health insurance Less inclusion in trials

6 Age and primary abnormalities in B-cell ALL 2000 Moorman A, in Harrison CJ. Br J Haematol 2009;144:147 56

7 Age and primary abnormalities in B-cell ALL 2017 Primary abnormalities with high-risk features t(9;22) / BCR-ABL1 Hypodiploidy/near-triploidy KMT2A(MLL)-r iamp21 t(17;19) / TCF3-HLF Ph-like : CRLF2-r, ABL-class MEF2D-r Iacobucci et Mullighan, J Clin Oncol Mar 20;35(9):

8 BCR-ABL1-like & Ph-like in children COALL-92/97 CCG 1961 Den Boer M et al., Lancet Oncol Feb; 10(2): Harvey RC, et al. Blood. 2010;116:

9 Signaling pathways in Ph-like ALL Iacobucci et Mullighan, J Clin Oncol Mar 20;35(9):

10 Genetic landscape of Ph-like ALL Hunger S & Mullighan C, Blood Jun 25; 125(26):

11 Ph-like ALL : an AYA disease? Herold, N Engl J Med 2014

12 CRLF2 deregulation 7% in children, 50% in Down syndrome Translocation involving locus : t(x;14)(p22;q32) or t(y;14)(p11;q32) Interstitial PAR1 deletion: P2RY8-CRLF2 fusion JAK2 mutation in 50% of cases Point mutation in the CRLF2 gene Russel, Blood Sep 24;114(13): Mullighan, Nat Genet Nov;41(11): Yoda, PNAS 2010 Jan 5;107(1):252-7.

13 Fusion transcripts activating kinases JAK2-translocations: 3/15 (20%) ABL1-translocations: 5/15 (33%) 4/15 (27%) Roberts, Cancer Cell Aug 14;22(2):

14 Minimal residual disease Kinase Rearrangements and Therapeutic Targets in Ph-like ALL Figure 1 A B 300 bp 100 bp EBF1-PDGFRB fusion transcript 174 bp C EBF1 exon 15 PDGFRB exon 11 Figure Mb deletion induction 5q33 consolidation BMT imatinib Time from diagnosis (days) Pui CH, Clin Lymphoma Myeloma Leuk Aug;17(8): Lengline E, Haematologica Nov;98(11):e146-8.

15 French GRAALL strategy to detect kinase activation in BCP-ALL PRIMARY WORKUP - Karyotype and/or DNA index and/or CGH-array - RQ-PCR and/or FISH for recurrent translocations - ERG del genomic PCR - RQ-PCR CRLF2 and P2RY8-CRLF2 GENETIC GROUPS High hyperdiploidy ETV6-RUNX1 TCF3-PBX1 BCR-ABL1 iamp21 MLL translocations ERG deletion TCF3-HLF Low hypodip. / Near trip. B-OTHER SECONDARY WORKUP - FISH (ABL1/2, PDGFRB, JAK2) - RT-MLPA (ABL1, EBF1-PDGFRB, ) ABL-class Unknown JAK-class CRLF2 deregulation Kinase sequencing EXPLORATORY WORKUP RNAseq / Exome Personal communication, Emmanuelle Clappier

16 Minimal/measurable residual disease (MRD) in ALL Induction Consolidation Maintenance MRD techniques Number of blast cells Relapse = 100% Residual disease Morphology MRD tools IgH/TcR rearrangement MolBiol, PCR (DNA) Leukemic blast phenotype Flow-Cytometry (blast cells) Fusion genes BCR-ABL1 MolBiol, RT-PCR (RNA) 10 2 Next-generation sequencing Years 2

17 CIR Probability of survival Post-induction MRD MRD1: molcr MRD1: <10-4 MRD Years y-OS: MRD <10-4 : 74.0% MRD 10-4 : 48.7% P< Years Beldjord K, et al. Blood 2014;123:

18 Age and post-induction MRD in children (>1y) and AYAs UKALL-2003 MRD < (n = 1520) (n = 767) (n = 610) (n = 229) High (>0.01%) 427 (28 1) 271 (35 3) 223 (36 6) 109 (47 6) Indeterminate 491 (32 3) 237 (30 9) 183 (30 0) 60 (26 2) Low 590 (38 8) 255 (33 2) 191 (31 3) 54 (23 6) * High versus Low P value (<10 vs. 10+) P value (10 15 vs. 16+) <0 0001* 0 004* NOPHO-2008 Hough R, Br J Haematol Feb;172(3): Toft N, Leukemia Mar;32(3):

19 Age and post-induction MRD in adults aged 18-59y MRD1<10-4 MRD P value Median age 30.5 y 31 y 0.30 T-ALL 42% 26% 0.02 Median WBC (G/L) WBC 30 G/L in BCP-ALL 20% 34% 0.08 Pro-B in B-lineage ALL 17% 24% 0.44 Poor cytogenetics 17% 11% 0.33 CNS+ 4% 6% 0.74 Slow response to steroids 19% 31% 0.05 Slow BM blast clearance 20% 61% <0.001 HR-ALL 50% 86% <0.001 GRAALL-2003/05, data out of file

20 Age and increasing risk of failure in children (>1y) and AYAs with Ph- ALL UKALL-2003 NOPHO-2008 Hough R, Br J Haematol Feb;172(3): Toft N, Leukemia Mar;32(3):

21 Age and increasing risk of TRM in adults (18-59y) with Ph- ALL Leukemia-related events Cumulative incidence of failure (primary resistance, relapse) Treatment-related events Cumulative incidence of TRM (induction death, death in CR1) Event-free survival 18-24y 25-34y 35-45y 46-54y 55-59y Huguet F., JCO 2018, in press

22 Cumulative incidence of TRM/Failure Cumulative incidence of TRM/Failure TRM and CI of Failure according to age and treatment intensity Treatment Intensity : Low/Medium/High TRM Failure Treatment Intensity : Low/Medium/High TRM Failure AYA Children Adults Elderly Children Adults Elderly

23 Paediatric vs. adult therapy in adolescents yr Age France 1 FRALLE (yr) Pts CR (%) EFS LALA Netherland 2 DCOG HOVON UK 3 ALL UKALLXII Sweden 4 NOPHO Adult ALL Group USA 5 CCG CALGB (%) 1. Boissel N, et al. J Clin Oncol 2003;21:774 80; 2. De Bont JM, et al. Leukemia 2004;18:2032 5; 3. Ramanujachar R, et al. Pediatr Blood Cancer 2007;48:254 61; 4. Hallböök H, et al. Cancer 2006;107: ; 5. Stock W, et al. Blood 2008;112:

24 Impact of age-based care organization on the outcome of AYA 18-39y Five-Year Relative Survival Rate by Single Year of Age at Diagnosis, 2000 to 2007 (SEER) Siegel SE, JAMA Oncol Feb 15.

25 AYA in pediatric-inspired trials Trial Patients N Age range years Median age years CR Early death Death in CR HSCT EFS/DFS/CRD years OS years PETHEMA ALL % 1% 1% # 0% # 6 EFS, 61% 6 69% HOVON (FRALLE 93) % 4% NR 35% 2 EFS, 66% 2 72% FRALLE % NR NR 28% 5 EFS, 61% 5 66% JALSG ALL202-U % 5% 4% 15% 5 DFS, 67% 5 73% Intergroup C NR NR NR NR 2 EFS, 66% 2 78% DFCI * 28* 86% 1% NR 21% 4 EFS, 58% 4 67% A-BFM (MDACC) % 1% 8% 10% 3 CRD, 70% 5 60% HyperCVAD (MDACC) % 1% 7% 6% 3 CRD, 67% 5 60% Modified DFCI 91-01** NR 98% 0% NR NR 3 DFS, 77% 3 83% GMALL 07/03** NR 91% 4% NR 43% 5 CRD, 61% 5 65% GRAALL-2003/2005** % NR NR NR 5 EFS, 59% 5 65% NOPHO NR NR 1% 6% NR 5 EFS, 74% 5 78% Boissel N & Baruchel A, Blood 2018, in press Death in CR 7-9% HSCT 10-43% 5y-OS 60-78%

26 Adolescents in recent pediatric trials Trial Patients Age range Median age CR Early death Death in CR HSCT EFS OS (N) years years years years CCG NR 95% 2% 3% 4% 5 72% 5 78% DFCI 9101/ % 4% 2% NR 5 78% 5 81% Total Therapy XV NR 98% 0% 7% 11% 5 86% 5 88% UKALL NR 97% NR 6% 6.1% 5 72% 5 76% FRALLE % 2% 2% 12% 5 74% 5 80% Death in CR 4-7% HSCT 4-12% 5y-OS 78-88% Boissel N & Baruchel A, Blood 2018, in press

27 Differences in outcome in adolescents with ALL: A consequence of better regimens? Better doctors? Both? Paediatricians administer these treatments with a military precision on the basis of a near-religious conviction about the necessity of maintaining prescribed dose and schedule come hell, high water, birthdays, Bastille Day, or Christmas. Schiffer CA. J Clin Oncol 2003;21:760 1

28 EFS (%) OS (%) FRALLE 2000, yr Adult vs. paediatric centres 1 1,8 82%,8 83%,6,6 56% 41%,4,4,2 0 p=.0001 Paediatric Adult,2 0 p=.0004 Paediatric Adult Years Years Differences in - Age Yes, but not relevant - ALL characteristics No - Doctors, facilities Yes, but which mechanism? Cluzeau T et al, ASH 2012, abstract 3561

29 Adherence to 6-MP during maintenance Paediatric COG study Variable Estimated Adherence (%) Time on study, months < < < < < <.001 Age at study participation <.001 < 12 years years 85.8 Household structure.001 Multiple caregivers 93.1 Single mother 80.6 Ethnicity <.001 Non-Hispanic whites 94.8 Hispanics 88.4 P Adherence <95% Bhatia S, et al. J Clin Oncol 2012;30:

30 Impact of age on major toxicities NOPHO-2008 Toft N, Leukemia Mar;32(3):

31 Avascular Necrosis (AVN) A major issue in Adolescents with ALL The risk of AVN is correlated to the cumulative dose of corticosteroids. Asparaginase and high-dose MTX may increase the risk of AVN Other factors associated with risk of AVN are : older age (>10 yr), Higher BMI, continuous steroid administration, HSCT, GvHD. AVN incidence rate is about 20% for patients > 15 yr in pediatric trials. by age Alternate week vs. Continuous Relling MV et al., J Clin Oncol Oct 1;22(19): Mattano LA et al., Lancet Oncol 13 (9): , 2012.

32 % patients Ovarian function after HSCT for ALL Infertility is common after SCT Persistent ovarian failure is shown in more than 80% of female after myeloablative regimen and almost all patients after Bu-Cy. Incidence of pregnancy less than 3% Increased risk for maternal and fetal complications after TBI-based regimen Gy 12 Gy Gy BuCy 10 Gy 12 Gy Gy BuCy TBI Ovarian recovery Pregnancy Sanders JE et al., Blood Apr 1;87(7): Salooja N et al., Lancet Jul 28;358(9278):271-6.

33 Recovery of spermatogenesis after HSCT Risk factors for azoospermia Rovò A et al., Haematologica Mar;98(3):339-45

34 Conclusion AYA with ALL The transition between children and adult ALL biology occurs in AYA patients. Adolescents aged years should be treated in paediatric trials Young adults benefit from full paediatric or paediatric-inspired approaches. Upper age limit to adopt such strategies should be prospectively explored. Rapid screening for targetable and/or high-risk diseases may help to offer early access to precision medicine. AYA programs should be developed : to offer specific psychological & social support, to maintain engagement in school, education & workplace (re)integration to ensure fertility preservation and survivorship care plan

35 Biologists Coordination Clinicians C. Abbal V. Asnafi M. Bakkus L. Baranger K. Beldjord MC. Béné ML. Boulland H. Cavé JM. Cayuela A. Chassevent E. Clappier E. Delabesse N. Grardel M. Lafage E. MacIntyre B. Schäfer J. Soulier V. Lhéritier N. Ifrah H. Dombret Biostatistics J. Lejeune S. Chevret N. Boissel T. Braun A. Buzyn JY. Cahn Y. Chalandon P. Chevallier A. Delannoy N. Dhédin M. Escoffre-Barbe C. Gardin C. Graux D. Heim U. Hess F. Huguet A. Huynh M. Hunault T. Leguay S. Leprêtre JP. Marolleau S. Maury P. Rousselot X. Thomas JP. Vernant N. Vey All GRAALL investigators