Pediatric Treatment Approaches for Adolescent and Young Adult Acute Lymphoblastic Leukemia 2017 Texas Adolescent and Young Adult (TAYA) Oncology Conference Elizabeth Raetz, MD Acute Lymphoblastic Leukemia (ALL) Across the Age Spectrum ALL is the most common and one of the most curable malignances in young children, however, it presents unique challenges in adolescents and young adults (AYAs) Outcome disparities Slower rates of improvement in survival Differences in cancer and host biology Unique side effect profiles compared to young children Complex psychosocial factors Objectives AYA ALL Survival Rates Evaluate the effectiveness of pediatric treatment approaches for ALL in AYAs Identify the acute toxicities associated with pediatric ALL treatment regimens in AYAs Assess the role of emerging new therapies for distinct biological subtypes of AYA ALL Lewis et al. J Natl Cancer Inst Monogr 2014;49:228 235
Plateau in AYA ALL Survival Rates in COG Trials All Patients Age 16+ years Age 16+ Overall Survival 5 yr OS±SE 2000 05 90±0.4 2006 09 92±0.5 Overall Survival 0.0 0.2 0.4 0.6 0.8 1.0 5 yr OS±SE 2000 05 78±2.5 2006 09 76±4.7 2000-05 (n=365) 2006-09 (n=427) P 0.2509 Defining Optimal Therapy for AYAs: Adult vs. Pediatric Regimens 0 2 4 6 8 10 12 Hunger et al. SIOP 2013 Why are Outcomes for AYAs with ALL Inferior? Assessment of the Components of Cure Genetic Polymorphisms Genome wide Profiling HOST TUMOR Drug Metabolism Minimal Residual Disease THERAPY A. Bleyer, 2009
Adult vs. Pediatric Regimens Outcomes for AYAs with ALL on Prospective Pediatric or Pediatric Inspired Trials Pediatric Regimens Increased vincristine dose intensity Increased asparaginase dose intensity Increased steroid dose intensity More intensive early CNSdirected therapy Delayed Intensification phase of treatment Prolonged antimetabolitebased Maintenance Adult Regimens Less asparaginase and vincristine Higher doses of cyclophosphamide and anthracyclines Designed to be tolerable for a broader age range and more heterogeneous population Community and universitybased practices More frequent allogeneic HCT in CR1 Country Protocol Age (Yrs) N CR (%) EFS (%) OS (%) France GRAALL 2003 15 45 172 95 58 (42 mo) 64 (42 mo) Spain PETHEMA ALL 96 15 30 81 98 61 (6 yr) 69 (6 yr) Australia FRALLE 93 16 45 40 98 70 (3 yr) 70 (3 yr) USA DFCI 01 175 18 50 92 85 58 (4 yr) 67 (4 yr) Curran & Stock. Blood 2015; 125:3702 30 Schafer & Hunger. Nat Rev Clin Oncol 2011; 8:417 24 C10403: US Intergroup Phase II Trial for AYAs with ALL Adaptation of Pediatric or Pediatric Inspired Therapy at Adult Centers Large prospective trial for treatment of AYAs (16 39 years of age) with newly diagnosed B or T ALL with a pediatric regimen by adult medical oncologists 318 patients enrolled; 296 treated from 2007 2012 Median age at diagnosis 24 years: 25% were 17 to 20 years, 53% were 21 to 29 years, and 22% were 30 to 39 years Objective: To evaluate the feasibility and effectiveness of the standard arm of COG AALL0232 in patients with AYA ALL treated at adult centers Stock W et al. Blood 2014; 124:796, ClinicalTrials.gov Identifier: NCT00558519
C10403: US Intergroup Phase II Trial for AYA ALL Reassessing the Role of Transplant in CR1 I C IM DI VCR, PRED, PEG ASP, DAUNO, IT ARA C and MTX CYCLO, ARA C, MP, VCR, PEG ASP, IT MTX IV ESC MTX, VCR, PEG ASP, IT MTX VCR, DOXO, DEX, PEG ASP, CYCLO, ARA C, TG, IT MTX Disease free Survival Overall Survival 4 yr OS 73% (95% CI: 63 81) 4 yr OS 45% (95% CI: 40 50) 4 yr DFS 71% (95% CI: 60 79) 4 yr DFS 40% (95% CI: 35 45) Cum Incidence Relapse TRM M VCR/PRED, MP, PO MTX, IT MTX DFCI Pediatric Inspired Therapy vs. HCT Stock W et al. Blood 2014; 124:796, ClinicalTrials.gov Identifier: NCT00558519 Seftel et al. Am J Hematol 2016; 91:322 9 C10403: Intergroup Phase II Clinical Trial for AYAs with Untreated ALL Contemporary Outcomes for AYAs with ALL on Pediatric Trials 2 yr EFS 66% (95% CI: 0.60 0.72) 2 yr OS 78% (95% CI: 0.72 0.83) 100% EFS in 22/58 [38%] MRD negative patients at day 28 of induction (P=0.0006) Stock W et al. Blood 2014; 124:796
AYA Outcomes on Recently Completed Pediatric ALL Studies DFCI 91 01 and 95 01: Outcome of Adolescents 15 18 Old, 1991 2000 5 yr EFS 78% 5 yr OS 81% COG ALL Trials: AYA Enrollment 2004 2017 Trial AALL0232 HR B ALL 2004 2011 AALL0434 T ALL 2007 2015 AALL1131 HR B ALL 2011 Present Total Enrollment 1 15 3104 eligible 2488 (80.2%) 1851 eligible 1570 (84.8%) 4447 eligible (as of 02/13/2017) 3688 (82.9%) 16 20.99 554 (17.8%) 228 (12.3%) 606 (13.6%) 21 30.99 62 (2%) 53 (2.9%) 153 (3.4%) Total 1388 268 Barry et al. J Clin Oncol 2007; 25:813 19 Courtesy of Charlotte Wood and Mini Devidas AYA Outcomes on Recently Completed Pediatric ALL Studies SJCRH: Outcome of Adolescents 15 18 Old, 2000 2007 COG AALL0232 Schema Induction Consolidation Interim Maintenance #1 Delayed Intensification # 1 IM #2 DI #2 5 wks 8 wks 8 wks 8 wks 8 wks 8 wks Pred vs Dex Escalating MTX/ASNase vs HD MTX Escalating MTX/ASNase Maintenance Total Duration of Therapy: Girls: 2+ years, Boys: 3+ years RER (Rapid Early Responder): M1 by Day 15 and MRD < 0.1% Day 29 1 IM/DI SER (Slow Early Responder): >M2 on Day 15 or MRD >0.1% Day 29 2 IM/DI CXRT: CNS3 1800cGy, SER 1200cGy during DI #2 Pui et al. J Clin Oncol 2011; 29:386 391 Larsen et al. J Clin Oncol 2016; 34:2380 2388
AYA Outcomes on COG AALL0232 Induction Events COG AALL0232 EFS probability 0.0 0.2 0.4 0.6 0.8 1.0 P 0.0001 16 yrs n 2073 EFS at 5y 0.809 0.016 16 yrs n 501 EFS at 5y 0.680 0.044 OS probability 0.0 0.2 0.4 0.6 0.8 1.0 P 0.0001 16 yrs n 2073 OS at 5y 0.884 0.013 16 yrs n 501 OS at 5y 0.798 0.038 Induction death Induction failure (M3) Age <16 yr (n= 2073) Age 16 yr (n= 501) P value 37 (1.78%) 12 (2.40%) 0.36 18 (0.87%) 8 (1.60%) 0.14 0 2 4 6 8 0 2 4 6 8 Larsen et al. J Clin Oncol 30, 2012; (suppl; abstr CRA9508) Larsen et al. J Clin Oncol 30, 2012; (suppl; abstr CRA9508) AALL0232: High Dose MTX is Superior to Escalating MTX/ASNase in AYA with B ALL 5 year EFS 72±3.2% 5 year EFS 61±3.9% Treatment Failures on COG AALL0232 Five year Cumulative Incidence Rates by Event Type Event Age < 16 yr Cum incidence ± std error Age 16yr Cum incidence ± std error P value Relapse 13.4 ± 0.9% 21.3 ± 2.7% 0.002 Marrow ± Extramed Relapse 9.0 ± 0.8% 15.2 ± 2.4% 0.0007 Isolated CNS Relapse 3.7 ± 0.5% 5.2 ± 1.4% 0.58 Other Relapse 0.7 ± 0.3% 0.8 ± 0.6% 0.95 SMN 0.9 ± 0.3% 1.3 ± 0.8% 0.91 Remission Death 2.1 ± 0.3% 5.5 ± 1.1% <0.0001 Larsen et al., unpublished data 2016 Larsen et al. J Clin Oncol 30, 2012; (suppl; abstr CRA9508)
Treatment Toxicities: C10403 Compared to COG AALL0232 Induction Toxicities Acute Toxicities Associated with Pediatric Therapy in AYAs C10403 (%) N=318 COG AALL0232 (%) N=159 Hyperglycemia 29.3 22.0 Hyperbilirubinemia 15.9 6.7 Allergic reaction 0.7 0.8 Pancreatitis 1.1 0.5 Thrombosis 2.9 1.5 Febrile neutropenia 19.2 7.0 Induction mortality 2 2 Advani et al. Blood 2013; 122:3903 Treatment Toxicity in AYA Patients Compared with Younger Patients Treated for High Risk B precursor ALL: COG AALL0232 16 30 yrs N=601 1 15 yrs N=2450 P value Febrile neutropenia 7.0% 13.4% <0.0001 Hyperglycemia 22.0% 15.4% 0.0002 Hyperbilirubinemia 6.7% 3.7%, 0.0022 Induction mortality 2.2% 1.7% 0.39 Mucositis 18.5% 11.3% 0.0002 Neuropathy 11.5% 7.4% 0.0015 CTCAE version 4.0 grade 3 and 4 toxicities Larsen et al. Blood 2011; 118:1510 Treatment Toxicities: C10403 Compared to COG ALL0232 Grade 3 5 AEs During Treatment C10403 (%) N=318 COG AALL0232 (%) N=159 Febrile neutropenia post induction 46.0 40.9 Hyperglycemia 32.3 35.4 Hyperbilirubinemia 22.9 24.7 Liver Failure 1.0 1.9 Pancreatitis 4.2 3.8 Sensory Neuropathy 14.2 11.4 Osteonecrosis 2.1 3.2 Allergic reaction 9.4 19 Thrombosis 7.6 3.8 Advani et al. Blood 2013; 122:3903
MRD Response in High Risk ALL According to Age 100 Emerging Targeted Therapies for Distinct Biological Subsets of AYA ALL Percentage End Induction MRD Negative 90 80 70 60 50 40 30 20 10 0 1 9 yrs 10 15 yrs 16 20 yrs 21 30 yrs End Induction MRD < 0.1% End Induction MRD < 0.01% Patients enrolled on AALL0232 who received PRED during Induction Raetz et al. J Clin Oncol 2010; 28 (Suppl 15) 9509 Distribution of Cytogenentic Subtypes of ALL by Age Gene Expression Profiling Reveals a BCR ABL1( Ph ) like Subgroup with Poor Outcomes COALL cohort 100 B-lineage - other pdfs (%) 80 60 40 20 BCR-ABL-like BCR-ABL positive p<0.0001 0 0 2 4 6 8 10 12 time from initial diagnosis (years) Resembles BCR ABL + leukemia Harrison. Brit J Haematol 2008; 144:147 56 den Boer et al. Lancet Oncology 2009; 10:125 134 Mullighan et al. NEJM 2009; 360:470 480
Ph like ALL: Prevalence and Outcomes Can We Build on the Success of TKI + Chemotherapy in Ph+ ALL? 0.0 0.2 0.4 0.6 0.8 1.0 AALL0031 (n=43) Historical Controls (n=120) P 0.0001 0 2 4 6 8 COG AALL0031: 7 yr DFS 71.7% vs. 21.4% for historical controls treated without TKIs Schultz et al. J Clin Oncol. 2009; 31:5175 81 and Leukemia 2014; 7:1467 71 Roberts KG et al. N Engl J Med 2014;371:1005 1015; Graubert TA. N Engl J Med 2014;371:1064 1066 Spectrum of Recurring Kinase Alterations in Ph like ALL Identifying Patients with Ph like ALL in Real Time HR B ALL AALL1131 ABL class fusions ABL class inhibitors EPOR or JAK2 rearranged CRLF2 rearranged JAK inhibitor Other JAK STAT pathway Ras pathway Misc or no kinase activation Roberts KG et al. N Engl J Med 2014; 371:1005 1015; Graubert TA. N Engl J Med 2014; 371:1064 1066 Induction LDA Not Ph like Risk adapted chemotherapy Ph+ imatinib/dasatinib + chemo multiplex RT PCR kinase fusion + ABL class kinase fusion JAK2 fusion IL7R alteration Post induction AALL1131 dasatinib Other testing recommended FoundationOne ArcherDx (RNA seq) EPOR rearrangement Other fusions? Post induction AALL1521 ruxolitinib Ph like CRLF2+ CRLF2 R + JAK1/JAK2 mutation analysis CRLF2 FISH & PCR NCI TARGET & COG ALL Committee University of New Mexico Nationwide Children s Hospital University of Alabama, Birmingham Slide courtesy of Sarah Tasian
Low Adherence to Oral 6MP Significantly Increases Relapse Risk Conclusions Age < 12 years (93.1%) Age 12 years (85.8%) 13.9% (2.6%) 4.7% (1.3%) Outcomes for AYAs with ALL have improved but remain inferior to those in younger children Survival benefits are achieved with pediatric treatment regimens and expanded access to clinical trials AYAs experience unique toxicities compared to younger children, however, most toxicities are manageable and reversible Ph like ALL is prevalent in AYAs and clinical strategies have been developed to prospectively identify Ph like ALL patients that may benefit from tyrosine kinase inhibitor therapy Objective: To determine the impact of an intervention package (IP) consisting of education, customized instructions, text message reminders, and direct supervision on medication eventmonitoring system (MEMS) based adherence to oral 6 mercaptopurine (6MP), MTX, and when relevant, TKI during maintenance Bhatia in et children, al. J Clin Oncol adolescents 2012; 30:2094 2102 and young and adults JAMA with Oncol. HR 2015; B ALL. 3:287 295 Promising New Immunotherapies Acknowledgements Mignon Loh David Freyer Stephen P. Hunger William L. Carroll Meenakshi Devidas Archie Bleyer Jennifer McNeer Nita Seibel Karen Rabin Wanda L. Salzer Michael M. Burke Smita Bhatia Eric Larsen Karen R. Rabin Saran Tasian Shalini Reshmi Julie Gastier Foster Rick Harvey Cheryl Willman I Ming Chen Wendy Stock Kathryn Roberts Charles Mullighan James Nachman Raetz E. The Hematologist 2017;14:10