The Future of Leukemia Therapy

Transcription

1 The Future of Leukemia Therapy

2 Total XV: Treatment Results %±1.1% 91.7%±4% Overall Survival Probability N= Years from Diagnosis Pui & Evans N Engl J Med 360: , 2009 (updated) 3.5% ± 0.8% any CNS relapse 2.2% ± 0.7% isolated CNS relapse

3 Characteristics of the Contemporary Clinical Trials Group Trial (Years of recruitment) No. of patients % Cranial Irradiation % Allogeneic Transplant AIEOP BFM COALL COG DCOG JACLS NOPHO SJCRH UK DFCI Vora A. J. Clin Oncol 2016;34:919-26

4 5-year Overall Survival for All Patients By Protocols Vora A. J Clin Oncol 2016;34:919-26

5 5-year Cumulative Incidence of Any Event for All Patients By Protocols Vora A. J Clin Oncol 2016;34:919-26

6 Adverse Events in Subgroups of High-risk Patients Treated with or Without Prophylactic Cranial Irradiation (CRT) 5 year cumulative incidence (%) B-cell WBC > 100 K T-cell WBC > 100 K B-cell Slow Early Response T-cell Slow Early Response CRT CRT CRT CRT Yes No Yes No Yes No Yes No Death * 24.7 Any event BM relapse Isolated CNS relapse Combined CNS relapse *P=0.02 P=0.08 Vora A. J Clin Oncol 2016;34:919-26

7 Adverse Events of Patients with CNS 3 Treated With or Without Prophylactic Cranial Irradiation % Cumulative Risk Irradiation No Irradiation P value Any event Isolated CNS relapse Bone marrow relapse Mortality Vora A. J. Clin Oncol 2016;34:919-26

8 Total XV: Risk Factors for isolated CNS Relapse Factor Relapse/Total Hazard Ratio (95% CI) t(1;19)(tcf3-pbx1) 3 / ( ) Blasts in CSF* 8 / (2-50) T lineage 6 / ( ) * CNS2, CNS3, traumatic LP with blasts Pui et al. N Engl J Med 2009;360:

9 Confirmation of Leukemic Nature of Blasts with TdT or Deep Sequencing of DNA Isolated from CSF Wright TdT IHC 100% Deep Sequencing 80% 60% 40% Positive Variable Negative 20% 0% CNS1 CNS2- CNS2+ CNS3 TdT- TdT+ # John Choi

10 Delayed Lumbar Puncture for Initial Triple Intrathecal Therapy (TIT) Until Clearance of Circulating Blasts 152 patients (11 T-ALL, 2 Ph+, 6 t(1;19), 6 MLL-rearranged; 14 WBC >100 x 10 9 /L). TIT performed after clearance of circulating blasts (no later than day 10 of induction; no CNS 2 or CNS 3 status at the time of initial TIT) under anesthesia by most experienced clinicians; 14 to 20 TIT for standard-risk and 17 to 23 for high-risk ALL patients No patient received prophylactic cranial irradiation 5-year EFS=84.2±3.0%; 5-year survival=90.6±2.4%; 2 combined CNS relapses and no isolated CNS relapse Liu & Liang et al. J Clin Oncol 2014;32:1825-9

11 CAR T Cells Induced Durable CNS Remission in Children with B-ALL and CNS Involvement 15 patients had CNS 3 within 12 months of infusion (4 had CNS 2 and 2 had CNS 3 on day 1 of infusion) Several had ocular or brain parenchymal involvement on MRI; all had 1 to 6 CNS relapses and had prior CNS irradiation CAR T cells persistent in CSF in 98% of patients up to 12+ months 11 of 15 patients in CCR up to 2.5 years (4 bone marrow relapse) Grade 2/3 encephalopathy developed in 25% patients, not different from 29% of other patients treated with CAR T cells Maude SL 2016 J Clin Oncol 34, 2016 (Suppl; abstr 3011); Rheingold SR ASH 2015, abstract 3769

12 Minimal Residual Leukemia Level: Most Important Prognostic Indicator Leukemic cell Tumor burden Growth potential Drug resistance Microenvironment Drug resistance Host Age Pharmacogenomics Treatment response Therapy Drug dosage Drug interactions Campana D Curr Opin Hematol 2012;19:313-8

13 Total XV ( ): Risk Classification Schema Provisional low-risk B-ALL with WBC<50x10 9 /L & age 1 to 9.9 years, DNA index 1.16, or TEL-AML1 Provisional standard-risk T-ALL and other B-ALL Provisional high-risk Ph + ALL Day 19 MRD <0.01% % 1% Low-risk Provisional lowrisk Provisional standard-risk Provisional standard-risk Day 46 MRD <0.01% 0.01% <1% 1% 1% <1% High-risk Low-risk Low-risk Standardrisk Standardrisk High-risk Pui et al. Lancet Oncol 2015;16:465-74

14 Risk Stratification and Treatment by MRD Level During induction (day 19) MRD 1% intensified remission induction End of induction (day 46) Low-risk ALL + MRD 0.01% intermediate-risk MRD 1% high-risk MRD successfully studied in all 492 patients: 491 by flow cytometry and/or PCR of Ig/TCR genes, and 1 by RT-PCR of MLL-AF4 fusion Pui et al. N Engl J Med 2009;360:

15 Total XV: MRD Was Still Prognostic in the Context of MRDdirected Treatment (Outcome According to Day 19 MRD) Provisional Risk Group % 10-year EFS MRD 1% (n) MRD < 1% (n) P value Low-risk 69.2 (36) 95.5 (244) <0.001 Standard risk 65.1 (56) 82.9 (142) Pui et al. Lancet Oncol 16:465-74, 2015

16 Treatment Outcome of Provisional Low-risk Patients Based on MRD on Day 19 and Day 46 MRD Day 19 <1% MRD Day 19 >1% Pui et al. Lancet Oncol 16:465-74, 2015

17 Treatment Outcome of Provisional Standard-risk Patients Based on MRD on Day 19 and Day 46 MRD Day 19 <1% MRD Day 19 >1% Pui et al. Lancet Oncol 16:465-74, 2015

18 Total XV: Leukemia Subtypes Remained Prognostically Important in MRD-directed Treatment Provisional Risk Low Risk Leukemia Subtype No. 10-yr EFS (%) 10-yr Survival (%) 10-yr Risk of Relapse (%) t(12;21)/(etv6-runx1) Hyperdiploidy > Other NCI standard-risk B-ALL t(1;19)/(tcf3-pbx1) Standard-risk T-ALL * 19.9* NCI high-risk B-ALL * 85.8* 15.3* *Data contributing to the significant difference (P<0.01) in a given column. Pui et al. Leukemia 2016;Sept 13 [Epub ahead of print]

19 t(12;21) or Hyperdiploid>50 ALL with Negative Day 19 MRD May Be Candidates for Treatment Reduction Leukemia Subtype No* EFS (%) Survival (%) Relapse (%) t(12;21)/(etv6-runx1) Hyperdiploidy > Other NCI standard-risk B-ALL t(1;19)/(tcf3-pbx1) T-ALL NCI high-risk B-ALL P=0.023 P=0.369 P=0.017 *Patients with negative MRD (<0.01%) on Day 19 Pui et al. Leukemia 2016;Sept 13 [Epub ahead of print]

20 T-ALL and NCI high-risk ALL had inferior Outcome Even with Undetectable Day 46 MRD No* EFS (%) Survival (%) Relapse (%) t(12;21)/(etv6-runx1) Hyperdiploidy > Other NCI standard-risk B-ALL t(1;19)/(tcf3-pbx1) T-ALL NCI high-risk B-ALL P=0.005 P=0.002 P=0.087 Pui et al. Leukemia 2016;Sept 13 [Epub ahead of print]

21 Positive Day 46 MRD (>0.01%) Predictive of Very Poor Outcome Not Only in NCI High-risk but Also in Other NCI Standard-risk ALL Leukemia Subtype MRD <0.01 % MRD 0.01%-0.99% MRD 1% No. EFS (%) No. EFS (%) No. EFS (%) P value Other NCI standard-risk B-ALL <0.001 NCI high-risk B-ALL No. Survival (%) No. Survival (%) No. Survival (%) Other NCI standard-risk B-ALL <0.001 NCI high-risk B-ALL No. Relapse (%) No. Relapse (%) No. Relapse (%) Other NCI standard-risk B-ALL NCI high-risk B-ALL Pui et al. Leukemia 2016;Sept 13 [Epub ahead of print]

22 Hypodiploid ALL in Total Therapy XV and XVI ( ) Frequency 2.1 % (20/908) Ploidy Near-haploid chromosomes: 8 Low-hypodiploid chromosomes:12 End-of-induction MRD Positive : 6 (5<1%) Negative: 14 Transplant Events 2 (1 due to MRD >1%, 1 with negative MRD due to physician decision) 5 relapses 1 transplant-related mortality (negative MRD at the end of induction) Overall 5-year EFS 74%±11% Mullighan & Pui, Blood 2015 ;126:2896-9

23 Hypodiploid ALL:EFS According to MRD at the End of Induction Mullighan & Pui Blood 2015 ;126:2196-9

24 Frequency and Outcome of Ph-like ALL According to Age Gene expression profiling of 1725 pediatric, adolescent and young adult B-ALL cases (St Jude, COG, Alliance, ECOG, CALGB, MDACC) Childhood SR Childhood HR Adolescent years Young adult years Total Ph+ 1.3% 4.1% 6.0% 23.0% Ph-like 10.8% 13.7% 21.1% 27.3% Roberts et al NEJM 2014;371:

25 Total XV: No difference in Event-free Survival Between Ph-like ALL and Other B-ALL Cases 88.4%±1.9% 86.6%±4.1% Other B-ALL (n=304) 90.0%±4.7% 81.7%±11.7% Ph-like ALL (n=40) Roberts et al J Clin Oncol 2014;32:

26 No Significant Difference in EFS and Survival Between Ph-like ALL and other B-ALL By Risk Group Risk Group Subtype No. %5-yr EFS % 5-yr Survival Low Standard Ph-like Other Ph-like Other ± 0 95 ± 2 89 ± 7 84 ± ± 0 98 ± 1 89 ± 7 93 ± 3 High Ph-like Other ± ± ± ± 11 Roberts et al J Clin Oncol 2014;32:

27 Study Date Sequential Studies of Patients with Negative MRD in the Prior Study Total Patient No. Positive MRD Clinical Outcome Week 7 continuation Only one MRD+ case alive 7.4+ years Week 17 continuation MRD+ case died Week 48 continuation MRD+ case died Week 120 continuation relapses* *20 hematologic, 10 CNS and 2 testicular relapse with cumulative risk of relapse of 7.8% Pui et al. Lancet Oncol 16:465-74, 2015

28 Clinical Utility of Sequential MRD Studies in Patients with Persistent MRD after Remission Induction Study Date Total Study Outcome Week with decreasing MRD transplanted: both alive at 8.2+ and years 11 with decreasing MRD treated with chemotherapy: 7 alive 8.2+ to years; 4 died (2 relapse, 1 sepsis and 1 accident) 3 with increasing MRD: 2 died of transplant-related toxicity or relapse, 1 alive years after transplant Week with decreasing MRD to 0.01%: both alive for 6.4+ and 8.2+ years after transplant and chemotherapy, respectively Pui et al. Lancet Oncol 16:465-74, 2015

29 All Patients have Specific Leukemic Genetic Abnormalities D DUX4 D / Pui, Mullighan et al. J Clin Oncol 2015;33: , Nature Genet, in press

30 ZNF384-related Gene Fusions 4.0% pediatric B-ALL High frequency of CD10-negative phenotype (19% vs 3% in other B-ALL) High frequency of expression of myeloid-associated antigens CD13 and CD33 (12% vs 2% in other B-ALL) High expression of GATA3, CEBPA and CEBPB, and upregulation of JAK-STAT pathway Intermediate outcome: 5-year survival (75% vs 69% in other B- ALL) Liu et al. EBioMedicine 2016;8:173-83

31 MEF2D-related Gene Fusions 3.5% pediatric B-ALL Older age at presentation (median, 12.1 years) Pre-B immunophenotype Upregulation of pre-b-cell receptor signaling molecules but downregulation of JAK-STAT signaling pathway Poor outcome: 5-year survival (33 vs 71% in other B-ALL) Liu et al. EBioMedicine 2016;8: MEF2D-BCL9 fusion found in 4 of 59 relapsed or refractory ALL patients, and was associated with older age (10 to 13 years), B-ALL, very early relapse, and very poor outcome (0% survival). Suzuki et al. J Clin Oncol 2016;34:

32 Overall Survival of Adult and Pediatric ALL by Genotype. Liu et al. EBioMedicine 2016;8:173-83

33 Genome Sequencing Identified Mutations Associated with Drug Resistance in Relapsed ALL Activating mutations in CREBBP: Glucocorticoid resistance Activating mutationss NT5C2: Thiopurine resistance Negative feedbackdefective mutations in PRPS1: Thiopurine resistance Mullighan et al. Nature 2011;471:235-9; Meyer et al. Nat Genet 2013;45:290-4; Tzoneva et al. Nat Med 2013;19:368-71; Li et al. Nat Med 2015;21:563-71

34 Molecular Target Therapy in ALL Bhojwani & Pui Lancet Oncol 2013;14:e205-17

35 New Immunological Approaches to Treat ALL Bhojwani & Pui Lancet Oncol 2013;14:e205-17

36 Novel Therapies Under Investigation Molecular therapy: ABL1 tyrosine kinase inhibitors (dasatinib, bosutinib, ponatinib) for Ph + or Ph-like ALL with the fusion; Bcl-2 inhibitors (venetoclax, navitoclax) for ETP, MLL-rearranged, or Ph + ALL; JAK inhibitor (ruxolitinib) for Ph-like or ETP JAK-dependent ALL; bortezomib for refractory B- or T-ALL; Notch inhibitor (LY ) for T-ALL Antibody therapy: anti-cd19 (blinatumomab, denintuzumab), anti-cd20 (ofatumumab, obinutuzumab), anti-cd22 (inotuzumab, moxetumomab) Cell therapy: CD19 CAR T cells, CD22 CAR T cells

37 Two Genomes Influence Every Cancer Patient Germline Somatic Host Genome Cancer Genome Evans & Relling Science 1999;286:487-91

38 US FDA: Pharmacogenetics in Drug Label Oncology Cardiovascular 6MP: TPMT Clopidogrel: CYP2C19 Irinotecan: UGT1A1 Antiviral Erlotinib/gefinitib: EGFR Abacavir: HLA-B Imatinib: BCR-ABL Analgesics Tamoxifen: CYP2D6 Codeine: CYP2D6 Hematology Neurology Warfarin: CYP2C9 and VKORC1 Carbamazepine: HLA-B 164 drugs with pharmacogenomic biomarkers labeling 18 therapeutic areas: oncology, hematology, antiviral, cardiovascular, analgesics, etc.

39 List of pharmacogenetic tests to move from research to clinical care TPMT---thiopurines CYP2D6 --- codeine, amitriptyline, ondansetron G6PD---rasburicase, Septra CYP2C9, VKORC1---warfarin CYP2C19---clopidogrel, voriconazole DPYD---5FU HLA-B* abacavir HLA-B* carbamazepine (Asians ancestry) HLA-B* phenytoin HLA-B* allopurinol UGT1A1---irinotecan NUDT thiopurines CEP vincristine

40 Peripheral Neuropathy in Total XVI Peripheral neuropathy (sensory and motor) and neuropathic pain Grade 2 or above Grade 3 or above 43.8% 82.0% 6.1% 28.1% Ind RI2 Ind RI2 RI1 RI1 Sima Jeha, PI

41 Vincristine Neuropathy Hind foot valgus - collapsed longitudinal arch Kristin Scobey and Kiri Ness

42 A SNP in the promoter region of CEP72 (encoding a centrosomal protein involved in microtubule assembly) is associated with vincristine-induced neuropathy CEP72 (Centrosomal Protein Of 72 Kda) Chromosome Diouf et al. JAMA 2015;303:815-23

43 Risk and Severity of VCR-induced Neuropathy Related to CEP72 Genotype (Risk allele T associated with low expression of CEP72 mrna) COG 0334: Grade 2+ Grade 2+ Combined Cohort (SJ, COG) d Grade 2+ Grade 3+ SJCRH T13B: Grade 3+ Only Diouf et al. JAMA 2015;303:815-23

44 East Asians Have Poorer Mercaptopurine Tolerance Regression coefficient estimate P East Asian ancestry Yang et al., J Clin Oncol 2015;33:

45 Second Genome-wide Significant Locus: NUDT15 Chromosome Each dot is a SNP and color indicates chromosome Inverse log-transformed P value on the Y axis The taller the peak, the smaller the P value, and the stronger the association Yang et al., J Clin Oncol 2015;33:

46 NUDT15 C416T Variant is Strongly Associated with Mercaptopurine Intolerance Discovery GWAS (AALL03N1) Replication Cohort (St. Jude Total XV) Yang et al., J Clin Oncol 2015;33:

47 NUDT15 contributes to Ancestry-related Differences in Mercaptopurine Tolerance NUDT15 Variant TPMT Variant 6% 9% 4% 6% 3% 2% 0% Africans Europeans Hispanics East Asians 0% Africans Europeans Hispanics East Asians Yang et al., J Clin Oncol 2015;33:

48 Host Pharmacogenetics Affecting Leukemogenesis Polymorphisms of ARID5B (encoding transcription factors important in embryonic development and cell growth regulation) and IKZF1 associated with the development of ALL IKZF1 ARID5B Trevino et al. Nat Genet 2009;41:101-5; Papaemmanuil et al. Nat Genet 2009;41:

49 ARID5B Genetic Polymorphisms Contribute to Racial/Ethnic Difference in the Incidence of Childhood ALL Frequency of the Risk Allele at rs % 60% 50% 40% 30% 20% 10% 0% Non-ALL controls ALL cases 18% 33% * 33% 48% 47% 62% Black White Hispanic N=112 N=93 N=1046 N=978 N=541 N=330 P= P=8.38x10-20 P=1x10-6 ALL Incidence (per million person-years) Black White Hispanic Frequency of the risk allele of ARID5B SNP (rs ) increases in order for Blacks, Whites and Hispanics, consistent with the racial differences in ALL incidence. Xu et al., J Clin Oncol 2012;30:751-7

50 BMI1-PIP4K2A SNPs Contribute to Racial/Ethnic Differences in Childhood ALL Incidence Cancer Jan 15;112(2): The frequency of the BMI1-PIP4K2A variant increases in the order of African, European, and Hispanic Americans, in parallel with racial differences in ALL incidence. Xu et al. J Natl Cancer Inst 2013;105:733-42

51 GATA3 SNP Genotype Associated With Ph-like ALL GATA3 P=2.17x Log 10 (P value) P= P=4.94x10-12 Perez-Andreu V et al., Nat Genet. 45:1494, 2013

52 GATA3 SNP Genotype Associated with ALL Relapse P=0.002 COG P9906 P=0.007 COG P9905 (N=28) AA (N=52) AC (N=287) (N=94) CC (N=438) (N=89) Years A allele was associated with higher risk of relapse A allele was associated with poorer early response (i.e., higher MRD at the end of induction therapy) Perez-Andreu V et al., Nat Genet. 45:1494, 2013

53 GATA3 Risk Variant Frequency Varied Among Worldwide Populations 52%, Native Americans Allele frequency at GATA3 SNP (%) 14%, Europeans 27%, Chinese 40%, Hispanics Perez-Andreu et al., Nat Genet 2013; 45:1494-8

54 GATA3 SNP Genotype Associated with ALL Genetic Subtypes in Adolescents and Young Adults with ALL Perez-Andreu et al. Blood 2015;125:680-6

55 Inherited Gene Variants Associated with the Development of Childhood ALL* Gene Odd Ratio 95% CI Comment IKZF Associated with B- and T-ALL ARID5B Associated with hyperdiploid ALL: Hispanics>Whites>Blacks CEBPE 1, Associated with B- and T-ALL CDKN2A Associated with B- and T-ALL BMI1-PIP4K2A 5, Hispanics>Whites>Blacks GATA3 6, Associated with Ph-like ALL and risk of relapse TP63, PTPRJ Associated with ETV6-RUNX1 ALL 1 Papaemmanuil et al, Nat Genet 2009; 2 Trevino et al, Nat Genet 2009; 3 Prasad et al, Blood 2010; 4 Sherborne et al, Nat Genet 2010; 5 Xu et al, J Natl Cancer Inst 2013; 6 Migliorini et al, Blood 2013; 7 Perez-Andreu et al, Nat Genet, 2013; 8 Ellinghaus, Leukemia 2012

56 ARID5B, IKZF1, CEBPE, and BMI1-PIP4K2A variants Cumulatively Conferred Predisposition to ALL Those with 6 risk alleles were at 9-fold higher risk than subjects with 0 1 copies Xu et al J Natl Cancer Inst 2013;105:733-42

57 Germline Mutations and ALL Risk TP53 in 50% low-hypodiploid ALL PAX5 G183S mutations in familial ALL Shah et al. Nat Genet 2013;45: ETV6 mutations in familial thrombocytopenia and hematopoietic malignancy Zhang et al. Nat Genet 2015;47:180-5 Noetzli et al. Nat Genet 2015;47:535-8 Topka et al. PLOS Genet 2015;11:e Moriyama et al. Lancet Oncol, 2015;16:

58 Inherited TP53 mutation in a low-hypodiploid ALL kindred Child: low hypodiploid ALL Father: glioblastoma multiforme p.gly302fs Homozygous in tumors Heterozygous skin biopsy TP53 immunoreactivity in glioblastoma multiforme Holmfeldt et al. Nature Genet;2013:45:242-52

59 31 ALL-related Germline ETV6 Variants in 0.8% of ALL Patients PNT ETS ALL-related variants Common variants 31 exonic variants (4 nonsense, 21 missense, 1 splice site, and 5 frameshift) were identified as potential ALL related total in 35 cases (0.79% in studied cases) 48% of the variants were clustered in ETS domain Moriyama et al., Lancet Oncol 2015;16:

60 Germline Mutations of Cancer Predisposition Genes in Children with leukemia Whole-genome or whole-exome sequencing or both of remission bone marrow or blood sample 567 genes were selected for in-depth analysis based on their associated inheritance patterns, associated syndromes, penetrance, de novo mutation rate, etc. Germline mutations involved in 26 of 588 leukemia patients (4.4%) vs. 1.1% in 1000 Genome Project and 0.6% in Autism study Hypodiploid ALL has the highest rate of germline mutation (TP53) 9 of 47 cases (19%); 53% among low-hypodiploid cases. Panel of genes associated with ALL: ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72, TERC, TERT, TP53 Zhang et al. N Engl J Med 2015;373:

61 Future Perspective No patients with ALL will require prophylactic nor therapeutic irradiation. Driver genetic mutations and leukemia-associated lesions targetable with molecular, immunologic or cellular therapeutics will be identified in all patients. Precision medicine will be based on leukemia cell characteristics and host pharmacogenetics/pharmacokinetics as well as minimal residual disease level. Conventional chemotherapy will be gradually replaced by targeted therapy.

62 Ultimate Goals Push the cure rate toward 100% Shorten duration of curative treatment (remission induction and consolidation) to 3 months or less Devise strategies to reduce the risk of leukemia development

63 Members of Leukemia Team