Treatment of High-risk Acute Lymphoblastic Leukemia With Precision Medicine

Transcription

1 Treatment of High-risk Acute Lymphoblastic Leukemia With Precision Medicine

2 Minimal Residual Leukemia Level: Independent 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

3 Clinical Application of MRD Measurement Predictive value of MRD depends on timing of measurement, leukemia subtype, and preceding and subsequent treatment. Negative MRD after exposure to only a few drugs during early remission induction (<2 weeks) confers outstanding outcome, and treatment intensity could be reduced in latter part of induction to decrease morbidity and mortality in these patients. All childhood cases require at least a course of reinduction or delayed intensification. Patients with TEL-AML or hyperdiploidy (56 to 67 chromosomes) and achieving early negative MRD status may receive low intensity postremission therapy subsequently. High level or persistent MRD after consolidation therapy denotes high risk of relapse. However, effective postremission therapy may cure certain patients without transplant, e.g., high-dose methotrexate for hyperdiploid>50 ALL, cyclophosphamide+cytarabine+mercaptopurine for early T-cell precursor ALL.

4 AIEOP-BFM-ALL 2000: Increased Relapse After Lowering Intensity of Delayed Intensification in Standard-risk Patients with Negative MRD After Remission Induction 4741 pediatric patients with standard-risk ALL and negative MRD on days 33 and 78 after the start of remission induction Randomized to receive standard protocol II (49 days) vs. protocol III (29 days with 30% less dexamethasone and 50% less vincristine, doxorubicin, and cyclophosphamide) for delayed reintensification The 4-year cumulative risk of relapse was 3.2%±0.7% and 6.3%±1.0% for patients treated with protocol II and protocol III, respectively (p=0.09) The 8-year DFS was 92.3%±1.2% and 89.2%±1.3% for patients treated with protocol II and protocol III (p=0.04), and the 8-year survival was 98.0%±0.6% and 96.1%±0.8%, respectively. Schrappe et al ASH

5 Among Patients with Negative Day 19 MRD, only t(12;21) and hyperdiploid >50 Cases Are Good 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 2017;34:333-9

6 Driver Genetic Mutations Identified in All Patients with Acute Lymphoblastic Leukemia D DUX4 D / Pui, Mullighan et al. J Clin Oncol 2015;33: , Zhang et al. Nature Genet 2016;48:1481-9

7 Ph-like or BCR-ABL1-like ALL BCR-ABL1 (Ph+) ALL: Alteration of IKZF1 (IKAROS), poor outcome Ph-like ALL: gene expression profile similar to Ph+ ALL but BCR-ABL negative Alteration of IKZF1, poor outcome RNA-seq identified ABL1, JAK2, PDGFRB, EPOR rearrangements in 15 cases Ph-positive Ph-like Ph-like Den Boer Lancet Oncol 2009; Mullighan NEJM 2009; Roberts Cancer Cell 2012

8 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 yrs Young adult yrs Total Ph+ 1.3% 4.1% 6.0% 23.0% Ph-like 10.8% 13.7% 21.1% 27.3% Roberts, NEJM 2014;371:1005

9 Prevalence of Ph-like ALL by Age Den Boer Lancet oncol 2009, Mullighan NEJM 2009, Roberts NEJM 2014, Roberts JCO 2016

10 Ph-like ALL in HOVON study 17% Ph-like ALL among 127 ALL patients aged 16 to 71 years. None of the 21 Ph-like ALL tested had fusions involving JAK2, ABL1, ABL2, PDGFRB, CSF1R, IL2RB, NTRK3, TSLP, or TYK2. Induction failure occurred in 29% Ph-like ALL vs 6% other B-ALL (P=0.003). The cumulative risk of relapse was highest and the event-free survival was lowest in Ph-like ALL. 1 of 5 Ph-like ALL patients treated with allogeneic transplant vs. 9 of 10 Ph-like ALL patients treated with chemotherapy relapsed. Boer T et al. Haematologica July :e261-e264

11 HOVON-18 & 37: Event-free Survival According to Genotypes Boer et al Haematologica 2015;100:e261

12 Ph-like ALL identified in two German reference laboratories 12.6% Ph-like ALL among 207 B-ALL patients years old. Ph-like ALL was associated with alterations of IKZF1, CRLF2, JAK2, BTG1 Ph-like ALL patients were less likely to attain molecular remission (33% vs. 79%, P=0.02), and had inferior 5-year survival (22% vs. 64%, P=0.006) compared to other B-ALL patients. Among Ph-like ALL patients, relapse occurred in only 1 of 4 attained molecular remission but in 7 of 8 without molecular remission (P=0.02); one of 3 transplanted patients remained in remission. Herold T et al. Haematologica 2017:102:130-8

13 Treatment Outcome of Ph-like ALL by Age Group Pui et al. Clin Lymphoma, Myeloma and Leuk ( in press)

14 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 & Pui et al J Clin Oncol 2014;32:

15 No Difference in EFS and Survival Between Ph-like ALL and other B-ALL By Risk Group With MRD-directed Treatment 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 & Pui et al J Clin Oncol 2014;32:

16 Frequency of Genetic Subtypes in Ph-like ALL by Age Group Pui et al. Clin Lymphoma, Myeloma and Leuk (in press)

17 Kinase Rearrangements and Therapeutic Targets in Ph-like ALL Mullighan et al, unpublished data

18 Comparisons of Gene Pathways Between Adult and Pediatric B-ALL Liu et al. EBioMedicine 2016;8:173-83

19 ZNF384-related Gene Fusions 4.0% pediatric and 7.3% adult B-ALL High frequency of CD10-negative phenotype compared to other B-ALL (19% vs 3% in pediatric and 16% vs 5% in adult). High frequency of expression of myeloid-associated antigens CD13 and CD33 compared to other B-ALL (12% vs 2% in pediatric and 13% vs 0% in adult) 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 among pediatric and 40% vs 30% among adult patients) Liu et al. EBioMedicine 2016;8:173-83

20 MEF2D-related Gene Fusions 3.5% pediatric and 6.8% adult B-ALL Pediatric patients tended to be older (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 among pediatric and 16% vs 31% among adult patients) 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:

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

22 Early T-cell Precursor ALL Immature phenotype (CD1a-, CD5 dim/neg, CD8-, myeloid/stem cell +) Distinct gene expression profile Genomic instability; activating mutations of genes regulating cytokine receptor and RAS signaling; inactivating mutations of histone modifying genes Poor early response with high MRD level at the end of remission induction Coustan Smith et al Lancet Oncol 10:

23 Treatment outcome of Early T-cell Precursor ALL Protocol Phenotype Steroid Daunorubicin Cyclo/ara-C 5y-EFS 5y-OS AIEOP-BFM2000 non-etp Pred 60mg or dex 80.8% 92.0% 10 mg/m 2 25mg/m 2 x2 2 courses ETP 86.2% at 3y 86.2% at 3 y St. Jude Total XVI non-etp 86.4% 91.3% Pred 40mg/m 2 25mg/m 2 x2 1 course ETP 71.4% 85.7% UKALL2003 non-etp 84.6% 90.9% Dex 6mg/m 2 25mg/m 2 x4 2 courses Probable ETP 76.7% 82.4% non-etp 86.9% 92.0% COG AALL0434 near-etp Pred 60mg/m 2 25mg/m 2 x4 2 courses 84.4% 91.6% ETP 87.0% 93.0% Conter et al. Lancet Hematol 2016;3:e80-6; Wood et al, Blood 2014, 124: abst 1; Patrick et al, BJH 2014; 166:421-24

24 Overall Survival According to Genetic Abnormality Among Patients with Induction Failure Schrappe M et al. N Engl J Med 2012;366:

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

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

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

28 Novel Therapies For B-ALL Under Investigation Molecular therapy: ABL1 tyrosine kinase inhibitors (dasatinib, bosutinib, ponatinib) for Ph + or Ph-like ALL with the ABL-class fusion; Bcl-2 inhibitors (venetoclax, navitoclax) for MLL-rearranged ALL; JAK inhibitor (ruxolitinib) for Ph-like or JAK-dependent ALL; bortezomib for refractory 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

29 Novel Therapies For T-ALL Under Investigation Molecular therapy: ABL1 tyrosine kinase inhibitors (dasatinib, bosutinib, ponatinib) for NUP-214-ABL1; Bcl- 2 inhibitors (venetoclax, navitoclax) for ETP; JAK inhibitor (ruxolitinib) for ETP or JAK-dependent ALL; bortezomib for refractory ALL; Notch inhibitor (LY ) for refractory ALL Antibody therapy: anti-cd38 (Daratumumab) for refractory ALL Cell therapy: CD7 CAR T cells for refractory ALL

30 Cellular- and Immuno-therapy for patients with MRD positive disease Chimeric antigen receptor T cells Phase I/II CTL019 (n=60) 56 (93%) CR; 52 (93%) MRD-negative Maude ASCO 2016 abst 3011 US Multicenter CTL019 (n=35) 20 (57%) CR; 18 (90%) MRD-negavie Maude ASH 2016 abst 2801 Blinatumomab (BITE) Phase I/II (n=70) 27 (39%) CR; 14 (52%) MRD negative Von Stackelberg JCO 2016;34:4381 Maude SL, NEJM 2014; Topp MS Lancet Oncol 2015

31 Phase I/II Study of Blinatumomab (anti-cd19) in Relapsed/Refractory Pediatric ALL Based on Phase I data (n=49), recommended dose for Phase II study was 5 µg/m2/day for 7 days followed by 15 µg/m2/day for 21 days. Among 70 patients treated with recommended dose, 27 (39%) achieved CR within the first two cycles, 14 (52%) of whom achieved MRD negative status. Grade 3 adverse events: anemia (36%), thrombocytopenia (21%), and hypokalemia (17%), and cytokine-release syndrome (5%). Two patients (3%) had grade 2 seizures. Von Stackelberg et al. J Clin Oncol 34:4381-9

32 Relapsed-free Survival of the 27 Completed Responders* *13 (48%) received subsequent transplant Von Stackelberg et al. J Clin Oncol 34:4381-9

33 Overall Survival: Blinatumomab vs. Standard Chemotherapy in Adults with Relapsed or Refractory ALL Kantarjian et al. N Engl J Med 2017;376:836-47

34 Overall Survival With or Without Censoring of Allogeneic Transplantation Following Blinatumomab Treatment in Patients with Relapsed or Refractory Ph+ ALL Progressed After TKI-based Therapy (including ponatanib in 51% of patients) 36% (16/45) patients achieved CR/CRh; 88% of responders achieved MRD-negative status; 7 responders proceeded to transplantation. Martinelli et al. J Clin Oncol 2017 March 29 [Epub ahead of print]

35 Duration of Remission in Adults with Relapsed/Refractory ALL: Inotuzumab (anti-cd22) vs. Standard Therapy Kantajian et al. N Engl J Med 2016;375:740-53

36 Hematological relapse-free survival after blinatumomab therapy in adults with B-ALL and persistent or recurrent MRD disease Gökbuget et al. Haematologica 2017 Jan 12 [Epub ahead of print]

37 Ponatinib Yielded Better Result than Dasatinib in Adults With New Diagnosed Ph+ ALL Treated with Hyper-CVAD Regimen Sasaki et al. Cancer 2016;122:3650-6

38 Rituximab improved outcome of Young Adults (18 to 59 Years) With CD20-positive, Ph-negative Newly Diagnosed B-ALL Maury S et al. N Engl J Med 2016;375:

39 Maude S

40 Schematic Representation of Chimeric Antigen Receptor (CAR) Structure Dai et al JNCI 2016;108:djv439

41 CAR T Cell Therapy for Refractory/Relapsed Pediatric ALL (N=30) We hope we can decrease the use of transplantation. Results confirmed by US multicenter trial (ENSIGN) and Global trial (ELIANA): 2016 ASH abstracts #2801 and #221 Maude AL et al, N Engl J Med 2014;371:

42 Overall Survival of 60 Patients Treated in Phase I/II CTL019 93% (56/60) achieved CR at day 28; MRD negative in 52 patients; 100% CNS remission 24 patients in continuous remission 1 year, 19 without further treatment; 7 proceeded to transplant Maude et al. ASCO Abstract 3011

43 CTL019: US Multicenter Trial in Pediatric Relapsed/Refractory ALL Of 35 patients enrolled, 29 (83%) infused (2 manufacturing failures, 4 deaths) CR achieved in 20/29 patients (69%) MRD negative CR achieved in 18/29 (62%) patients Maude et al ASH 2016 Abstract 2801

44 Global Registration Trial of CTL019 in Pediatric and Young Adults with Relapsed/Refractory ALL 57 patients enrolled (15 pending infusion) in 25 centers in US, Europe, Australia and Japan 34/42 (81%) patients were infused (3 manufacturing failures, 5 not infused due to death or adverse events) 24/29 patients (84%) reached day 28 achieved CR or CRi Grade 3/4 toxicities: 45% cytokine release syndrome, 21% neuropsychiatric events, 29% febrile neutropenia, 21% hypotension, 21% increased AST, 21% increased bilirubin Grupp et al 2016 ASH abstract #221

45 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

46 Cloforabine (40 mg/m 2 ) + Cyclophosphamide (440 mg/m 2 ) + Etoposide 100 mg/m 2 ) daily for 5 days in Chinese Children with Relapsed or Refractory ALL 13 patients with refractory disease at diagnosis or relapse; median prior regimens was 2 (range, 1 to 4) Among 9 B-ALL, 2 achieved CR, 2 CRi, and 1 PR, and among 4 T-ALL, 3 attained CR and 1 PR. Eight of 9 responders bridged to hematopoietic cell transplantation; 4 remained alive in remission. All patients had febrile neutropenia or sepsis, and 31% had grade 3 hepatoxicity Liu et al. Ann Hematol 2016;95:501-7

47 Survival After Bridging Therapy with Cloforabine + Cyclophosphamide + Etoposide to Transplant in Chinese Patients with Relapsed/ Refractory ALL Liu et al. Ann Hematol 2016;95:501-7

48 Clofarabine in Combination With Mitoxantrone, Etoposide, Asparaginase and Dexamethasone in Pediatric ALL in Early Relapse Escalating dose of clofarabine (25% increments from 20 to 40 mg/m 2 /day for 5 days) with fixed doses of mitoxantrone, etoposide, asparaginase and dexamethasone Maximal tolerated dose was 32 mg/m 2 in 19 evaluable patients Of 19 evaluable patients, 11 (58%) achieved CR, of whom 6 proceeded to transplant, and 5 were alive for 16+ to 39+ months Nelken et al. Pediatr Blood Cancer 2016;63:270-75

49 Overall Survival of the 19 Patients Treated with VANDEVOL Regimen Nelken et al. Pediatr Blood Cancer 2016;63:270-75

50 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

51 Germline Mutations and ALL Risk TP53 in 50% low-hypodiploid ALL Holmfeldt et al. Nat Genet 2013;45: 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:

52 Future Perspective of Precision Medicine Precision medicine should be based on leukemia characteristics, host pharmacogenetics, treatment response, and availability of targeted therapy. Conventional therapy will be gradually replaced by targeted therapy, including antibodies, kinase inhibitors, and cellular therapy.