This activity is jointly sponsored by Robert Michael Educational Institute LLC and Postgraduate Institute for Medicine, and is supported by an

Transcription

1 This activity is jointly sponsored by Robert Michael Educational Institute LLC and Postgraduate Institute for Medicine, and is supported by an educational grant from Enzon Pharmaceuticals.

2 Disclosure of Conflicts of Interest Charles A. Schiffer, MD Dr. Charles A. Schiffer has no affiliations with commercial interests to disclose. Faculty Charles A. Schiffer, MD (Moderator) Professor of Medicine and Oncology Wayne State University School of Medicine and Karmanos Cancer Institute Detroit, Michigan Deborah Thomas, MD Associate Professor University of Texas MD Anderson Cancer Center Houston, Texas Dan Douer, MD Associate Professor of Hematology University of Southern California Los Angeles, California Lewis Silverman, MD Assistant Professor of Pediatrics Harvard Medical School Dana-Farber Cancer Center Boston, Massachusetts Stephen Hunger, MD Ergen Family Chair in Pediatric Cancer and Director, Center for Cancer and Blood Disorders Chief, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation Professor of Pediatrics, University of Colorado School of Medicine The Children's Hospital Aurora, Colorado

3 Philadelphia Chromosome Positive (Ph+) Acute Lymphocytic Leukemia (ALL): A New Era of Treatment Challenges Deborah A. Thomas, MD Associate Professor Department of Leukemia University of Texas MD Anderson Cancer Center Houston, Texas Disclosure of Conflicts of Interest Deborah A. Thomas, MD Dr. Deborah A. Thomas has affiliations with Bristol-Myers Squibb, Hana Biosciences, Inc., and Novartis (Honoraria); and Amgen Inc. and Hana Biosciences, Inc. (Research Funding).

4 Philadelphia-Positive (Ph+) ALL t(9;22) or bcr-abl in 20% 30% adults with ALL p190 bcr-abl in 70%, p210 bcr-abl in remainder CD10+ B-lineage (CALLA, pre-b) Frequent coexpression of CD13 and CD33 Distinguish from bilineage leukemia Myeloperoxidase negative C-kit negative Increased incidence with older age Over 50% for age > 50 years Outcome in Adult Ph+ ALL Chemotherapy in the Pre-Imatinib Era Study Year No. % CR % Survival (X yrs) Bloomfield * Gotz * Larson (3) Secker-Walker (3) Wetzler (5) Faderl * Dombret (3) Gleissner (3) Cimino (7) *Median survival in months. Hyper-CVAD.

5 Single Agent Imatinib in Relapsed/Refractory Ph+ ALL and CML-LBP % Response ALL (n=48) CML-LBP (n=8) All Sustained All Sustained Overall CR Marrow CR Marrow PR %CG CR TTP (mo) 2.2 NA Survival (mo) Ottmann OG, et al. Blood. 2002;100: Philadelphia Positive (Ph+) ALL: Challenges Optimizing frontline therapy Tyrosine kinase inhibitor (TKI) alone? Combination chemotherapy + TKI? Which TKI? Treatment of the elderly Circumventing mechanisms of resistance ABL TK domain mutations (T315I) Other mechanisms Allogeneic stem cell transplant (SCT)

6 Imatinib + Chemotherapy for De Novo Adult Ph+ ALL: Regimens Concurrent induction and consolidation Hyper-CVAD + imatinib (Thomas et al.) PETHEMA (Ribera et al.) Concurrent induction, alternating consolidation JALSG ALL202 (Yanada et al.) After induction, alternating consolidation Hyper-CVAD (Lee et al.) GRAALL AFR09 (Delannoy et al.) GMALL 06/99 (Wassmann et al.) After induction, concurrent consolidation AFR03 HAM + imatinib (Dombret et al.) GMALL 07/03 (Wassmann et al.) GMALL (Ottmann et al.) After consolidation only GIMEMA LAL0201 (Vignetti et al.) Imatinib + Hyper-CVAD in Ph+ ALL Intensive phase Maintenance phase 12 mos 12 mos Hyper-CVAD MTX-cytarabine Imatinib Vincristine + prednisone Thomas DA, et al. Blood. 2004;103:

7 Imatinib + Hyper-CVAD in Ph+ ALL: Induction Response (n=54) Category No. CR/Total %CR De Novo 36/39 92 Primary refractory 6/6 100 CR at start 9 Molecular CR (nested PCR for BCR-ABL) in 58% Failures: 1 CRp, 1 PR, 1 early death (sepsis) Thomas DA, et al. ASH Survival in in De De Novo Groups by by Regimen 0.8 Hyper-CVAD + imatinib Hyper-CVAD No. No. Fail P<0.001 p< Median follow-up 4 years (range, 13 to 78 mos) Thomas DA, et al. ASH Months

8 Remission Duration by Therapy Hyper-CVAD + imatinib Hyper-CVAD No. No. Fail p<.001 P< Thomas DA, et al. ASH Months Imatinib-Based Chemotherapy Regimens for De Novo Ph+ ALL Regimen No. %CR %Rel Age > 15 years %DFS (X yrs) %OS (X yrs) Hyper-CVAD (4) 55 (4) Adults age < 65 years JASALG ALL (1) 76 (1) GMALL Alternating Concurrent NA NA NR NR 52 (2) 61 (2) 36 (2) 43 (2) GRAAPH (1.5) 65 (1.5) Thomas DA, et al. ASH Yanada M, et al. J Clin Oncol. 2006;24: Wassmann B, et al. Blood. 2006;108: de Labarth A, et al. Blood. 2007;109:

9 Imatinib Concurrently vs Alternating With Chemotherapy for Ph+ ALL Sequential GMALL Protocols 06/99 or 07/03 Imatinib alternating or concurrent PCR negativity 52% for concurrent, 19% for alternating Failures to induction had similar outcome after concurrent consolidation as CRs Higher incidence of cytopenias and transient hepatotoxicity with concurrent therapy Rates of SCT similar in both regimens Wassmann B, et al. Blood. 2006;108: De Novo Ph+ ALL: GRAAPH of 118 younger than 60 years evaluable 7-day prednisone prephase, randomization Imatinib (800), VCR, dexamethasone (A) Imatinib + hyper-cvad (B) 100% CR arm A, 95% arm B Arm B superior in clearing MRD by PCR 67% allogeneic SCT (18% autologous) OS 62% arm A, 54% arm B, 29% LALA-94 Median follow-up 13 mos, 18 (22%) relapsed Chalandon Y, et al. ASH Abstract 12.

10 Imatinib-Based Regimens for De Novo Elderly Ph+ ALL (Age >55) Regimen No. %CR %Rel GMALL Chemotherapy Imatinib %DFS (X yrs) 29 (1.5) 57 (1.5) %OS (X yrs) 35 (1.5) 41 (1.5) GIMEMA (1) 74 (1) GRAALL AFR (1) 66 (1) Ottmann OG, et al. Cancer. 2007;109: Vignetti M, et al. Blood. 2007;107: Delannoy A, et al. Leukemia. 2006;20: Mechanisms of Resistance to Imatinib Single point mutation ATP binding site (e.g., T315I), P-loop or activation loop Amplification of BCR-ABL fusion gene Upregulation of BCR-ABL transcription Increased imatinib efflux Decreased cellular bioavailability BCR-ABL independence (SRC) Hofmann WK, et al. Blood. 2002;99: Hofmann WK, et al. Lancet. 2002;359:

11 Resistance to Imatinib: Tyrosine Kinase Domain (TKD) Mutations Direct Contact 1. T315I 2. F F359 P-loop 4. M G Q Y E255 Activation loop 9. M E V L H396 ABL TKD Mutations in De Novo Ph+ ALL TKD mutation detected prior to therapy in 41% (T315I in 17%) No association pretreatment parameters No difference CR rate, molecular CR rate or remission duration compared with unmutated Frequency of mutant allele <2% Concordance at diagnosis and relapse Pfeifer H, et al. Blood. 2007;110:

12 TKD Mutations in Ph+ ALL Incidence and kinetics of ABL KD mutations in de novo and recurrent disease after imatinibbased chemotherapy or monotherapy De novo % (No./Total) Advanced % (No./Total) Pre-imatinib 31 (9/29) 33 (21/63) Post-imatinib 84 (22/26) 70 (33/50) TKDM at relapse P-loop T3151 A-loop Pfeifer H, et al. ASH Abstract 10. Dasatinib for Imatinib-Resistant Ph+ ALL Dual Src/Abl inhibitor 325-fold more potent than imatinib in vitro 30- to 50-fold more potent in vivo In vitro efficacy against imatinib-resistant KD mutations, except T315I or F317L Phase I 80% hematologic responders Phase II START (Src/Abl Tyrosine Kinase Inhibition Activity: Research Trials of Dasatinib) Talpaz M, et al. N Engl J Med. 2006;354:

13 Phase II Dasatinib: Imatinib Resistant or Intolerant Ph+ ALL International START-L CA Study Parameter Response (%) Major HR CHR NEL Ph ALL (n=36) 15 (42) 11 (31) 4 (11) No. CGCR (%) 21 (58) PFS (mos) 3.1 Toxicities: diarrhea, N/V, peripheral edema; 12% pleural effusions Ottmann H, et al. Blood. 2007;110: Dasatinib + Hyper-CVAD in Ph+ ALL De novo Ph+ ALL (n=28) Median age 52 yrs (21 79); 57% > 50 yrs CR rate 93%; 2 induction deaths (sepsis) Early molecular CR rate 50% Median follow-up 10 mos (2 21) 5 (19%) relapsed (3 T315I, 1 F359V) weeks Toxicity 2 deaths in CR (1 cardiac, 1 infection) GI bleeding (n=8), pleural effusions (n=3), subdural hematomas (n=2) Ravandi F, et al. ASH Abstract 2921.

14 Dasatinib for De Novo Ph+ ALL GIMEMA LAL 1205 untreated Ph+ ALL Dasatinib 70 mg twice daily until day 84 + prednisone 60 mg/m 2 days -7 to day 31 IT methotrexate days 22, pts, median age 54 yrs (24 76) 34 evaluable, 100% CHR (94% by day 22) Median follow-up 11 months; 9 (26%) pts relapsed (5 with T3151, 1 with E255K) Degree of decrease PCR < 10-3 prognostic Foà R, et al. ASH Abstract 305. Dasatinib + Chemotherapy (EWALL-Ph-01) for De Novo Elderly Ph+ ALL Dasatinib 140 mg daily Dexamethasone pre-phase, concurrently MTX, asparaginase, HD cytarabine 22 pts, median age 71 yrs (61 83) 95% CHR (28% MCR) Median follow-up, 5.8 months; 1 relapse Rousselot P, et al. ASH Abstract 2920.

15 Nilotinib for Imatinib-Resistant Ph+ ALL Aminopyrimidine derivative of imatinib Inhibits c-kit and PDGFR like imatinib 20- to 50-fold more potent, active in imatinibresistant cell lines Resistance screening low mutation rate Phase II trial of nilotinib 400 mg twice daily, escalation to 600 mg 41 pts, median age 46 years (18 75) CR in 24% Ottmann O, et al. ASH Abstract ABL TKD Mutations: Sensitivity to TKIs

16 SCT in First CR for Adult Ph+ ALL: Pre-Imatinib Era UKALL XII/ECOG E2993 (n=167) 5-yr Chemotherapy/Autologous SCT Allogeneic SCT Relapse risk EFS OS LALA-94 (n=154) SCT improved DFS, overall survival Achievement PCR negativity for bcr-abl favorable Relapse is primary cause of treatment failure Eligibility for SCT limited by availability of suitable donor, comorbidities, need to maintain CR Goldstone AH, et al. Blood. 2001;98:856a. Dombret H, et al. Blood. 2002;100:

17 Imatinib + Hyper-CVAD in Ph+ ALL: Outcome After CR [No. molecular CR] Chemo (n=35) [14] CR (n=51) SCT (n=16) [2] CCR (n=16) [8] Deaths in CR (n=10) [3] Relapse (n=9) [3] CCR (n=10) [2] Deaths in CR (n=4) [0] Relapse (n=2) [0] 7 infection; 1 pancreatitis, 1 CNS hemorrhage; 1 unknown 2 infection; 2 GVHD Thomas DA, et al. ASH Survival by by Allogeneic SCT in in First First CR CR Custom Text No. No. Fail Yes 16 7 No Median time to SCT 5 mos (range, 1 13) 1-13) Thomas DA, et al. ASH Months

18 1.0 Survival by Allogeneic SCT SCT After After Hyper-CVAD Hyper-CVAD and Imatinib and Imatinib (De (De Novo Novo Group) Group) No. No. No. No. Fail Fail Median Median age (range) age (range) 0.2 Yes ( ) (17 60) p=.09 P=0.09 No ( ) (27 84) Median time to SCT 5 mos (range, 1-13) Thomas DA, et al. ASH Months 1.0 Survival Survival by by Age Age After Hyper-CVAD and and Imatinib Imatinib (De (De Novo Group) No. No. Fail No. Rel. No. SCT < P=0.02 p=.02 > Thomas DA, et al. ASH Months

19 Allogeneic SCT in Ph ALL MRC UKALL XII/ECOG E2993 Ph ALL aged < 55 in CR after induction therapy (n=919) High-dose methotrexate (3 courses) HLA-matched sibling donor available? High-dose methotrexate (3 courses) Sibling allogeneic SCT (n=389) Autologous BMT (n=530) Consolidation/maintenance chemotherapy 2.5 years Rowe et al. ASH Abstract 2. Imatinib + SCT in Ph+ ALL UKALLXII/ECOG2993 Induction (2 phases) then high-dose MTX intensification Allogeneic SCT (etoposide/tbi) with either MRD or MUD Imatinib No. %CR %SCT %Survival None Post-induction Phase 2 induction } Fielding et al. ASH Abstract 8.

20 Imatinib After Allogeneic SCT: Adult Ph+ ALL Imatinib 400 mg if PCR+ for bcr-abl (n=27) Detected earlier post-sct if positive prior to SCT 52% undetectable within median 6 weeks Continued CR if sustained If MRD persisted for 6 12 weeks High incidence relapse (92%) Donor lymphocyte infusions ineffective Molecular relapse when imatinib discontinued Wassmann B, et al. Blood. 2005;106: Future Directions in Ph+ ALL Optimize frontline chemotherapy TKI therapy clearly indicated Concurrent appears superior for imatinib Further explore mechanisms of resistance TKIs that circumvent T315I Resistance without ABL mutations Novel agents, e.g., HSP90 or histone acetylase inhibitors Role of allogeneic SCT in first CR Risk stratification? TKI maintenance therapy

21 Panel Discussion Current and Future Treatment Options for Adult Acute Lymphoblastic Leukemia Dan Douer, MD Associate Professor of Hematology University of Southern California Norris Cancer Center Los Angeles, California

22 Disclosure of Conflicts of Interest Dan Douer, MD Dr. Dan Douer has an affiliation with Enzon Pharmaceuticals (Speakers Bureau and Contracted Research). Principles of Current Adult ALL Protocols (All Include Maintenance and Central Nervous System Prophylaxis) BFM-based Induction Phase 1 (4 weeks): vincristine, prednisone, daunorubicin, asparaginase (VPDA) Induction phase 2 (4 weeks): cyclophosphamide, cytarabine (ara-c), 6-mercaptopurine Consolidation Cycles of intensive multi-agent chemotherapy (most include asparaginase with delayed reinduction) Hyper-CVAD (alternate parts A and B 4) Part A: dexamethasone, vincristine, doxorubicin (CI), cyclophosphamide Part B: High-dose methotrexate (MTX) + ara-c No asparaginase Others Induction: VPDA Consolidation BFM=Berlin-Frankfurt-Munich. Gökbuget N, Hoelzer D. Hematology Am Soc Hematol Educ Program. 2006;

23 Large Adult Clinical Trials Years of Study N Age Treatment No asparaginase in induction, only in consolidation CR (%) DFS (%) SWOG VPA + con 6 (A 6 doses) SWOG 8471* VPA + con 6 (A 6 doses) >15 62 SWOG 8419* VPA + con 6 (A - Capizzi) 25 Asparaginase in induction only GMALL 02/ BFM GIMEMA 0288* VPDA ± Cy MRC-UKALL XA >15 VPDA + early intensification Hussein KK, et al. Blood. 1989;73: Petersdorf SH, et al. Leukemia. 2001:15: Hoelzer D, et al. Blood. 1988;71: Annino L, et al. Blood. 2002;99: Durant IJ, et al. Br J Haematol. 1997;99: *Randomized. Large Adult Clinical Trials Years of Study N Age Treatment Asparaginase in induction plus consolidation GMALL 05/93 1 BFM, high-dose ara-c, high-dose MTX CR (%) DFS (%) CALGB BFM, Cy, ASP CALGB BFM, Cy, DNR MRC/ECOG- UKALLXII/E2993* BFM + high-dose MTX ± SCT 90 OS 39 UCSF VPDA + intensified No Asparaginase Hyper CVAD 6 Cy, D, AD, high-dose MTX, high-dose ara-c 1. Gökbuget N, et al. Blood. 2001;98:802a. 2. Larson RA, et al. Blood. 1995;85: Stock W. Blood. 2005;106:521a [abstract1833]. 4. Goldstone AH. Blood. 2008;111: Linker C, et al. J Clin Oncol. 2002;20: Kantarjian H, et al. Cancer. 2004;101: *Randomized Single institution.

24 Strategies to Improve Outcome of Adult ALL Should we transplant every Ph- ALL patient aged < years who has an HL-A identical sibling? Should we use a more intensive pediatric-like approaches (with more asparaginase)? Special subtypes Mature B cell ALL Ph+ ALL New drugs Overall Survival by Cytogenetic Subgroup of Patients Registered on MRC UKALLXII/ECOG 2993 Moorman AV, et al. Blood. 2007;109:

25

26 MRC UKALL XII/ECOG 2993 Overall Survival (Philadelphia Chromosome Negative [Ph ] Patients) Donor (Actual allo SCT 310) n=443 Donor % No Donor n= 558 (Off prot. CR 1 allo SCT 43) n=43 53% 45% No Donor P= Years Goldstone AH, et al. Blood. 2008;111: Stem Cell Transplantation MRC/ECOG UKALLXII/E2993 Trial Ph ALL Overall Survival Relapse Nonrelapse Death Donor No Donor Donor No Donor Donor No Donor High risk Standard risk 41% 35% 37% 63% 36% 14% NS P< P< % 52% 24% 49% 20% 7% P<0.02 P<0.05 P<0.05 Autologous SCT less favorable than consolidation/maintenance Goldstone AH, et al. Blood. 2008;111:

27 Pediatric Approaches in Adult ALL Most adult regimens are adopted from pediatric protocols but are used less intensively with less physician adherence to protocol than seen with pediatric teams (dose, timing) Adult protocols use lower doses and shorter duration of asparaginase therapy Adopt pediatric approach: Intensive therapy including longer asparagine depletion CALGB 9511: Peg-Asparaginase in Newly Diagnosed Adults Key effect: Asparagine depletion Depleted (n=63) Non-depleted n=22) Time (years) Wetzler M, et al. Blood. 2007;109:

28 Newly Diagnosed Pediatric ALL Randomized Trials of Prolonged Post-Remission Asparaginase Treatment* Consolidation (DFCI 77-01) 1 Consolidation 2 (DFCI 91-01) Maintenance 3 (BFM) Consolidation 4 (BFM CCG 1882) Consolidation 4 (BFM CCG 1991) None 25,000 IU/m 2 q wk 20 weeks 25,000 IU/m 2 q wk <25 weeks 25,000 IU/m 2 q wk >25 weeks None 25,000 IU/m 2 q wk 20 Standard BFM 36,000 IU/m 2 (1 cycle) Augmented BFM 318,000 IU/m 2 (5 cycles) Escherichia coli - ASP 6000 IU/m (1 2 cycles) PEG-ASP 2500 IU/m (4 7cycles) EFS 45% 70% 73% 90% 78% 87% 55% 75% *All patients received asparaginase during induction; EFS=event-free survival. 1. Sallan SE, et al. Cancer Res. 1983;43: (update courtesy of Dr. DeAngelo). 2. Silverman LB, et al. Blood. 2001;97: Pession A, et al. J Clin Oncol. 2005;23: Nachman JB, et al. N Engl J Med. 1998;338: Seibel NL, et al. Blood. 2008;111: P Value < % 81% < Asparaginase Doses (IU/m 2 ) Newly Diagnosed Adults With ALL Protocol ASP Form Induction Dose Consolidation Dose Cycles GMALL 02/84 GIMEMA 0288 MRC-UKALL XA E. coli 54,000 70, days 0 0 CALGB 8811 CALGB E. coli 36, (biw) 48, (biw) 2 2 UCSF 8707 E. coli 84, days 72,000 12,000 6 (tiw) 1 MRC/ECOG UKALLXII/E2993 E. coli 140,000 10, days 30,000 10,000 3 (2,9,23) 1 CALGB 9511 PEG doses Hyper-CVAD 7 N/A 0 0 0

29 GRAALL-2003 Protocol Pediatric Approach for Patients years More cumulative dose compared with historical trial LALA 94 Prednisone 9-fold Vincristine 4-fold E. coli asparaginase 4 yrs Total Ph patients % CI CR rate 93% EFS 55% 48% 62% Overall survival 58% 51% 65% Relapse 32% 26% 38% Death in CR 1 9% 6% 14% High-risk patients allo BMT: no difference, donor vs no donor Huget P, et al. ASCO Abstract DFCI Pediatric Approach for Patients years DFCI pediatric protocol intensified includes 30 weekly high-dose E. coli asparaginase Patients (N) 74 (Ph+ 8) Median Age, 28 years CR rate: 85% EFS (2-yr) 72% (95% CI: 52% 77%) DFS (2-yr) 76% (95% CI: 64% 90%) Overall Survival 73% (95% CI: 61% 85%) Median follow-up = 24.1 months (range, mos) DeAngelo DJ, et al. ASH Abstract 587.

30 USC Study Patients (N) 39 Median age, years (range) 33 (18 57) Median WBC 21,000 ( ,000) Immunophenotype Precursor B-cell 34 T-cell 5 Ph (+) 8 Latinos 33 (85%) CR 37 (95%) all after cycle 1 Douer D, et al. EHA Abstract 920.

31 USC Study Asparaginase-Related Grade 3 or 4 Toxicity 39 Patients % (N) 127 Doses % Hypersensitivity 0 0 Pancreatitis 13 (5) 4 DVT (SVC) 8 (3) 3 Elevated liver enzymes 59 (23) 30 Hyperbilirubinemia 18 (7) 8 Hyperglycemia 31 (12) 16 Fatigue 8 (3) 3 Hypertriglyceridemia 6 (3) 4 Douer D, et al. EHA Abstract 920. USC Study Patient Discontinuation (N=15) Reasons for Discontinuation Patients (N) BMT in first remission 7 Moved 1 Toxicity: Pancreatitis 5 (1 had BMT) Toxicity: DVT (SVC) 1 8 Toxicity: Neutropenic sepsis, death 2

32 EFS (%) USC Study Event-Free Survival Ph- (N=31) 72% All pts. (N=39) 67% Median follow-up, 17 months Douer D, et al. EHA Abstract 920. Months Investigational Targeted Treatments Subtype Target Treatment Ph + bcr/abl Imatinib, dasatinib, AMN107 T cell NUP214-ABL1 (5%) Imatinib B cell CD 20 Rituximab Precur B cell CD 20 (50%) Rituximab All CD 52 (70%) Alemtuzumab (CAMPATH) T cell NOTCH1 mutation (55%) Gamma-secretase inhibitor MLL, hyperploid FLT3 overexpression CEP701, PKC412

33 Future Studies in Ph ALL Questions in adults age years Intensive pediatric approach vs allo BMT Prolonged (sustained?) asparaginase depletion vs no asparaginase (e.g., hyper CVAD) in multicenter trials Define the time and level of minimal residual disease in CR as a point of changing therapy Panel Discussion

34 Treatment of Adolescents and Young Adults With Acute Lymphoblastic Leukemia Lewis Silverman, MD Assistant Professor of Pediatrics Dana-Farber Cancer Institute/ Children s Hospital Boston, Massachusetts Disclosure of Conflicts of Interest Lewis Silverman, MD Dr. Lewis Silverman has no affiliations with commercial interests to disclose.

35 Childhood Acute Lymphoblastic Leukemia (ALL) Most common malignancy observed in children Current multiagent therapy: event-free survival (EFS) ~80% Age: important determinant of outcome Best outcomes in children 1 10 years old Adolescents/young adults: inferior outcomes ALL: EFS by Age 1 10 years years <1 year ALL-BFM Möricke A, et al. Klin Padiatr. 2005;217: ; with permission.

36 Adolescent ALL: Why Inferior Outcomes? Underlying biology Higher frequency of treatment-related toxicities Therapy: adult vs pediatric-based regimens ALL: Distinctive Biology by Age Sex (% male) WBC (median) 1 10 years years years P Value 54% 56% 61% , T cell 7% 14% 29% <0.001 Dana-Farber Cancer Institute (DFCI) ALL Consortium Studies, WBC=white blood cell count. Barry E, et al. J Clin Oncol. 2007;25:

37 ALL: Distinctive Biology by Age 1 10 years (%) years (%) years (%) P Value TEL/AML <0.001 DNA Index > <0.001 t(9;22) <0.001 Day 15 bone marrow >25% blasts <0.001 ALL-BFM : B-precursor ALL only Möricke A, et al. Klin Padiatr. 2005;217: Treatment-Related Toxicities by Age Asparaginase Corticosteroids

38 Asparaginase: Toxicity by Age 1 10 years years years P Value Number Allergy 15% 10% 10% 0.38 Pancreatitis 3% 9% 6% 0.02 Thrombosis 2% 14% 10% <0.01 DFCI ALL Consortium, Barry E, et al. J Clin Oncol. 2007;25: Osteonecrosis by Age (CCG) 5-year CI 18.0% 13.5% 0.9% CCG=Children s Cancer Group. Mattano LA Jr., et al. J Clin Oncol. 2000;18: ; with permission.

39 Adolescent ALL: Therapy Older adolescents (15 21 years of age) may be treated on pediatric or adult ALL trials More favorable outcomes with pediatric regimens DFCI ALL Consortium: EFS by Age 5-year EFS (%) years years years P=0.09 Adapted from Barry E, et al. J Clin Oncol. 2007;25:

40 FRALLE/LALA Studies: Patient Characteristics FRALLE-93 Ages years LALA-94 Ages years Patients Median age (years) Male sex (%) T lineage (%) B lineage (%) Cytogenetics Evaluable cases (%) t(9;22) or t(4;11) (%) FRALLE=The French Group on Therapy for Adult Acute Lymphoblastic Leukemia; LALA=Leucemies aigues lymphoblastiques de l apus; adulte. Boissel N, et al. J Clin Oncol. 2003;21: Outcome of Patients Aged Years in France OS EFS Boissel N, et al. J Clin Oncol. 2003;21: ; with permission.

41 Outcomes of Patients Treated on Either Pediatric or Adult ALL Clinical Trials Study Group Years USA Dutch Sweden UK Age (years) EFS by Regimen Type (%) Pediatric Adult Barry EV, Silverman LB. Curr Hematol Malig Rep. 2008;3: FRALLE vs LALA: Comparison of Regimens FRALLE-93 LALA-94 Prednisone 4340 mg/m mg/m 2 Vincristine 19 doses 4 doses L-asparaginase 180,000 U/m U/m 2 Interval between complete remission (CR) date and start of next chemotherapy course: FRALLE: median 2 days (only 15% >7 days) LALA: median 7 days P= Boissel N, et al. J Clin Oncol. 2003;21:

42 Could the relatively favorable results for adolescents treated with pediatric ALL regimens be extended to young adults with ALL? PETHEMA ALL-96 Trial (Spain) N=81 patients Ages years Standard risk features WBC <30,000 Absence of t(9;22), t(9;11), MLL gene rearrangements Treatment: pediatric-based protocol PETHEMA=Programa Español de Tratamiento en Hematologia Pediatric-Based Protocol. Ribera J-M, et al. J Clin Oncol. 2008;26:

43 PETHEMA ALL-96 Trial (Spain) 98% CR rate 6-year EFS by age years: 60% years: 63% Therapy well-tolerated No significant agerelated differences in treatment-related toxicities From Ribera J-M, et al. J Clin Oncol. 2008;26: ; with permission. Adolescent and Young Adult ALL: Summary Biologically higher risk disease Lower incidence of TEL/AML1; high hyperdiploidy Higher incidence of T-cell, Ph+ Increased risk for treatment-related complications: Asparaginase: Pancreatitis/thrombosis Corticosteroids: osteonecrosis Better outcomes on pediatric ALL regimens Pediatric regimens currently being piloted in adults with ALL

44 Panel Discussion The Prognostic Implications of Minimal Residual Disease in Acute Lymphoblastic Leukemia Stephen P. Hunger, MD Professor and Ergen Family Chair in Pediatric Cancer Director, Center for Cancer and Blood Disorders Chief, Pediatric Hematology/Oncology/BMT University of Colorado Denver and The Children s Hospital Aurora, Colorado Chair, Children s Oncology Group ALL Committee

45 Estimated Survival Percentage Disclosure of Conflicts of Interests Stephen P. Hunger, MD Dr. Stephen P. Hunger has no affiliations with commercial interests to disclose. Improved Survival in Childhood Acute Lymphoblastic Leukemia (ALL) Children s Oncology Group Years From Study Entry (n=3421) (n=5121) (n=3711) (n=2984) (n=1313) (n=936) (n=499) (n=402)

46 Survival Comparison: Children s Oncology Group (COG) ALL Study Series (Overall: n=21,644 patients) Overall Survival Probability (n=7293) (n=7180) (n=7171) P< year OS±SE RHR ± ± ±0.5 Baseline Years Hunger SP, et al. Presented at the 40th Congress of the International Society of Paediatric Oncology (SIOP), October 2-6, 2008; Berlin, Germany. Risk of Death: 42% Decrease vs Patient Group 5-year OS, % Decrease, %* 1 9 years 88.7 vs years 70.8 vs years 68.9 vs B-lineage 84.9 vs T-lineage 70.7 vs NCI SR 90.4 vs NCI HR 73.8 vs *All P< except 16+ years; P=0.06. HR=high risk; NCI=National Cancer Institute; SR=standard risk. Hunger SP, et al. Presented at SIOP 2008.

47 COG ALL Survival : Conclusions Substantial reduction in deaths since 1990 Reductions occurred in all patient subsets To further improve outcome, efforts must focus on both high-risk patient subsets (Ph+ ALL and others) and patient subsets with excellent outcome, in which 35% 40% of deaths still occur Clinical Utility of Early Response to Therapy in ALL Poor outcome for patients who fail to enter remission Because the complete response (CR) rate is 98% 99% in ALL, limited clinical utility Degree and rate of blast clearance during induction is a powerful predictor of outcome; novel therapies can improve outcome of poor responders Rapidity and depth of early clearance of blasts is highly predictive of outcome Response to prednisone prophase Bone marrow morphology during induction Detection of subclinical levels of minimal residual disease (MRD)

48 Minimal Residual Disease (MRD) Morphologic assessment is a crude but accurate and reproducible way to identify patients likely to have good or bad outcomes MRD is the presence of cells following chemotherapy below the level of morphologic detection Techniques to assess MRD should achieve a sensitivity of at least 1/10,000 (0.01%) More sensitive measures should be a more accurate way to identify groups for risk-adapted therapy ALL: Major Techniques Used to Assess MRD Detection of leukemia-associated phenotypes via flow cytometry Applicable in almost all cases Fast, relatively inexpensive Less sensitive than molecular methods PCR amplification of antigen receptor loci (Ig or TCR) Applicable to ~80% of cases Laborious and expensive (10 flow), but very sensitive Parallel studies of flow and PCR show very similar results PCR of translocation-derived fusion transcripts Only suitable for defined subgroups, such as Ph + ALL Ig=immunoglobulin; PCR=polymerase chain reaction; TCR=T-cell receptor.

49 Normal CD45 is too dim on CD10+ ALL At diagnosis Diagnosis Day %+

50 COG P9900: MRD Testing Bone marrow (BM) (day 29 and week 22 30) and peripheral blood (PB) (day 8) samples collected from >2500 patients enrolled in COG P9900 and shipped from >100 centers to a single central reference laboratory at Johns Hopkins Hospital Data available from >98% of patients within 24 hours Established feasibility of real-time central reference lab flow cytometry based MRD testing MRD results were blinded and not used to alter therapy

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52 Day 8 PB MRD is Highly Prognostic: COG P9900 EFS probability P< Borowitz M, et al. Blood. 2008;111: : MRD<0.01% (n=603) 2: 0.01%<MRD 0.1% (n=341) 3: 0.1%<MRD 1.0% (n=501) 4: 1.0%<MRD 10.0% (n=373) 5: MRD>10% (n=116) 90±2% Years 5-year EFS Only 16% of events occur in the MRDnegative group COG P9900: Multivariate Analyses Variable Hazard Ratio P Value Day 29 BM MRD >0.01% 3.86 < NCI risk group 2.1 < Trisomy Day 8 PB MRD >0.01% Day 8 BM morphology not significant Borowitz M, et al. Blood. 2008;111:

53 COG P9900 MRD Testing: Conclusions Day 29 BM and day 8 PB MRD highly predictive of BM, but not central nervous system, relapse Best cut-off for identifying patients at increased risk of relapse is day 29 MRD >0.01% Can eliminate day BM morphologic responses Day 29 BM MRD predicts both early and late relapse Can MRD results from later time points further refine prognosis? COG P9900: Late MRD Assessment MRD samples requested from all patients at week depending on clinical trial 58/1219 (4.8%) were positive at >0.01% 26/1219 (2%) were positive at >0.1% 11/1219 (0.9%) were positive at >1% Borowitz MJ, et al. J Clin Oncol (May 20 Suppl). Abstract

54 COG P9900 MRD >0.01% Day 29: EFS by MRD at Week (Threshold 0.1%) EFS probability P= Negative ( 0.1%) (n=215) Positive (>0.1%) (n=16) Years 56 ± 4% 31 ± 15% 6.9% of d29 MRD+ patients I-BFM MRD (IgH/TCR PCR) Study 91: Long-Term Results MRD Group MRD Definition Patients, n (%) 10-year EFS, % MRD-SR TP1 + TP2 negative 55 (43) 93 MRD-MR Other 55 (43) 74 MRD-HR TP1 + TP2 > (15) 16 I-BFM=International Berlin Frankfurt Münster. Flohr T, et al. Leukemia. 2008;22:

55 AEIOP-BFM ALL 2000: Risk Groups Based on IgH/TCR MRD MRD Group MRD Definition Patients, n (%) MRD-SR TP1 + TP2 negative 1031 (39.7) MRD-MR Other 1345 (51.9) MRD-HR TP1 + TP2 > (8.4) Schrauder A et al, Proc SIOP #A0.003 ALL-BFM 2000: Outcome of MRD-HR Group Patients with IgH/TCR PCR MRD >10 3 at TP2 (n=116) had 4-year EFS of 35% Received 3 HR blocks post TP2 If became MRD negative: 4-year EFS 78% post SCT If remained MRD >10 3 EFS 43% with stem cell transplant; 17% with chemotherapy Schrauder A et al, Proc SIOP #A0.003

56 Conclusions End-induction MRD is highly prognostic and can be used to assign postinduction treatment intensity Inverse relationship between increasing MRD and decreasing EFS Earlier MRD measures (day 8 PB) may help identify ultra good-risk patients Detection of MRD via flow cytometry has logistical advantages for large-scale clinical trials MRD at end consolidation (week 12 13) may help refine prognosis and identify patients in whom novel interventions should be tested Acknowledgment Michael Borowitz

57 Panel Discussion Future Questions What can be done after MRD is detected? Are the pediatric findings relevant to adults? Why are the biologic cytogenetic characteristics of ALL so different in children compared with adults? Should all adults with B lineage ALL undergo allogeneic transplantation in first CR? Why are patients cured?

58 Thank you for participating in this educational activity. Please complete the CME/CE Test Questions (Learning Assessment) and Evaluation Form found on the home page of this activity.