This activity is jointly sponsored by Robert Michael Educational - PDF document

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.

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

Philadelphia Chromosome–Positive (Ph+) Acute Lymphocytic Leukemia (ALL): A New Era of Treatment Challenges Deborah A. Thomas, MD ������������������� 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 ������������� and Amgen Inc. and Hana Biosciences, Inc. ����������� ������!

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 1989 29 46 11* Gotz 1992 25 76 8* Larson 1995 25 70 16 (3) Secker&Walker 1997 40 83 13 (3) Wetzler 1999 67 82 11 (5) Faderl † 2000 67 90 16* Dombret 2002 154 67 19 (3) Gleissner 2003 175 68 13 (3) Cimino 2006 101 67 16 (7) *Median survival in months. † Hyper&CVAD.

Single Agent Imatinib in Relapsed/Refractory Ph+ ALL and CML/LBP ALL (n=48) CML&LBP (n=8) % Response All Sustained All Sustained Overall 60 27 50 25 CR 19 6 50 12.5 Marrow CR 10 0 0 0 Marrow PR 31 21 0 12.5 %CG CR 17 12.5 TTP (mo) 2.2 NA Survival (mo) 4.9 6.6 Ottmann OG, et al. "����! 2002;100:1965&1971. 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)

Imatinib + Chemotherapy for �������� 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 1 2 3 4 5 6 7 8 Maintenance phase 12 mos 12 mos Hyper/CVAD Imatinib Vincristine + prednisone MTX/cytarabine Thomas DA, et al. "����! 2004;103:4396&4407.

Imatinib + Hyper/CVAD in Ph+ ALL: Induction Response (n=54) Category No. CR/Total %CR ���#�$�� 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 2007. Survival in �������� Groups by Regimen Survival in De Novo Groups by Regimen 1.0 No. No. Fail Hyper/CVAD + imatinib 48 21 � <0.001 � <0.001 0.8 Hyper/CVAD 50 45 0.6 0.4 0.2 Median follow/up 4 years (range, 13 to 78 mos) 0.0 0 12 24 36 48 60 72 84 96 108 120 Thomas DA, et al. ASH 2007. Months

Remission Duration by Therapy Remission Duration by Therapy 1.0 No. No. Fail Hyper/CVAD + imatinib 45 12 � <.001 � <0.001 Hyper/CVAD 47 33 0.8 0.6 0.4 0.2 0.0 0 12 24 36 48 60 72 84 96 108 120 Months Thomas DA, et al. ASH 2007. Imatinib/Based Chemotherapy Regimens for ������� Ph+ ALL %DFS %OS Regimen No. %CR %Rel (X yrs) (X yrs) Age > 15 years Hyper&CVAD 39 92 22 66 (4) 55 (4) Adults age < 65 years JASALG ALL202 80 96 26 60 (1) 76 (1) GMALL Alternating 47 NA NR 52 (2) 36 (2) Concurrent 45 NA NR 61 (2) 43 (2) GRAAPH&2003 45 96 19 55 (1.5) 65 (1.5) Thomas DA, et al. ASH 2007. Yanada M, et al. %����������� . 2006;24:460&466. Wassmann B, et al. "����! 2006;108:1469&1477. de Labarth A, et al. "����! 2007;109:1408&1413.

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. "����! 2006;108:1469&1477. ������� Ph+ ALL: GRAAPH/2005 • 84 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 2008. Abstract 12.

Imatinib/Based Regimens for ������� Elderly Ph+ ALL (Age >55) %DFS %OS Regimen No. %CR %Rel (X yrs) (X yrs) GMALL Chemotherapy 28 50 41 29 (1.5) 35 (1.5) Imatinib 27 96 54 57 (1.5) 41 (1.5) GIMEMA 30 100 48 48 (1) 74 (1) GRAALL AFR09 30 72 60 58 (1) 66 (1) Ottmann OG, et al. ������ . 2007;109:2068&2076. Vignetti M, et al. "���� . 2007;107:3676&3678. Delannoy A, et al. &� '���� . 2006;20:1526&1532. Mechanisms of Resistance to Imatinib • Single point mutation ATP binding site (e.g., T315I), P&loop or activation loop • Amplification of "��(�"& fusion gene • Upregulation of "��(�"& transcription • Increased imatinib efflux • Decreased cellular bioavailability • "��(�"& independence (SRC) Hofmann WK, et al. "���� . 2002;99:1860&1862. Hofmann WK, et al. &����� . 2002;359:481&486.

Resistance to Imatinib: Tyrosine Kinase Domain (TKD) Mutations Direct Contact 1. T315I 2. F317 3. F359 P/loop Activation loop 4. M244 9. M351 5. G250 10. E355 6. Q252 11. V379 7. Y253 12. L387 8. E255 13. H396 ABL TKD Mutations in ������� 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. "����! 2007;110:727&734.

TKD Mutations in Ph+ ALL • Incidence and kinetics of ABL KD mutations in �����$� and recurrent disease after imatinib& based chemotherapy or monotherapy ������� Advanced % (No./Total) % (No./Total) Pre&imatinib 31 (9/29) 33 (21/63) Post&imatinib 84 (22/26) 70 (33/50) TKDM at relapse P&loop 46 48 T3151 15 16 A&loop 9.5 2 Pfeifer H, et al. ASH 2007. Abstract 10. Dasatinib for Imatinib/Resistant Ph+ ALL • Dual Src/Abl inhibitor • 325&fold more potent than imatinib ���$���� • 30& to 50&fold more potent ���$�$� • )��$���� 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. #������%����! 2006;354:2531&2541.