Can ALL be managed without chemotherapy/transplant? (Position: NO) D.Hoelzer J.W.Goethe University Frankfurt

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1 Can ALL be managed without chemotherapy/transplant? (Position: NO) D.Hoelzer J.W.Goethe University Frankfurt Barcelona, September 2012

2 First report of Monotherapy in childhood ALL 10/16 children with acute leukemia treated with aminopterin responded No evidence has been mentioned in this report that would justify the suggestion of the term cure of acute leukemia in children

3 The New England Journal of Medicine 2006;354: Treatment of Acute Lymphoblastic Leukemia Ching-Hon Pui, M.D., and William E. Evans, Pharm.D. ~90% cure in ALL in children with Multiagent chemotherapy

4 Current therapy strategies in ALL Children, cure rate in SR patients 80-90% Deescalation, but not to MONOTHERAPY Adults, cure rate in SR patients >50-70% Further chemo intensification no improvement New Targeted therapy; Tyrosine kinase inhibitors Antibody therapy An option to cure with MONOTHERAPY?

5 Treatment Strategies in Ph+ ALL with TKI IND TKI Imatinib IND Consol TKI Monotherapy ±SCT TKI Non toxic Chemo

6 Imatinib and intensive chemoinduction in adult Ph+ ALL Study Group N Imatinib dose [mg/day] KOREA Lee, 2005 GMALL Wassmann, 2006 JALSG Yanada, 2006 GRAALL De Labarthe, 2007 MD Anderson Thomas, 2008 PETHEMA Ribera, 2009 NILG Bassan, 2010 CR Induction Death PCR negativity % 5% 72% Ch. before IM Ch. + TKI % 7% 52% % 2.5% 71% CR 70% 95% % 5% 38% Mol CR <5% 50-70% % 2% 52% OS 10%? +SCT 30% 70% % 7% 86% % 9% 40%

7 What is the outcome of a TKI Mono induction therapy in Elderly Ph+ ALL? Age distribution of cytogenetic abnormalities Szczepanski T et al. Lancet Oncol 2010; 11: Ph+ ALL substantially increasing with age! Half of elderly ALL pts are Ph+!

8 Imatinib Monotherapy (± CTX) in Elderly Patients with Ph+ ALL Author Age Therapy IM Year (Median) Induct. Consol. Dose N CR Survival Vignetti 69 GMALL y IM + Pred GIMEMA % GRAALL 74% (1 yr) Blood Delannoy 66 y CTX IM + ster % (IM) 66% (1 yr) Leukemia 50 CTX / IM 70% (CH) GMALL 1 P ro b a b ility of d is e a s e - f r e e s u r v i val GIMEMA 2 GRAALL 3 Ottmann 68 y IM CTX+IM % (IM) 57% (1 yr) 0 Cancer CTX % (CH) 42% (2 yrs) months 2007 High CR rates: %; Mol CR ~ 50%, less induction death! But high relapse rate Monotherapy with IM alone failed to cure! Why?

9 Proportion of Mutant BCR-ABL Alleles in Relation to Treatment Response of de novo Ph+ALL % unmutated BCR-ABL CR Mol. CR REL Time Chemotherapy IMATINIB % mutated BCR-ABL D. Hoelzer, H.Pfeifer,O.G.Ottmann

10 Kinetics of bcr-abl mutations in Ph+ ALL H. Pfeifer et al. Leukemia 2012 Mutations at diagnosis, e.g. T315I do reappear despite Molecular Remission

11 Chemoimmunotherapy Reinduction With Epratuzumab (Anti- CD22) in Children With Acute Lymphoblastic Leukemia in Marrow Relapse: A Children s Oncology Group Pilot Study Raetz et al. JCO (22): N 15: 10yrs (med) Stage of disease 11 first rel 4 sec rel Epratuzumab dose/ timing 360 mg/m 2 /day i.v. 3x wkly Limited success with Response CR Mol. CR 9 7 Anti-CD22 alone Toxicity; dose limiting 2; 1 o 4 seizure; 1 o 3 ALT elevation Raetz et al. ASH 2011, Abstract # yrs 1 st relapse <> 18 mo twice wkly x 8 + chemo 65/66% 42% Historical Chemo alone 67% 25% Hoe 2011

12 MT103 is a bispecific single-chain antibody derivative designed to link B cells and T cells resulting in T-cell activation and a cytotoxic T-cell response against CD19 expressing cells. Blinatumomab Bargou et al. Science 2008, 321, 974

13 Blinatumomab in MRD+ B-precursor B ALL GMALL-Study Topp et al. J Clin Oncol Jun 20;29(18): MRD response rate: 80% (16/20) - All 16 responders MRD neg. after 1 cycle Blina. All patients Patients without HSCT - Some patients survive >2 yrs without SCT 08/2012

14 Could the bispecific AB Blinatumomab potentially have a role as Monotherapy Mechanisms 1) Short term effect Release of cytokines IL-1, IL-10, IL-6, IFN-γ B cell apoptosis; substantial decrease <2 days Cave: all MRD pos. or relapse pts. responding to 2) Blinatumomab Later effect had chemo before T cell decline <1 day; reappear, CD4/8 expansion Newly activation marker CD69 expression Prospective study in de novo ALL required (Klinger et al., Blood : ) 3) Long-term effect Memory T-cells? Or are all cells eradicated?

15 Conclusion Monotherapy in ALL so far unsuccessful, unproven no significant long-term cure rate shown Multiagent therapy still best probability of cure children >80%, AYA SR (high Asp) 60-70% Currently two biological principles Chemo ± Antibody therapy ± TKI Future Non-chemotherapeutic approaches e.g. TKI+MoAB in Ph+ ALL