Can ALL be managed without chemotherapy/transplant? (Position: NO) D.Hoelzer J.W.Goethe University Frankfurt Barcelona, September 2012
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
The New England Journal of Medicine 2006;354:166-78. 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
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?
Treatment Strategies in Ph+ ALL with TKI IND TKI Imatinib IND Consol TKI Monotherapy ±SCT TKI Non toxic Chemo
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 20 600 95% 5% 72% Ch. before IM Ch. + TKI 92 400 95% 7% 52% 80 600 96% 2.5% 71% CR 70% 95% 45 600 96% 5% 38% Mol CR <5% 50-70% 54 600 93% 2% 52% OS 10%? +SCT 30% 70% 32 400 90% 7% 86% 59 600 92% 9% 40%
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: 880-89 Ph+ ALL substantially increasing with age! Half of elderly ALL pts are Ph+!
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 800 29 100% GRAALL 74% (1 yr) Blood 100 2006 75 Delannoy 66 y CTX IM + ster. 600 30 90% (IM) 66% (1 yr) Leukemia 50 CTX / IM 70% (CH) 2006 25 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 400 27 96% (IM) 57% (1 yr) 0 Cancer 0 100 200 300 400 500 600 700 CTX 800 900 1000 1100 26 50% (CH) 42% (2 yrs) months 2007 High CR rates: 90-100%; Mol CR ~ 50%, less induction death! But high relapse rate Monotherapy with IM alone failed to cure! Why?
Proportion of Mutant BCR-ABL Alleles in Relation to Treatment Response of de novo Ph+ALL % unmutated BCR-ABL 100 90 80 70 60 50 40 30 20 10 0 CR Mol. CR REL 1 3 5 7 9 11 13 15 Time 17 19 21 23 25 27 29 31 Chemotherapy IMATINIB % mutated BCR-ABL 100 90 80 70 60 50 40 30 20 10 0 D. Hoelzer, H.Pfeifer,O.G.Ottmann
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
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 2008. 26(22):3756-3762 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 #573 114 2-30 yrs 1 st relapse <> 18 mo twice wkly x 8 + chemo 65/66% 42% Historical Chemo alone 67% 25% Hoe 2011
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
Blinatumomab in MRD+ B-precursor B ALL GMALL-Study Topp et al. J Clin Oncol. 2011 Jun 20;29(18):2493-8 - 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
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 2012 119:6226-6233) 3) Long-term effect Memory T-cells? Or are all cells eradicated?
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