6th edi(on Highlights from EHA Leucemia acuta linfoblas6ca

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1 6th edi(on Highlights from EHA Leucemia acuta linfoblas6ca

2 HOT QUESTIONS ü Which Biomarkers in ALL? ü Will NGS be the future standard for MRD? ü Which are the most promising new drugs in ALL? ü What about allo-sct in Ph ALL?

3 Definition of biomarker? A feature that reflects a biologic process that is predictive for: v Susceptibility to develop leukemia Tutti nel gruppo concordano che un Biomarker deve v Diagnosis of the disease essere utile per la diagnosi, la stratificazione prognostica v Subtype of a e, disease ove possibile, la valutazione della Risposta e della MRM. v Recurrence of the disease v Response to a given treatment in an invidual patients den Boer ML, EHA 2013, Educational Program

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5 Biomarkers nella pratica Ø Ph+ Ø IKZF1 Ø MRD NGS

6 IKZF1 DELETION STATUS DISCRIMINATES FOR OUTCOME IN IMATINIB TREATED BCR-ABL1-POSITIVE CHILDHOOD ALL v The BCR-ABL1-translocation predicts for an unfavorable outcome in ALL, at least in pre-tki era v BCR-ABL1-positive ALL is characterized by a high frequency (70%) of IKZF1 deletions. v IKZF1 deletions are correlated to an unfavorable outcome in BCR- ABL1-negative ALL. Ven der Veer et al., EHA 2013, Abst S1123

7 Ven der Veer et al., EHA 2013, Abst S1123

8 v This is the first study demonstrating that IKZF1 deletions are correlated to a poor outcome in a relative large cohort of childhood BCR-ABL1-positive ALL. v IKZF1-deleted patients need a more intensified or alternative therapy. v Since IKZF1 wild-type BCR-ABL1-positive patients treated with Imatinib have a good outcome comparable to BCR-ABL1-negative ALL, the absence of an IKZF1 deletion may be used as marker to exclude HSCT. Ven der Veer et al., EHA 2013, Abst S1123

9 IKZF1 stratifica le LAL Ph+ MRM Rapidità e Livello Un nuovo marker per identificare i pazienti pediatrici e adulti? Identificare i Candidati ad allostc??

10 NSG Comparison of MRD results obtained by sequencing, FC, and ASO-PCR. Malnassy et al, et al. EHA 2013, Abst S537

11 In at least one patient, the relative frequencies of the 3 clonal sequences changed dramatically over the disease course

12 NSG method enables MRD detection without the need for development of patient-specific reagents v Concordance data between sequencing and ASOPCR are high Malnassy et al. EHA 2013 Tutti riconoscono il prezioso contributo di questa tecnologia e auspicano che in tempi brevi possa essere Introdotta nella pratica clinica.. Faham M et al, Blood 2012

13 NUOVI FARMACI

14 Pona6nib for Ph+ T315I Re- ALL T315I: most frequent point muta5on in TK P190/210 domain, associated with Ph+ Re- ALL Pona5nib: oral pan- BCR ABL inhibitor highly ac5ve against mutated BCR ABL I315 triple bond ponatinib BP- CML, Ph+ ALL MHR (%) MCyR (%) CCyR (%) MMR (%) Resistant/intolerant (R/I) to dasa6nib or nilo6nib 17/46 (37) 14/41 (34) 11/41 (27) 9/41 (22) T315I muta6on 16/43 (37) 15/41 (37) 11/41 (27) 2/29 (7) Total 33/89 (37) Courtesy C Gambacor6- Passerini, Monza Italy CORTES et al, ASH 2011

15 WEEKLY INOTUZUMAB OZOGAMICIN (INO) IN ADULT PATIENTS WITH RELAPSED OR REFRACTORY CD22- POSITIVE ALL De Angelo et al, EHA 2013, Abst S1125

16 INO had a tolerable safety profile consistent with prior reports, primarily characterized by hematologic, gastrointestinal, and hepatic AEs. Single-agent INO demonstrated encouraging clinical activity in this relapsed/refractory population; Preliminary efficacy results appear dynamically related to exposure and circulating blasts. De Angelo et al, EHA 2013,

17 IMMUNOPHARMACODYNAMIC RESPONSES FOLLOWING TREATMENT WITH THE BISPECIFIC T-CELL ENGAGER ANTIBODY BLINATUMOMAB AMONG PATIENTS WITH RELAPSED/REFRACTORY B-PRECURSOR ALL Schubb et al, EHA 2013, Abst S555

18 Blinatumumab for relapsed adult ALL Cohort Patients Treated Initial Dose Week 1, Cycle 1 µg/m²/day Dose Week 2, Cycle 1 µg/m²/day Dose Weeks 3 4, Cycle 1 µg/m²/day Maintenance Dose, Subsequent Cycles µg/m²/day CR or CRh* Serious Adverse Events n Pts a b planned n.a. n.a. n.a Topp et al. ASH 2011

19 Time to clinical relapse. Topp M S et al. JCO 2011;29: Targeted Therapy With the T-Cell Engaging Antibody Blinatumomab of Chemotherapy-Refractory Minimal Residual Disease in B-Lineage Acute Lymphoblastic Leukemia Patients Results in High Response Rate and Prolonged Leukemia-Free Survival 2011 by American Society of Clinical Oncology

20 Blinatumumab High response in Pts with MRD+ But also in Ø Poor quality CR Ø Haematological Relapse Issues No di Linfociti T Blastosi.