Future of CML: ABL001 and other treatments in the pipeline. Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy

Transcription

1 Future of CML: ABL001 and other treatments in the pipeline. Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy

2 Primitive sleeping BCR-ABL-positive leukemic stem cells are less sensitive to imatinib Graham et al. Blood 2002

3 Second generation TKIs do not result in cell death of CML stem cells

4 Discontinuation is Possible The overall probability of maintenance of Complete Molecular Response (CMR) at 24 and 36 months was 39% (95% CI 29-48). Molecular relapse occurred in 61 patients, with 58 relapses occurring during the first 7 months, 3 late relapses at month 19, 20 and 22, respectively Mahon FX, et al. Blood 2011;118:abstract 603

5 Dormant stem cells show the highest repopulation activity

6 Methods to overcome the resistance of Philadelphia-positive progenitor cells To exploit some differences in cell characteristics (phenotype differences) with respect to their normal counterpart To hit the molecular pathways implicated in their resistance

7 CML haematopoietic stem cell targeting agents IFN-alpha Hh pathway antagonist/smo inhibitor HDAC inhibitor (e.g., panobinostat) PI3K +/- mtor inhibitors STAT5 pathway inhibitor PP2A activator (e.g., FTY720) FTI (e.g., BMS ) Wnt/beta catenin inhibitors IL-1 receptor accessory protein Old known drug Low cost Powerful Investigational drugs Long term side effects unknown

8 Ph-positive cells are very sensitive to immuno-mediated suppression Data from bone marrow / stem cell transplant: Clear Graft-Versus-Leukemia effect (less in twins transplant) Efficacy of Donor Lymphocyte (DLI) therapy in patients who relapsed Long-term relapses in patients who became apparently PCR-negative

9 Interferon-alpha therapy Reducing cell division (anti-proliferative effect)? Immuno-mediated suppression? Combination of the two mechanisms?

10 Interferon IFN IFN IFN no TKI IFNAR1 IFNAR2 JAK1 TYK2? p38 IRF9 p110 p85 apoptosis inhibition BCR-ABL signaling Interferon signaling BCL- x L MYC transformation apoptosisresistance ISRE-site ref. 52 ISGs: IRF1, IRF9, ISG15 Ifit-2, STAT1, 2, p53, Hif1α Mx1, RIG-1, Fas/Apo1, MHC-class I, etc. apoptosis induction GAS-site ISGs: PML differentiation cell cycle inhibition

11 Interferon IFN IFN IFN + TKI IFNAR1 IFNAR2 JAK1 TYK2 p38 IRF9 p110 p85 GAS-site Interferon signaling ISRE-site ref. 52 ISGs: IRF1, IRF9, ISG15 Ifit-2, STAT1, 2, p53, Hif1α Mx1, RIG-1, Fas/Apo1, MHC-class I, etc. ISGs: PML apoptosis induction differentiation cell cycle inhibition

12 P P P P P P BCR/ABL P210 P210 STATs (+) Grb2 Grb2 Sos Grb2 Shc SHP-2 (+) Crkl Cbl Shc Cbl p85 p85 p110 P13-K Proliferation RAS (+) Ciclina D Crkl Proliferation and cell cycle control Integrina Vinculina PaxillinaTalina FAK Adhesion (to stroma) abnormalities E2F1 Myc

13 Interferon + Imatinib combination studies FRENCH NORDIC 3 Ger-CML MDAnderson 4 SPIRIT 1 Study IV 2 IFN type PEG PEG No PEG PEG + G-CSF (IMA 800) MMR Yes Yes No No CCyR No No No No Survival No NA No No Toxicity Yes Yes No Yes 1. Preudhomme C et al., N Engl J Med. 2010;363(26): Hehlmann R et al., JCO 2011;29: Simonsson B, et al. Blood 2011;118(12): Cortes J et al. Cancer. 2011;117(3):

14 CML V (TIGER) study (Nilotinib + PEG-IFN) Induction Maintenance Cure? >36 months therapy Discontinuation Nilotinib 2x300mg/d cont. Nilotinib --- R Confirmed MMR after > 24 mo. > 12 mo. MR 4 Nilotinib 2x300mg/d PEG-IFN 30(-50)µg/w PEG-IFN 50µg/w --- Nilotinib Intolerance Imatinib Nilotinib Resistance Transplantation/Dasatinib Suboptimal Response Nilotinib 400 mg BID A. Hochhaus, pers. comm.

15 Immuno-adoptive therapy approaches to try to eradicate Ph-positive stem cells Ph-positive cells specific antigens? BCR-ABL junction peptides 4 Antigens preferentially expressed by Ph-positive cells: IL1R1¹ WT1² PR1 antigens³ ¹Järås M et al., PNAS 2010 ²David Scheinberg, Baltimore 2012 ³Kanodia S et al., PLoSOne 2010) 4 Bocchia M et al.

16 Conclusion: Major questions are still unanswered Does the immune system still play a role in CML in the TKI era? To which extent could we use drugs that will target not only the leukaemic stem cells but also other stem cells?

17 Several strategies to hit pathways preferentially activated in leukemic stem cells with respect to normal stem cells have been presented in this meeting Hamad A et al. Stem cell int 2013

18 The presence of a cytokine-enriched microenvironment leads to a BCR-ABL independent activation of STAT3 and STAT5 via JAK2. Targeting both pathways via BCR-ABL1 and JAK2 TKIs would interfere with these essential survival signals.

19 JAK2 -- Yes but Combination of JAK2 inhibitor and TKI: Risk of aplasia Effect on non haematopoietic cells (or stem cells) is unknown Effect on dormant CML stem cells unknown

20 ABL001 is a potent, specific inhibitor of BCR-ABL with a distinct allosteric mechanism of action Developed to gain greater BCR-ABL inhibition, with activity against BCR-ABL mutations conferring resistance to TKIs Potential to combine with TKIs for greater pharmacological control of BCR-ABL BCR-ABL Protein Nilotinib (ATP Site) T ABL001 (Myristoyl Site) Ottmann O, et al. Blood. 2015:[abstract 138].

21 Auto-inhibition of ABL1 by engagement of Myristoyl binding site SH2 SH3 Kinase SH2 SH3 Kinase Myristoylated N- terminus INACTIVE ACTIVE Ottmann O, et al. Blood. 2015:[abstract 138].

22 Loss of ABL1 auto-inhibition due to BCR-ABL1 translocation SH3 t(9;22) SH2 BCR Kinase ACTIVE Ottmann O, et al. Blood. 2015:[abstract 138].

23 ABL001 allosterically inhibits BCR-ABL1 kinase activity BCR SH3 SH3 t(9;22) SH2 Kinase SH2 BCR ABL001 Kinase INACTIVE ACTIVE ABL001 Ottmann O, et al. Blood. 2015:[abstract 138].

24 ABL001 and classical TKIs exhibit complementary mutation profiles ATP Binding Site Mutations Proliferation IC 50 Profiles in Ba/F3 BCR- ABL1 Mutant Lines G250H T315I E255K Y253H F359V I502L P223S K294E 10 WT G250H Q252H Y253H V468F E255K Myristoyl Binding Site Mutations P465S A337V V299L E255V E459K F359V E355G T3151 A337V P465S V468F Nilotinib ABL001 ATP binding site mutations Myristoyl binding site mutations Ottmann O, et al. Blood. 2015:[abstract 138].

25 Combination of ABL001 and Nilotinib prevents the emergence of resistance (KCL-22 CML Xenograft) a A337V/P223S detected Tumor Volume, mm T315I detected Tumor Volume, mm Days Post-implant Days Post-implant Nilotinib (75 mg/kg) BID ABL001 (30 mg/kg) BID Nilotinib (75 mg/kg) BID + ABL001 (30 mg/kg) BID Dosing stopped on day 77, all mice remain disease free > 176 days a Each line represents individual animals. Ottmann O, et al. Blood. 2015:[abstract 138].

26 ABL001X2101: Study Design A multicenter, phase 1, first-in-human study Dose Escalation CML, Resistant/Intolerant to Prior TKI ABL001 BID, Oral MTD/RDE Dose Expansion CML, Resistant/Intolerant to Prior TKI ABL001 BID, Oral Ph+ ALL, Resistant/Intolerant to Prior TKI ABL001 BID, Oral CML, Resistant/Intolerant ABL001 QD, Oral MTD/RDE CML, Resistant/Intolerant ABL001 QD, Oral Combo Dose Escalation CML ABL mg BID + Nilotinib 300 mg BID, Oral MTD/RDE Dose Expansion CML ABL mg BID + Nilotinib 300 mg BID, Oral Primary outcome: estimation of minimum tolerated dose / recommended dose for expansion Secondary outcomes: safety, tolerability, preliminary anti-cml activity, pharmacodynamics, pharmacokinetic profile Ottmann O, et al. Blood. 2015:[abstract 138].

27 Conclusions on ABL001 Allosteric inhibition of BCR-ABL is a promising therapeutic approach in patients with CML Early evidence of single-agent efficacy at 10 mg twice daily Clinical activity across TKI-resistant mutations (eg, V299L, F317L, Y253H) Myristoyl binding pocket mutations (V468H, I502L) may lead to clinical resistance ABL001 was generally well tolerated in heavily treated CML patients resistant to or intolerant of prior TKIs Enrollment ongoing to determine a recommended dose and to assess safety and tolerability Ottmann O, et al. Blood. 2015:[abstract 138].

28 Future of CML: ABL001 and other treatments in the pipeline. Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy