T315I Mutation: Incidence, Implications, and Therapy - Educational ...

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T315I Mutation: Incidence, Implications, and Therapy - Educational ...

T315I MUTATION:INCIDENCE, IMPLICATIONS, AND THERAPYNeil Shah, MD, PhDDivision of Hematology/OncologyUCSF School of MedicineSan Francisco, California


Many Chronic Phase CML Patients Require AlternateTherapies – 8-Year Update of the IRIS Study17%53%5%15%37%No CCyRLost CCyRCCyR Other7%3%SafetyLost-regained CCyRSustained CCyR on studyDeininger M, et al. Blood (ASH Annual Meeting Abstracts). 2009;114(22):1126.


Why Do Some Patients LoseResponse to Imatinib?


Clinical Loss of Response to Imatinib is MostOften Associated With Restoration of BCR-ABLKinase ActivityDrug-resistant BCR-ABL kinase domain mutationsOverexpression of BCR-ABL (eg, genomic amplification)Gorre ME, et al. Science. 2001;293(5531):876-880.


ATP-Binding Pocket of T315I Mutant BCR-ABLCannot Accommodate ImatinibWILD-TYPET315I MUTANT (MODEL)Structural data provided by B. Nagar and J. Kuriyan (UC Berkeley)Gorre ME, et al. Science. 2001;293(5531):876-880.


More Than 100 BCR-ABL Kinase Domain MutationsHave Been Associated With Clinical Loss ofResponse to Imatinib – An Incomplete MapL298VE292VxP C AGorre et al, 2001; von Bubnoff et al, 2002; Branford et al, 2002; Hofmann et al, 2002; Roche-L’Estienne et al,2002; Shah et al, 2002; Hochhaus et al, 2002; Al-Ali et al, 2004.Courtesy Tim Hughes


Patients (%)Frequency of BCR-ABL Kinase Mutations181614121086420Deininger MW. Exp Hematol. 2007;35(4 suppl 1):144-154.


Dasatinib 70 mg PO BID in Chronic Phase CMLResponse by IndividualBaseline BCR-ABL MutationCellular IC 50 (nM)Dasatinib Imatinib nM244V 1.3 2000 17L248V 1500 9G250E/V 1.8 1350–3900 23Y253F/H/K 1.3–10 >10000 14E255K/V 5.6–13 4400–8400 10D276G 1500 3T315I >1000 >10000 3F317L 7.4 1050 4M351T 1.1 930 15E355G 400 6F359C/I/V 2.2 1200 8L387M 2.0 1000 2H396P/R 0.6–1.13 850–4200 17Other 30Complete CyRPartial CyRComplete HRNo responseStone RM, et al. ASH Annual Meeting Abstracts. 2007;110(11):734.


Dasatinib 70 mg PO BID in Chronic Phase CMLResponse by IndividualBaseline BCR-ABL MutationCellular IC 50 (nM)Dasatinib Imatinib nM244V 1.3 2000 17L248V 1500 9G250E/V 1.8 1350–3900 23Y253F/H/K 1.3–10 >10000 14E255K/V 5.6–13 4400–8400 10D276G 1500 3T315I >1000 >10000 3F317L 7.4 1050 4M351T 1.1 930 15E355G 400 6F359C/I/V 2.2 1200 8L387M 2.0 1000 2H396P/R 0.6–1.13 850–4200 17Other 30Complete CyRPartial CyRComplete HRNo responseStone RM, et al. ASH Annual Meeting Abstracts. 2007;110(11):734.


IC50 (nM) on proliferationmaternal+ IL3bcr-abl wtM237IM244VL248VG250AG250EG250VQ252HY253HE255DE255KE255VE255RE275KE276GE281KK285NE292KF311VT315IF317CF317LF317VD325NS348LM351TE355AE355GF359CF359VA380SL387FM388LF468SActivity of Nilotinib on Imatinib-Resistant BCR-ABL Mutants In VitroBa/F3 cell proliferation30002500ImatinibNilotinib200015001000500072-hour proliferation assay with BCR-ABL–expressing Ba/F3 cellsWeisberg E, et al. Br J Cancer. 2006;94(12):1765-1769.O’Hare T, et al. Cancer Res. 2005;65:(11):4500-4505.Weisberg E, et al. Cancer Cell. 2005;7(2):129-141.


Phase II Nilotinib in CML-CP:Response, Progression Based on Mutation(Excluding T315I IC 50 )Patients, n/N (%)Mutation CCyR ProgressedNo mutation 35/83 (42) 19/83 (23)IC 50 ≤ 150 nM 18/45 (40) 14/45 (31)IC 50 > 150 nMY253H 0/8 (0) 3/8 (38)E255K/V 0/8 (0) 6/8 (75)F359C/V 0/10 (0) 9/10 (90)Others 14/33 (42) 13/33 (39)• Response rates and progression rates were similar in patients without baselinemutations and in patients with mutations with IC 50 ≤ 150 nM for nilotinib• Less favorable responses seen in patients with Y253H, E255K/V, and F359C/V• 8 of 26 patients were dose escalated to 600 mg PO BID• Highest rates of progression for E255K/V and F359C/VHughes T, et al. ASH Annual Meeting Abstracts. 2007;110(11):320.


Patients (%)Frequency of BCR-ABL Kinase Mutations181614121086420Deininger MW. Exp Hematol. 2007;35(4 suppl 1):144-154.


Patients (%)Frequency of Dasatinib-Resistant MutationsFollowing the Development of Imatinib Resistance181614121086420dasatinib-resistantdasatinibT315I/AV299LF317L/IDeininger MW. Exp Hematol. 2007;35(4 suppl 1):144-154.Branford S. Hematology. 2007;2007(1):376-383.


Patients (%)Frequency of Nilotinib-Resistant MutationsFollowing the Development of Imatinib Resistance18161412108nilotinib-resistantnilotinibT315IY253HE255K/VF359V/C6420Deininger MW. Exp Hematol. 2007;35(4 suppl 1):144-154.Branford S. Hematology. 2007;2007(1):376-383.


BCR-ABL genotypeDisease BurdenResistance to Sequential Kinase Inhibitor Therapy:Molecular MechanismsimatinibdasatinibtimeBCR-ABL KD mutationnative BCR-ABL KDor?BCR-ABL amplification


Loss of Dasatinib Response: Baseline Imatinib-Resistant MutationsDiseasePhase/PatientBaseline imatinib-resistantmutation(s)New mutation(s)identified at time ofdasatinib resistanceCompound mutation(s)CP-1Y253HM388LV299LT315IV299L/M388LY253H/F317LF317LCP-2 E355G F317IF317I/L387ML387MAP-1 None V299LAP-2 None V299LAP-3 None T315IMBC-1L364IM244V/L364IT315AT315A/L364IM244V/T315A/L364IMBC-2 E255V V299L E255V/V299LMBC-3 F359V T315IMBC-4 None T315IMBC-5 None T315ILBC-1 None T315ILBC-2 None T315ILBC-3 None T315IPh+ ALL-1 Y253H T315I Y253H/T315IPh+ ALL-2 M244V T315IPh+ ALL-3 E255K T315IPh+ ALL-4 None T315IShah NP, et al. J Clin Invest. 2007;117(9):2562-2569.


Loss of Dasatinib Response: Evolution of One of Five MutationsDiseasePhase/PatientBaseline imatinib-resistantmutation(s)New mutation(s)identified at time ofdasatinib resistanceCompound mutation(s)CP-1Y253HM388LV299LT315IV299L/M388LY253H/F317LF317LCP-2 E355G F317IF317I/L387ML387MAP-1 None V299LAP-2 None V299LAP-3 None T315IMBC-1L364IM244V/L364IT315AT315A/L364IM244V/T315A/L364IMBC-2 E255V V299L E255V/V299LMBC-3 F359V T315IMBC-4 None T315IMBC-5 None T315ILBC-1 None T315ILBC-2 None T315ILBC-3 None T315IPh+ ALL-1 Y253H T315I Y253H/T315IPh+ ALL-2 M244V T315IPh+ ALL-3 E255K T315IPh+ ALL-4 None T315IShah NP, et al. J Clin Invest. 2007;117(9):2562-2569.


The Presence of the BCR-ABL T315I Mutation InCP CML Resistant to Tyrosine Kinase InhibitorsProfoundly Compromises Overall Survival andProgression Free SurvivalNicolini FE, ASH 2010. Abstract 3410.


Investigational Options for PatientsWith the BCR-ABL/T315I MutationDanusertib (PHA-739358) - an ABL/Aurora inhibitor


Danusertib Hydrochloride (PHA-739358),a Multi-Kinase Aurora Inhibitor, ElicitsClinical Benefit in Advanced ChronicMyeloid Leukemia and PhiladelphiaChromosome Positive Acute LymphoblasticLeukemiaJ. Cortes, H. Dombret, P. Schafhausen,T. Bruemmendorf, N. Boissel, F. Latini,L. Capolongo, B. Laffranchi, S. ComisCortes-Franco J, et al. ASH Annual Meeting Abstracts. 2009;114(22):864.


Danusertib in CML AP/BP and ALLPatient CharacteristicsCharacteristics (N = 24) No. (%) Median [range]Age 53.5 [23-81]Months from diagnosis 16.5 [8-99]Prior therapies 5 [1-12]1 TKI 3 (13)≥ 2 TKI 21 (88)T315I 14 (58)Diagnosis {T315I}CML – AP 5 (21) {2}CML – BP 8 (33) {3}ALL 11 (46) {9}Clonal evolution 13/17 (76)WBC (x10 9 /L) 19.1 [1.2-96.6]PB blasts (%) 33.5 [0-94]BM blasts (%) 60.5 [1-94]Cortes-Franco J, et al. ASH Annual Meeting Abstracts. 2009;114(22):864.


ResponseHematologicDanusertib in CML AP/BP and ALLResponse to TherapyAPN = 5No. (%)BPN = 8ALLN = 11CHR - - 1Minor 1 - -HI - 3 6CytogeneticMCyR - - 2CCyR - - 1PCyR - - 1Minor 1 - -Cortes-Franco J, et al. ASH Annual Meeting Abstracts. 2009;114(22):864.


% Blasts1009080706050403020100Danusertib in CML AP/BP and ALLClinical ActivityPatient # 0016 Ph+ T315I ALL: 150 mg/m 2Off Study after Cycle 40 7 14 21 28 35 42 49 56Days on Therapy% PB Blasts % BM BlastsCortes-Franco J, et al. ASH Annual Meeting Abstracts. 2009;114(22):864.


PercentageDanusertib in CML AP/BP and ALLClinical Activity• 55 y/o female, Ph+ ALL with T315I• CT + Imatinib + SCT Relapse Dasatinib + DLI Relapse Dasatinib + Steroids Relapse (T315I)• Danusertib 120 mg/m 2 IV, over 3h, days 1-7, Q2wks10080BM blasts% Ph+60402001 35 64 100 147 150 183 266 390Days on therapyCortes-Franco J, et al. ASH Annual Meeting Abstracts. 2009;114(22):864.


Investigational Options for PatientsWith the BCR-ABL/T315I MutationDanusertib (PHA-739358) - an ABL/Aurora inhibitorOmacetaxine (Homoharringtonine) - a protein synthesis inhibitor


Safety and Efficacy of Subcutaneous-Administered Omacetaxine Mepesuccinate inImatinib-Resistant Chronic Myeloid Leukemia(CML) Patients Who Harbor the BCR-ABL T315IMutation – Results of An Ongoing MulticenterPhase II/III StudyJ Cortes, HJ Khoury, F Nicolini, S Corm,J Lipton, D Jones, A Hochhaus, A Craig,A Benichou, E Humphriss, H KantarjianOn behalf of the CML-202 Study GroupCortes-Franco J, et al. ASH Annual Meeting Abstracts. 2009;114(22):644.


Omacetaxine for CML With T315IMechanism of Action First-in-class cetaxine, inhibitor of protein elongation 1 Potent inhibitory activity against leukemic cells, includingT315I+ cells 1 Activity independent of BCR-ABL binding Induces apoptosis by inhibiting the anti-apoptoticoncoprotein Mcl-1 2 Inhibits cell growth and induces apoptosis in CD34+ cells 3 Clinical activity in CML after imatinib failure 41Chen R, et al. Cancer Res. 2006;66(22):10959-10966.2Tang R, et al. Mol Cancer Ther. 2006;5(3):723-731.3Allan, et al. Haematologica. 2009;94(suppl.2):423:1052.4Quintas-Cardama A, et al. Cancer. 2007;109(2):248-255.


Omacetaxine for CML With T315IResponse to TherapyNo. (%)ResponseCPN = 49APN = 17BPN = 15Hematologic 42 (86) 6 (35) 7 (47)CHR 42 (86) 5 (29) 3 (20)HI NA 3 (18) 1 (7)RCP NA 1 (6) 4 (27)Cytogenetic 20 (41) 1 (6) -MCyR 13 (27) 1 (6) -CCyR 9 (18) 1 (6) -PCyR 4 (8) - -Minimal 7 (14) - -Data independently adjudicated by Data Monitoring CommitteeCortes-Franco J, et al. ASH Annual Meeting Abstracts. 2009;114(22):644.


Omacetaxine for CML With T315IDuration of ResponseMedian Duration in monthsResponseCPN = 49APN = 17BPN = 15Hematologic 9.1 6.6 2Range 0.7-30.3 0.9-14.8 0.5-4.7MCyR 4.7 8.3 -Range 0.1-14.1 - -Cortes-Franco J, et al. ASH Annual Meeting Abstracts. 2009;114(22):644.


Omacetaxine for CML With T315IPatient DispositionNo. (%)Patient DispositionCPAPBPN = 49N = 17N = 15Treatment ongoing 19 (39) 2 (12) 1 (7)Treatment discontinued 30 (61) 15 (88) 14 (93)Disease progression 9 (19) 6 (34) 10 (66)Lack of response 6 (12) 1(6) 0 (0)Adverse event 4 (8) 3 (18) 0 (0)Death on study 4 (8) 3 (18) 4 (27)PI/patient request 3 (6) 2 (12) 0 (0)Other 4 (8) 0 (0) 0 (0)Cortes-Franco J, et al. ASH Annual Meeting Abstracts. 2009;114(22):644.


Investigational Options for PatientsWith the BCR-ABL/T315I MutationDanusertib (PHA-739358) - an ABL/Aurora inhibitorOmacetaxine (Homoharringtonine) - a protein synthesis inhibitorPonatinib (AP24534) - a BCR-ABL kinase inhibitor


AP24534 Skirts Increased Bulk ofIle Side-ChainI315• Imatinib NH clashes withCβ and Cγ of Ile sidechain• Linear triple bond ofAP24534 skirts Ile side chainmaking productive vdWcontactimatinibI315AP24534


Percent viable cellsAP24534 Potently Inhibits Ba/F3Cell Lines Driven by BCR-ABL T315I120100806040200-201 10 100 1000Compound Conc. (nM)AP24534imatinibdasatinibnilotinibIC90 = 28 +/- 8 nM,or 15 ng/mL• Cells killed by apoptosis within 24hrO'Hare T, et al. Cancer Cell. 2009;16(5):401-412.


A Phase I Trial of Oral AP24534 inPatients With Refractory ChronicMyeloid Leukemia and OtherHematologic Malignancies: FirstResults of Safety and Clinical ActivityAgainst T315I and Resistant MutationsJ Cortes, M Talpaz, M Deininger, N Shah,I Flinn, M Mauro, T O’Hare, N Spinos, S Hu,L Berk, N Narasimhan, VM Rivera,T Clackson, FG Haluska, H KantarjianCortes J, et al. ASH Annual Meeting Abstracts. 2009;114(22):643.


Phase I Study of AP24534Patient Characteristics (N = 44)CharacteristicsNo. (%) or Median [range]Age, y 62 [26-85]Years from diagnosis to Rx 2 [0-17]Diagnosis All (n = 44) T315I (n = 18)CML – CP 28 (64) 10 (56)CML – AP 5 (11) 2 (11)CML – BP 5 (11) 4 (22)Ph+ ALL 2 (5) 2 (11)Myelofibrosis 2 (5) --MDS 1 (2) --Multiple Myeloma 1 (2) --Ph+ patients (n = 36)≥ 2 Prior TKIs 35 (97)≥ 3 Prior TKIs 29 (81)Ph+ patients with mutations 34 (85)Cortes J, et al. ASH Annual Meeting Abstracts. 2009;114(22):643.


Phase I Study of AP24534Current StatusStatus (N = 44) No. (%)Still on therapy 28 (64)Discontinued treatment 16 (36)Toxicity 1 (2)Disease progression 7 (16)Death on study 2 (5)Investigator decision/other 6 (14)Median duration (days) 55 (1-360)Cortes J, et al. ASH Annual Meeting Abstracts. 2009;114(22):643.


Phase I Study of AP24534Best Response to Therapy (Ph+ T315I)BestResponseNo. (%)CP AP, BP, ALL OverallHematologic N = 7 N = 8CHR 7 (100) -- 7 (100)MHR -- 3 (38) 3 (38)Cytogenetic N = 7 N = 8 N = 15MCyR 3 (43) 1 (13) 4 (27)CCyR 2 (29)* 1 (13) 3 (20)PCyR 1 (14) 0 (0) 1 (7)Minor 1 (14) 0 (0) 1 (7)Minimal 0 (0) 1 (13) 1 (7)*8/11 (73%) CP/T315I patients have achieved CCyR – Cortes J, et al. ASH 2010. Abstract 210.Cortes J, et al. ASH Annual Meeting Abstracts. 2009;114(22):643.


The BCR-ABL/T315I Mutation in 2010• The BCR-ABL/T315I mutation is uncommon, estimated to arise inapproximately 2-5% of imatinib-treated chronic phase CMLpatients (4-19% of imatinib-resistant patients)– The incidence of the BCR-ABL/T315I mutation in imatinibresistantblast phase CML and Ph+ ALL is substantially higher• BCR-ABL/T315I may be more common in patients with loss ofresponse to second generation BCR-ABL TKIs, although it isplausible that loss of response to these TKIs will occur lessfrequently than for imatinib• For patients who evolve the BCR-ABL/T315I mutation, severalpromising investigational options exist

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