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CML & MPDs Practitioner Conference CML: Cases and interactive voting Brian Huntly University of Cambridge and Addenbrookes Hospital.

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Presentation on theme: "CML & MPDs Practitioner Conference CML: Cases and interactive voting Brian Huntly University of Cambridge and Addenbrookes Hospital."— Presentation transcript:

1 CML & MPDs Practitioner Conference CML: Cases and interactive voting Brian Huntly University of Cambridge and Addenbrookes Hospital

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3 Case 1 37 year old male WCC 80, Plts 840, Baso 6%, Blasts 2%, no spleen BCR-ABL positive, Sokal/Hasford low-risk 3 siblings Started on Nilotinib in ENEST trial, March 2011

4 Case 1 Patient entered CHR but problems with cytopenias Further cytopenias (Gd III thrombocytopenia and neutropenia) required dose interruption Early marrow 3 months of Nilotinib – Ph 40%, BCR-ABL:ABL ratio 43% Tissue typing demonstrates a fully matched sib What would you do now?

5 Case 1 – decision 1 A - Continue on Nilotinib B - Change to other TKI C – Consider/refer for allo SCT D - Other

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7 Case 1 Patient continued on Nilotinib 2 further 3 week interruptions due to cytopenias Repeat marrow at 6 months – 25% Ph positive, 31% BCR-ABL:ABL ratio 43% What would you do now?

8 Case 1 – decision 2 A - Continue on Nilotinib B - Change to other TKI C – Consider/refer for allo SCT D - Other

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10 Case 1 Patient continued on Nilotinib No further interruptions due to cytopenias Repeat marrow at 12 months – 0/200 cells Ph positive, BCR-ABL:ABL ratio 0.1%

11 Case 1 Patient continued on Nilotinib No further interruptions due to cytopenias Repeat marrow at 12 months – 0/200 cells Ph positive, BCR-ABL:ABL ratio 0.1% BUT – Karyotype shows 3 small separate clones /200 +X 10/ /200 NO evidence of dysplasia What would you do now?

12 Case 1 – decision 3 A - Continue on Nilotinib B - Change to other TKI C – Consider/refer for allo SCT D - Other

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14 Case 1 Patient continued on Nilotinib Repeat marrow at 18 months – ALL cells Ph-ve, ONLY /200 cells Foe repeat marrow at 2 years and ?beyond

15 Significance of clonal abnormalities in Ph- clone following TKI? Incidence of clonal cytogenetic abnormalities in Ph NEGATIVE clone (CCA/Ph-) following TKI Rx varies (range of 2-17% of patients in described series) -7, -5, -Y and +8 most common Significance unknown Overall prognosis is good – one series of 515 patients – 30 CCA/Ph- patients with no difference in survival vs similar CCR patients (only 2/30 patients developed MDS median FU 51 months) MD Anderson evaluable patients, 21 with CCA/Ph-, 3 developed other haem malignancies – (1 AML and 2 MDS-> AML)

16 Case 2 Patient year old female lawyer Presented 2009 at 12 week booking – WCC 220, Plt 372, Spleen 3cm Sokal/Hasford – Low African ethnicity, 6 siblings Patient decided on a TOP Declined trial entry (SPIRIT 2, BELA) started Imatinib 400mg

17 Case 2 CHR at 3 months 6 month marrow – 18% Ph positive, BCR-ABL:ABL ratio 21% 1 year – 4% Ph pos, BCR-ABL:ABL ratio 9.7% What would you do now?

18 Case 2 – decision 1 A - Continue on Imatinib B - Change to 2TKI C – Consider/refer for allo SCT D - Other

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20 Case 2 Patient reports that she is pregnant! What would you do now?

21 Case 2 – decision 2 A - Continue on Imatinib B – Stop Imatinib and manage with leucapheresis C – Change to Interferon D - Other

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23 Management of pregnancy in patients with CML Tyrosine kinase inhibitors are associated with adverse outcomes during pregnancy (180 pregnancies, 12 (7%) fetal abnormalities, 18 (10%) spontaneous abortions) Of the 63 normal births in the series 18 (29%) received IM for the duration of the pregnancy Risk of interrupting therapy to the patient - relates to degree of response seen before cessation (Kuwabara et al Blood 2010 – only 2/7 patients achieved ≥ MMR after reintroduction TKI, both had an optimal MMR response before stopping) Options for control of disease: α-IFN Leucapheresis Use of TKI in 3 rd trimester?

24 Case 2 Imatinib stopped and patient discussed with fetal medicine – pregnancy monitored as high-risk 18/40 loss of HR - α-IFN and dose titrated against SE, LMWH Rx instituted MTD 3MU/3 x per week 28/40, WCC 58 -Leucapheresis instituted weekly, total of 9 required Scans all normal with no evidence of IUGR Induced at 36 weeks in discussion with obstetricians

25 Case 2 Following delivery patient commenced upon Dasatinib, advised not to breast feed, WCC 43, BCR-ABL: ABL ratio 117% CHR 3 weeks 3 months BCR-ABL: ABL ratio 64% 6 months BCR-ABL: ABL ratio 9.9% 12 months BCR-ABL: ABL ratio 1.3%, mutation screen negative 18 months BCR-ABL: ABL ratio 0.9% What would you do now?

26 Case 2 – decision 3 A - Continue on Dasatinib B - Change to other TKI (bosutinib, nilotinib, ponatinib) C – Consider/refer for allo SCT D - Other

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28 Case 2 Patient continues on Dasatinib Tissue typed and early discussions re transplant

29 Case 3 Patient 3 28 y male diagnosis in 2005 WCC 143, Spleen 12cm Sokal/Hasford – Low No siblings, caucasian background Started IM 400mg

30 Case 3 CHR but not CCR(4% Ph+) after 1 year, BCR-ABL 2% IM increased to 600mg and then 800mg ( ) Eventual CCR (~24/12), without MMolR, BCR-ABL: ABL ratio – % Mutation screen negative What would you do now?

31 Case 3 – decision 1 A - Continue on 800mg Imatinib B - Change to 2TKI C – Consider/refer for allo SCT D - Other

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33 Case 3 Patient changed to Dasatinib 100mg in May 2007 No change in BCR-ABL: ABL ratio on 3/12 100mg Dasatinib increased to 140mg Slow but steady response over next next 2.5 years Achieved MMolR in Feb 2010 – continues on Dasatinib 140mg in MMolR

34 Heart murmur picked up coincidentally 2012 – No symptoms Previous episode of palpitations 2008 – 24h Holter monitor and echo normal Repeat echo 2012– flow murmur, normal LV and RV function but increased pulmonary artery pressure suggested Confirmed by stressdoppler echo – Right heart catheterisation awaited ? Pulmonary Arterial Hypertension ? Dasatinib related What would you do now? Case 3

35 Case 3 – decision 2 A - Continue on Dasatinib at a lower dose B – Change back to Imatinib C – Change to another TKI (which Nilotinib/Bosutinib/Ponatinib) D - Consider/refer for allo SCT

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37 Reduction in dasatinib (100mg, possibly 50mg) with CML response and PAH monitoring ?Other TKI –which If PAH improves but molecular response worsens - ?Allo SCT Case 3

38 Dasatinib and PAH – learning points Reports from 2009 onwards Incidence is not known – French registry 0.45% (Montani et al Circulation 2012) Majority of patients are symptomatic (exertional dyspnoea) Pre-capillary, mutation negative for inherited PAH, no other predisposition Withdrawl, dose reduction are recommended Reversible component upon cessation of Dasatinib – degree variable Consider if DAS patients with exertional dyspnoea, no evidence of pleural effusion, pulmonary oedema, anaemia or lung infiltration Registry for side-effects of TKI – Dragana Milojkovic Hammersmith ( )

39 Acknowledgements Tessa Holyoake, Glasgow Adam Meade, Oxford


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