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
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?
Case 1 – decision 1 A - Continue on Nilotinib B - Change to other TKI C – Consider/refer for allo SCT D - Other
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%
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 - +6 8/200 +X 10/200 + 8 20/200 NO evidence of dysplasia What would you do now?
Case 1 – decision 3 A - Continue on Nilotinib B - Change to other TKI C – Consider/refer for allo SCT D - Other
Case 1 Patient continued on Nilotinib Repeat marrow at 18 months – ALL cells Ph-ve, ONLY + 8 18/200 cells Foe repeat marrow at 2 years and ?beyond
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- 1701 evaluable patients, 21 with CCA/Ph-, 3 developed other haem malignancies – (1 AML and 2 MDS-> AML)
Case 2 Patient 2 - 36 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
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?
Case 2 – decision 1 A - Continue on Imatinib B - Change to 2TKI C – Consider/refer for allo SCT D - Other
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?
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
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?
Case 2 – decision 3 A - Continue on Dasatinib B - Change to other TKI (bosutinib, nilotinib, ponatinib) C – Consider/refer for allo SCT D - Other
Case 2 Patient continues on Dasatinib Tissue typed and early discussions re transplant
Case 3 Patient 3 28 y male diagnosis in 2005 WCC 143, Spleen 12cm Sokal/Hasford – Low No siblings, caucasian background Started IM 400mg
Case 3 CHR but not CCR(4% Ph+) after 1 year, BCR-ABL 2% IM increased to 600mg and then 800mg (2005-2007) Eventual CCR (~24/12), without MMolR, BCR-ABL: ABL ratio – 0.4-0.7% Mutation screen negative What would you do now?
Case 3 – decision 1 A - Continue on 800mg Imatinib B - Change to 2TKI C – Consider/refer for allo SCT D - Other
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
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
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
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
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 ( email@example.com ) firstname.lastname@example.org
Acknowledgements Tessa Holyoake, Glasgow Adam Meade, Oxford