Chronic myeloid leukemia (CML) Warunsuda Sripakdee, BCOP,BCP Prince of Songkla University

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1 Chronic myeloid leukemia (CML) 1 Warunsuda Sripakdee, BCOP,BCP Prince of Songkla University

2 Hematologic malignancies CML ALL AML 2

3 CML CD34+ results from an acquired mutation that affects hematopoietic stem cells excessive mature neutrophil production median age at diagnosis is 67 years old more common in males 3

4 Pathogenesis of CML 95% of CML patients have the BCR-ABL fusion gene ₒ TK region 4

5 Molecular abnormality in CML 5

6 Molecular abnormality in CML promoting instability of the leukemic clone marrow progenitor cells - increasing ly likely to undergo proliferation less capacity for selfrenewal! Additional cytogenetic abnormalities such as trisomy 8, isochromosome 17, trisomy 21 and deletion 7 End-stage disease 6

7 CML Risk Factors : ionizing radiation! Signs and symptoms Clinical - abdominal pain - early satiety due to splenomegaly - anorexia - bone pain purport - unexplained weight loss ±fatigue Laboratory - leukocytosis(usua lly >25,000 cells/ mm - increased LDH - other CBC: megakaryocytosis, basophilia, eosinophilia Bone marrow - hypercellular (75-90%) - increased erythropoiesis & megakaryocytic - Blasts <10% 7

8 Natural history of disease Chronic phase Accelerated phase Blast phase World Health Organization (WHO) Criteria Accelerated Phase Blast Crisis Blasts 10-19% of WBCs in peripheral and/or bone marrow Persistent thrombocytopenia (< 100,000 cells/mm 3 ) unrelated to therapy or persistent thrombocytosis (>1,000,000 cells/mm 3 ) unresponsive to therapy Increasing spleen size and increasing WBC unresponsive to therapy blood cells or of bone marrow cells Extramedullary blast proliferation Large foci or clusters of blasts in the bone marrow biopsy Cytogenetic evidence of clonal evolution additional cytogenetic abnormalities (extra Ph, trisomy 8, trisomy 19 and/or isochromosome 17) 8

9 Risk stratifications Study Calculation Sokal et al, Exp x (age in years ) + (spleen ) x 700) 2 Low <0.8 Intermediate High >1.2 Hasford et al, when age 50 years + (0.042 x spleen) when platelet count > 1500 x 10 9 /L + ( x blast cells) when basophils > 3% + ( x eosinophils) x 100 Low 780 Intermediate High >1480 clinical trial & initial treatment selection 9

10 Treatment of CML tyrosine kinase inhibitors (TKIs): 10 yrs OS 80-90% dasatinib, nilotinib, bosutinib, and ponatinib others agent : omacetaxine goals of treatment CP-CML: prevent progression to AP or BP AP-CML : induce second chronic phase BP-CML : induce second chronic phase!! 10

11 Response criteria in CML Type of Response Hematologic Cytogenetic Molecular Criteria Complete (CHR): Normal peripheral blood count WBC < 10,000 cells/ mm 3 Platelets < 450,000 cells/mm 3 No immature cells in the peripheral blood No signs or symptoms of disease Complete (CCyR): 0% Ph+ metaphases Partial (PCyR): 1-35% Ph+ metaphases Major (MCyR): 0-35% Ph+ metaphases (complete + partial responses) Minor: >35% Ph+ metaphases Complete (CMR): no detectable BCR-ABL mrna by QPCR (IS) Major (MMR): Cytogenetic remission with 3 log or greater reduction in BCR- ABL transcripts by QPCR (IS) goal standard - CCyR at 12 month; improved survival now- MMR is early goal for CML 4.5 log reduction of BCR-ABL - outcome predictor 11

12 Response criteria in CML Time Optimal response Warning Failure Baseline 3 mos. BCR-ABL IS 10%* Ph+ 35% (PCyR) 6 mos. BCR-ABL IS <1%* Ph+ 0% (CCyR) High risk Major route CCA/Ph+ BCR-ABL IS >10%* Ph % BCR-ABL IS 1-10%* Ph+ 1-35% 12 No CHR* Ph+ >95% BCR-ABL IS >10%* Ph+ >35% 12 mos. BCR-ABL IS 0.1%* (MMR) BCR-ABL IS 0.1-1%* BCR-ABL IS >1%* Ph+ >0% Then, and at any time UPDATE 2013 European LeukemiaNet Recommendations for the Management of Chronic Myeloid Leukemia (CML) Response definitions for any TKI first line, and 2nd line in case of intolerance, all patients (CP, AP, and BC) MMR or better CCA/Ph- (-7, or 7q-) Loss of CHR Loss of CCyR Loss of MMR, confirmed** Mutations CCA/Ph+ *and/or **in 2 consecutive tests, of which one 1% IS: BCR-ABL on International Scale Treatment recommendations

13 Response criteria in CML RESPONSE MILESTONES c,e BCR-ABL1 (IS) 3 months 6 months 12 months >12 months >10% f YELLOW RED >1% 10% GREEN YELLOW RED >0.1% 1% GREEN YELLOW 0.1% GREEN RED YELLOW CLINICAL CONSIDERATIONS Evaluate patient compliance and drug interactions Mutational analysis Evaluate patient compliance and drug interactions Mutational analysis SECOND-LINE AND SUBSEQUENT TREATMENT OPTIONS Switch to alternate TKI (CML-5) and Evaluate for HCT (CML-6) Switch to alternate TKI (CML-5) or Continue same TKI (CML-F) g or Dose escalation of imatinib (to a max of 800 mg) and Evaluate for HCT (CML-6) GREEN Monitor response (CML-F Continue same TKI (CML-F) h 13

14 First line therapy for chronic phase CML 14

15 First line therapy Imatinib: irreversible TKI,bind to the inactive / closed conformation of ABL enzyme, c-kit, PDGFR Results of the IRIS trial Selected Results of the IRIS Trial and Follow-up Studies Endpoint Imatinib IFN + Cytarabine P value FFP at 18 months 96.7% 91.5% < MCyR at 18 months 87.1% 34.7% < CCyR at 18 months 76.2% 14.5% < CCyR at 5 years 87% --- NR OS at 5 years 89% --- NR EFS at 8 years 81% --- NR FFP at 8 years 92% --- NR 15

16 Trial Cortes et al. (2010) ( TOPS ) Hehlmann et al. (2011) ( German CML IV ) Selected Trials of High-Dose Imatinib in Newly Diagnosed CP-CML Population Imatinib Imatinib Endpoint 800 mg/day 400 mg/day 476 patients with newly diagnosed CP-CML 1551 patients with newly diagnosed CP- CML First line therapy Imatinib: TOPS and German CML IV trials: high-dose versus low dose imatinib P value CCyR at 12 months 70% 66% 0.35 High-dose imatinib (>400 mg/day) MMR at 12 months is not currently 46% recommended 40% 0.20 as initial therapy for patients with newly diagnosed CP-CML. MMR at 42 months 50.2% 51.6% NS MMR at 12 months 59% 44% < PFS at 3 years 94% 94% NS OS at 3 years 95% 95% NS PFS at 60 months 87.5% 87.5% NS OS at 60 months 90% 90% NS higher rates of dose interruption, reduction and discontinuation due to grade 3 or 4 adverse events 16

17 First line therapy Dasatinib: inhibit active/inactive ABL and Src family of kinases, c-kit, PDGFR 325 times more potent than imatinib activity against nearly all BCR-ABL mutations resistant to imatinib (except T315I)! Results of the DASISION trial Selected Results from the DASISION Trial and Follow-Up Studies Endpoint Dasatinib Imatinib P value (n = 259) (n = 260) Median time to CCyR 3.1 months 5.8 months NR CCyR at 12 months 83% 72% MMR by 12 months 46% 28% < Median time to MMR 15 months 36 months NR MMR at any time 52% 34% < Disease progression during study treatment 3% 5% NR CCyR at 60 months 83% 78% MMR at 60 months 76% 64% PFS at 60 months 85% 86% NR OS at 60 months 91% 17 90% NR

18 First line therapy Nilotinib inhibit inactive/closed ABL, c-kit, PDGFR better topographic fit to the ATP binding site than imatinib 30 times more potent than imatinib Endpoint CCyR by 12 months MMR by 12 months CCyR by 24 months MMR by 24 months Disease progression by 24 months Treatment failure at 12 months PFS at 48 months OS at 48 months MMR at 60 months Still on initial treatment at 60 months Results of the ENESTnd trial Selected Results from the ENESTnd Trial Nilotinib Nilotinib 300 mg BID 400 mg BID (n = 282) (n = 281) 80% 78% (p < 0.001) (p < 0.001) 44% 43% (p < 0.001) (p < 0.001) 87% 85% (p = ) (p = 0.016) 71% 67% (p < ) (p < ) < 0.7% < 1.9% (p = ) (p = ) 3% 2% (p = NR) (p = NR) 96.7% 97.8% (p = NR) (p = NR) 92.7% 96.7% (p = NR) 77% (p < 0.001) 60% (p = NR) 18 (p = NR) 77% (p < 0.001) 62% (p = NR) Imatinib 400 mg daily (n = 283) 65% 22% 77% 44% 4.8% 8% 93.1% 93.3% 60% 50%

19 Initial selection of TKI low-risk disease: imatinib, nilotinib, dasainib (category 1) high-risk disease : nilotinib, dasatinib (categoy 1) dasatinib and nilotinib -superior CCyR and MMR at lower rates of PD when compared to imatinib Neither dasatinib nor nilotinib - improved OS or PFS compared to imatinib. the DASISION and ENESTnd - intermediate- and high- risk patients may preferentially benefit from dasatinib or nilotinib 19

20 Initial selection of TKI NCCN Guidelines Version Chronic Myeloid Leukemia NCCN Guidelines Index Table of Contents Discussion CLINICAL PRESENTATION PRIMARY TREATMENT Chronic phase CML Treatment Considerations: Patient comorbidities and drug toxicities Monitor response c Evaluate patient compliance and drug interactions Early toxicity monitoring Low-risk score (See Risk Calculation Table CML-A) Intermediate- or highrisk score (See Risk Calculation Table CML-A) First generation TKI (Imatinib or generic imatinib 400 mg QD) (category 1) or Second generation TKI (Bosutinib or Dasatinib or Nilotinib or Clinical trial First generation TKI (Imatinib or generic imatinib 400 mg QD) or Second generation TKI (Bosutinib d or Dasatinib 100 mg QD d or Nilotinib 300 mg BID d ) or Clinical trial See Response Milestones and Treatment Options (CML-3) c See Response Milestones and Treatment Options (CML-3) c 20

21 Initial selection of TKI Choice of first-line therapy should be individualized. a. Potential toxicity profiles b. Patient s age and ability to tolerate therapy c. Presence of comorbid conditions d. Patient s risk score e. Physician experience 21

22 ! Responding patients should continue therapy indefinitely. STIM & TWISTER trials STIM TWISTER EURO-SKI 100 patients with CP- CML who had CMR for > 2 yrs. 61% of patients relapsed after stop imatinib 95% of relapses occurring within 7 months of stopping imatinib low-risk Sokol score and duration of imatinib therapy >54 months -continued response after imatinib cessation Discontinuation of TKI!! 40 patients with CP- CML who had been in CMR for 2 or more years TFR at 2 years was 45% High Sokal score and shorter duration of interferon treatment - increased risk of relapse patients with CP-CML who had been in long term MR 70% TFR

23 Discontinuation of TKI ALL of the following criteria are met: 1) Consultation with a CML Specialty Center 2) Age 18 years 3) no history of accelerated phase or blast crisis 4) On TKI therapy 3 years 5) Prior evidence of detectable disease via BCR-ABL1 transcript 6) Stable molecular response (MR4) for 2 years (at least 4 tests performed at least 3 months apart) 7) No history of resistance to any TKI 8) Access to reliable response monitoring 9) Monthly molecular monitoring for the first 6 months following discontinuation, bimonthly during months 7-24, and quarterly thereafter if still in MMR 10) Prompt resumption of TKI in patients with loss of MMR 23

24 Second line therapy 24

25 Second line therapy the selection of an alternative TKI is based on prior therapy concurrent disease states mutational testing 25

26 Second line therapy 2nd lind Tx: dasatinib, nilotinib or bosutinib 1st line imatinib yes no other TKIs other TKIs except imatinib 26

27 Second line therapy TREATMENT OPTIONS BASED ON BCR-ABL1 MUTATION PROFILE Mutation Y253H, E255K/V, or F359V/C/I F317L/V/I/C, T315A, or V299L E255K/V, F317L/V/I/C, F359V/C/I, T315A, or Y253H T315I Treatment Recommendation j Dasatinib Nilotinib Bosutinib Ponatinib, k Omacetaxine, l allogeneic HCT (CML-6), or clinical trial 27

28 Predictive factors for achievement of a cytogenetic response to second-line TKI therapy 1. Low Sokal score at diagnosis 2. Best cytogenetic response on imatinib 3. Neutropenia at any time during imatinib therapy requiring dose reduction despite growth factor support 4. Time from detection of imatinib failure to start of second-line TKI 28

29 Second line therapy Bosutinib : inhibit dual ABL/SRC family of kinases! minimal inhibit: c-kit, PDGFR, Src, Lyn and Hck kinases against many BCR-ABL kinase domain mutations that are resistant to imatinib, dasatinib and nilotinib (except T315I and V299)! 200 times more potent than imatinib 29

30 Second line therapy: Bosutinib Bosutinib Versus Imatinib in Newly Diagnosed Chronic- Phase Chronic Myeloid Leukemia: Results From the BELA Trial A Complete Cytogenetic Response (%) Bosutinib Imatinib * B Major Molecular Response (%) Bosutinib Imatinib 3 27 * * * 27 Time Since Treatment Initiation (months) Time Since Treatment Initiation (months) The trial did not meet its primary endpoint of improved CCyR at 12 months. 30

31 not currently recommended in the first-line setting (prep course 2017) The ASCO Post Results from the randomized BFORE trial. J Clin Oncol. November 1, 2017 Second line therapy: Bosutinib FDA Grants Accelerated Approval to Bosutinib for Treatment of Newly Diagnosed Philadelphia Chromosome " Positive CML # $ By The ASCO Post December 25, 2017 Tweet this page On December 19, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval to bosutinib (Bosulif) for treatment of patients with newly diagnosed chronic-phase Philadelphia chromosome positive chronic myelogenous leukemia (CML). Approval was based on data from an open-label, randomized, multicenter BFORE trial in 487 patients with Philadelphia chromosome positive newly diagnosed chronic phase CML who were randomized to receive either bosutinib at 400 mg once daily or imatinib (Gleevec) at 400 mg once daily. The major e!cacy outcome measure was major molecular response (MMR) at 12 months, defined as 0.1% BCR-ABL ratio on international scale (corresponding to 3 log reduction from standardized baseline) with a minimum of 3,000 ABL transcripts as assessed by the central laboratory. MMR at 12 months was 47.2% (95% confidence interval [CI] = ) in the bosutinib arm and 36.9% (95% CI = ) in the imatinib arm (P =.0200). The most common adverse reactions in patients with newly diagnosed CML (incidence 20%) are diarrhea, nausea, thrombocytopenia, rash, increased alanine aminotransferase, abdominal pain, and increased aspartate aminotransferase. 31 1

32 Second line therapy: Bosutinib Selected Trials of Bosutinib in the Second-Line Setting Citation Population MCyR CCyR PFS OS Cortes et al. (2011) 288 pts with imatinib-resistant or intolerant CP-CML 53% 41% 79% at 24 mo 92% at 24 mo 32

33 Second line therapy: Dasatinib Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA Am. J. Hematol. 91: , VC 2016

34 Second line therapy: Dasatinib Drug-Related Adverse Events of Interest Over Time Treated patients, n/at risk (%) 100 mg QD (n 5 165) Other dose groups (n 5 497) 2-year 5-year 7-year 2-year 5-year 7-year Pleural effusion 23/121 (14) 40/55 (24) 46/42 (28) 118/309 (24) 158/127 (32) 174/91 (35) Pulmonary hypertension 0 (0) 0 (0) 3 (2) 5 (1) 8 (2) 13 (3) Pulmonary arterial hypertension 0 (0) 1 (<1) 0 (0) 0 (0) 34

35 Second line therapy: Nilotinib nilotinib in the second-line setting Selected Trials of Nilotinib in the Second-Line Setting Citation Population MCyR CCyR PFS OS Kantarjian et al. (2011) Giles et al. 321 pts with imatinib-resistant or intolerant CP-CML 321 pts with imatinib-resistant or intolerant CP-CML 59% 44% 64% at 24 mo 87% at 24 mo 59% 45% 57% at 48 mo 78% at 48 mo 35

36 Second line therapy: Milestone for second line drug Time Optimal response Warnings Failure Baseline 3 mos. BCR-ABL IS 10%* Ph+ <65% 6 mos. BCR-ABL IS 10%* Ph+ <35% (PCyR) 12 mos. BCR-ABL IS <1%* Ph+ 0 (CCyR) Then, and at any time MMR or better No CHR Loss of CHR on imatinib Lack of CyR to 1 st line TKI High risk BCR-ABL IS >10%* Ph % BCR-ABL IS 10%* Ph % BCR-ABL IS 1-10%* Ph+ 1-35% CCA/Ph- (-7 or 7q-) or BCR-ABL IS >0.1% No CHR, or Ph+ >95%, or New mutations BCR-ABL IS >10%* Ph+ >65%* New mutations BCR-ABL IS >10%* Ph+ >35%* New mutations Loss of CHR, or Loss of CCyR or PCyR New mutations Loss of MMR** CCA/Ph+ *and/or **in 2 consecutive tests, of which one 1% IS: BCR-ABL on International Scale NCE EUROPEAN LEUKEMIANET - PUBLISHER: 36

37 Third line therapy and beyond 37

38 Third line therapy and beyond No TKI is specifically indicated for treatment failure of both first- and second-generation TKIs. current literature restricted to observational studies or studies with small patient populations Allogeneic stem cell transplantation may be considered! 38

39 Third line therapy and beyond Omacetaxine mepesuccinate (Synribo ) MOA antileukemic effect of omacetaxine is independent of BCR-ABL binding option for patients with resistance and/or intolerance to two or more TKIs 39

40 Third line therapy and beyond Omacetaxine mepesuccinate (Synribo ) 2 phase II studies have been conducted in CP-CML: patients with a T315I mutation or who had failed treatment with one or more TKIs patients that had failed treatment with two or more TKIs allowed enrollment of patients who were in AP-CML CCyR of 4-16% ; median PFS months major adverse effects - myelosuppression subcutaneous, twice-daily dosing schedule - limit compliance 40

41 Primary Resistance Resistance to TKIs A. Primary hematologic resistance failure to achieve a hematologic remission 3-6 months after initiation of therapy B. Primary cytogenetic resistance! failure to achieve any cytogenetic response at 6 months, MCyR at 12 months, or CCyR at 18 months! 41

42 Resistance to TKIs Primary Resistance Dose escalation of imatinib : 800 mg/day Pt with cytogenetic relapse who achieved a complete cytogenetic response with standarddose imatinib suboptimal cytogenetic response to standard dose imatinib! 42

43 Resistance to TKIs Secondary Resistance T315I mutation gatekeeper resistance to all currently available TKIs except ponatinib 43

44 BCR-ABL1 mutation analysis results may predict response to TKIs BCR-ABL1 mutation T315I V299L Predicts resistance to Imatinib Dasatinib Nilotinib Bosutinib Dasatinib Bosutinib Consider preferential use of Ponatinib Nilotinib F317L/V/I/C Dasatinib Bosutinib Y253F/H Nilotinib Bosutinib E255K/V Nilotinib No preference F359V/I/C Nilotinib Bosutinib 44

45 Treatment of T315I mutated CML Ponatinib or Omacetaxine Ponatinib : 3rd generation TKIs PACE study : patients with resistance or intolerance to prior TKI therapy or with the T315I mutation A Chronic-Phase CML Total Resistance or side effects (N=267) (N=203) Patients (%) Complete Hematologic Response Major Cytogenetic Response Complete Cytogenetic Response Major T315I (N=64) Molecular Response Total (N=149) Probability of Susatained Major Cytogenetic Response Resistance or side effects (N=104) Months after First Major Cytogenetic Response T315I (N=45) Probability of Overall Survival Total (N=267) Resistance or side effects (N=203) Months T315I (N=64) 4-year MMR rate - 61%, 4-year PFS- 56%, 4- year OS -77%

46 Treatment of T315I mutated CML Ponatinib : Epic trial was terminated after the observation of arterial thrombotic events.! pan-vegf inhibition Black Box Warning Current guidelines recommend consideration of ponatinib only for patients with a T315I mutation and for patients who have failed 2 or more prior TKIs 46

47 TKI Toxicities 47

48 TKI Toxicities strong negative association between comorbidities at diagnosis and OS in patients with CP-CML no negative effect of comorbidities on remission rates or progression to advanced stages of disease 48

49 TKI toxicities Suggestions for management of common TKI toxicities Toxicity Neutropenia Anemia Thrombocytopenia Rash Management Strategy Hold until recovery, potential dose reduction Myeloid growth factors may be considered ESAs not supported in patients with myeloid malignancies. Hold until recovery, potential dose reduction Topical or systemic steroids Dose reduction, interruption or discontinuation 49

50 Unique TKI toxicities related to the agent s off-target kinase profile Imatinib Dasatinib Fluid retention (pleural effusion, pericardial effusion, edema, ascites) Muscle cramps Pulmonary arterial hypertension (PAH) Fluid retention (pleural effusion, pericardial effusion, edema, ascites) Platelet inhibition Loop diuretics Decrease sodium intake Supportive care Consider checking left ventricular ejection fraction Dose reduction, interruption or discontinuation Calcium supplementation Tonic water Discontinue therapy Diuretics Supportive care, including oxygen and thoracentesis Consider short course of corticosteroids Dose reduction, interruption or discontinuation Use caution with other anti-platelet agents (e.g., aspirin, clopidogrel) 50

51 Unique TKI toxicities Nilotinib Bosutinib Ponatinib QT prolongation Elevated serum lipase or amylase Hepatic toxicity Peripheral arterial occlusive disease (PAOD) Metabolic syndrome (hyperglycemia, hypercholesterolemia, hypertriglyceridemia) Hepatic toxicity Diarrhea Hepatic toxicity Ischemic reactions, hypertension, vascular occlusion, heart failure Elevated serum lipase or amylase Symptomatic pancreatitis ECG to measure QTc at baseline, 7 days after initiation and periodically thereafter Correct hypokalemia and hypomagnesemia Consider dose reduction or discontinuation 51 Hold until recovery, then dose reduction Hold until recovery, then dose reduction or discontinuation Eliminate all risk factors (smoking, obesity, hypertension, etc) Consider prophylactic aspirin therapy Discontinue therapy Maximize glycemic, cholesterol and triglyceride control Hold until recovery, then dose reduction or discontinuation Antidiarrheal medication and fluid replacement Hold until recovery Hold until recovery, then dose reduction or discontinuation Control risk factors for hypertension and atherosclerosis Referral to cardiologist Discontinue therapy Hold until recovery, then dose reduction

52 Pharmacologic considerations of TKI therapy Table 12. Pharmacologic considerations of TKI therapy. Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Chronic phase dosing Dose reductions required Food-drug interactions 400 mg PO daily Hematologic Renal impairment Hepatic impairment Improved tolerability with food Take with a large glass of water 100 mg PO daily Hematologic Improved tolerability with food 300 mg PO twice daily Hematologic Hepatic impairment Take on an empty stomach (1 hour before or 2 hours after eating) 500 mg PO daily Hematologic Hepatic impairment Improved tolerability with food Take with a large glass of water 45 mg PO daily Hematologic Hepatic impairment Can be taken with or without food Metabolism CYP3A4 substrate and inhibitor Weak inhibitor of CYP2D6 and 2C9 CYP3A4 substrate CYP3A4 substrate and inhibitor *Also 2C8, 2C9 and 2D6 CYP3A4 substrate CYP3A4 substrate Potential drug interactions Use warfarin with caution Requires acidic gastric environment - avoid acid reducers (H2 antagonists and PPIs) and separate antacids by 2 hours Black box warning for QT-prolonging drugs PPIs may decrease bosutinib concentrations consider using H2 antagonists or short-acting antacids Elevated gastric ph may reduce bioavailability avoid PPIs, H2 antagonists and antacids if possible Assistance 52

53 Accelerated phase / blast crisis Goal - return patient to chronic phase Bone marrow cytogenetics and mutational analysis prior to the initiation of treatment use TKIs to reduce the disease burden prior to allo HSCT Achieving MCyR or CCyR to TKI therapy prior to allo HSCT - better transplant outcome! 53

54 Accelerated phase Treatment : accelerated phase - imatinib 600 mg OD, dasatinib 140 mg OD, nilotinib 400 mg bid or bosutinib 500 mg OD - Omacetaxine - not an option for patients who present with AP-CML. 54

55 Blast crisis blast crisis - TKI+chemotherapy - RR 25-60% (AML or ALL) + HCST - TKI + steroids! 55

56 TKIs for the treatment of relapse after allo HSCT! 1.TKI ± DLI- imatinib, dasatinib, nilotinib, bosutinib 2. Omacetaxine! 56

57 57