Colt 2014 - Devendra Hiwase - CML

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Advanced Phase CML :

Advanced Phase CML Devendra Hiwase RAH/SA Pathology

Advanced phase CML:

Advanced phase CML Diagnostic and management issues in CML-AP Diagnostic criteria and management of blast crisis

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Clinical Course: Phases of CML Chronic phase Median survival 4–6 years Advanced phases Accelerated phase Median survival ~1 year Blast crisis Survival ~ 4 to 6 months

1st CML patient (EW): Clinical Summary:

1 st CML patient (EW): Clinical Summary 54 year old lady presented with fatigue Aboriginal Heritage High BMI, smoker CBC (March 2013): Hb 76, WBC 9.38, platelet 960, neutrophils 5.82, basophils 1% and blasts 16% Bone Marrow: Hypercellular with blast 13 to 14% Bone marrow cytogenetic: 46XX, t(9;22) (q34;q11.2) [24] What is the diagnosis? CML-CP vs AP How shall we treat?

Staging of chronic myeloid leukemia in the imatinib era:

Staging of chronic myeloid leukemia in the imatinib era Cortes et al Cancer ; 2006;106 (6):1306-1315 Standard Criteria WHO Criteria 3 years OS 91% 3 years OS 95% 3 years OS 65% 3 years OS 10% 3 years OS 63% 3 years OS 16%

Survival benefit with IM therapy in CML-AP: Comparison with historic experience:

Survival benefit with IM therapy in CML-AP: Comparison with historic experience Kantarjian et al , Cancer , 2005, 103 (10): 2099-2108

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Talpaz M et al. Blood 2002;99:1928-1937 ©2002 by American Society of Hematology Overall Survival Overall Survival by 3-month cytogenetic response Talpaz, Blood. 2002;99:1928-1937

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n=111 CML-AP patients Therapies prior to IM therapy 29(26%) chemotherapy including ASCT (n=4) and Allo SCT (n=5) 82 (74%) patients received interferon-alpha, hydroxyurea and/or busulfan After median follow-up of 82 months 70 (63%) patients have died 61 (86%) died because of disease progression to blast crisis Palandri F et al. Haematologica 2009;94:205-212

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Palandri F et al. Haematologica 2009;94:205-212 ©2009 by Ferrata Storti Foundation Progression-free survival Event-free survival Overall survival At 7 years 43% (95%CI 33-53%) At 7 years 36.5% (95%CI 27-45%) At 7 years 15% (95%CI 7-26.5%) PFS: Calculated from the day of starting IM to progression to blast crisis, death from any cause or lost to follow up EFS: from start of IM to blast crisis, failure of IM therapy, death from any cause or lost to follow up

Duration of Response by Landmark Analysis at Three-months:

Duration of complete cytogenetic response Palandri F et al. Haematologica 2009;94:205-212 Duration of complete hematologic response (CHR) 56% 81% Duration of Response by Landmark Analysis at Three-months

Long-term follow-up of the IM therapy for CML-AP and BC: STI571 0109 trials :

Long-term follow-up of the IM therapy for CML-AP and BC: STI571 0109 trials N=181 of CML-AP were enrolled in the study treated with IM 600 mg daily Analysis at 48 months: 18% (32) patients remained on imatinib therapy while 82% (149) discontinued the therapy Primary reasons for discontinuation included Progression or lack of efficacy for 100 patients (67.1%) Protocol violations or administrative reasons for 17 patients (11.4%) Adverse events or toxicity for 13 patients (8.7%) Bone marrow transplant for 5 patients (3.3%) Death for 14 patients (9.3%) Silver et al, Haematologica 2009

Long-term follow-up of the IM therapy for CML-AP and BC: STI571 0109 trials :

Complete hematologic response- 40%, Partial cytogenetic response -7%, Complete cytogenetic response- 20% At 48 months estimated OS rate was 45% for patients treated with imatinib 6000 mg daily At 48 months: 73% of patients with MCyR at three months were alive While only 41% patients without MCyR at three months Silver et al, Haematologica 2009 Long-term follow-up of the IM therapy for CML-AP and BC: STI571 0109 trials

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Retrospective analysis of newly diagnosed CML-AP patients (n=42) Patients were classified as: Haematological acceleration without chromosomal abnormalities (HEM-AP n=16) Solely ACA (n=16) HEM-AP+ ACA (n=10) MCyR was 93.7%, 75% and 40% in HEM-AP, ACA-AP and HEM-AP +ACA patients respectively

Progression-free Survival with 1st line IM in CML-AP patients:

Disease progression: treatment discontinuation due progression to blast crisis or death Progression-free Survival with 1 st line IM in CML-AP patients

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Single-treatment arm, open label phase 2 study of CML-AP patients resistant to or intolerant of imatinib (n=137) Estimated OS and PFS at 24 months were 70% and 33% respectively 20/137 (15%) of patients remained on study whereas 85% (117/137) discontinued by the data cutoff Leukemia (2012) 26, 1189 -- 1194

Nilotinib in CML-AP patients resistant or intolerant to imatinib:

Leukemia (2012) 26, 1189 -- 1194 Nilotinib in CML-AP patients resistant or intolerant to imatinib

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Leukemia (2012) 26, 1189 -- 1194 Nilotinib in CML-AP patients resistant or intolerant to imatinib Duration of haematologic response Duration of Major Cytogenetic response Overall Survival

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Phase II trial of CML-AP (n=174) IM resistant (n=161) or intolerant (n=13) CML-AP patients Median follow up 14.1 months Median time from initial diagnosis to start of dasatinib was 82 months Apperley J F et al. JCO 2009;27:3472-3479

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Apperley J F et al. JCO 2009;27:3472-3479 ©2009 by American Society of Clinical Oncology Progression free survival Overall survival

Probability of survival after HLA-matched sibling donor transplant for CML, by disease status and transplant year, 1998-2008:

Years Probability of survival after HLA-matched sibling donor transplant for CML, by disease status and transplant year, 1998-2008 0 2 6 1 3 4 5 CP, 1998-2000 (N=2,302) 0 20 40 60 80 100 10 30 50 70 90 0 20 40 60 80 100 10 30 50 70 90 Probability of Survival, % CP, 2001-2008 (N=2,412) AP, 2001-2008 (N=314) AP, 1998-2000 (N=301) P < 0.0001

Slide24:

Jiang et al Blood . 2011;117(11): 3032-3040 CML-AP patients diagnosed at the Peking University People ’ s Hospital, Beijing, China between April 2001 to Sept 2008 were enrolled WHO definition of CML-AP Patients receiving TKI therapy prior to the diagnosis of CML-AP were excluded Non-randomised study, IM vs SCT was nonrandomly assigned based on patient choice IM 400-600 mg/daily (n=87) Allogeneic SCT (n=45)

Imatinib vs. Allogeneic SCT for CML-AP Patients:

Variables Imatinib Allo-SCT p Number of patients 87 45 - Median age (range) 44 (22-60) 34 (10-59) 0.000 CML duration, median (range) months 26 (0.5-192) 5 (2-80) 0.006 Interval from CML diagnosis to AP, mo Median (range) 17 (0-191) 2 (0-75) 0.001 Interval from onset AP to treatment 1 (0-66) 3(1-11) 0.06 Hb g/L, median (range) 112 (45-162) 106.5 (53-152) 0.76 PB blasts (%) 0 (0-19%) 0(0-13) 0.28 Blood . 2011;117(11): 3032-3040 Imatinib vs. Allogeneic SCT for CML-AP Patients

Imatinib vs. Allogeneic SCT for CML-AP Patients:

Jiang Q et al. Blood 2011;117:3032-3040 Events : Lack of haematologic response at 3 months, loss of previously obtained CHR, MCR or CCR; post SCT molecular relapse, relapse in AP/BC or death from any cause Progression: relapse in AP or BC Imatinib vs. Allogeneic SCT for CML-AP Patients

Imatinib vs. Allogeneic SCT for CML-AP Patients:

Survival in low-, intermediate-, and high-risk patients by therapy. Jiang Q et al. Blood 2011;117:3032-3040 Poor prognostic factors for OS and PFS CML duration > 12 months, Haemoglobin < 100 g/L, and Peripheral blood blasts > 5% Three risk groups Low risk (none of the factors, n 40) Intermediate risk (one of the factors, n 59) High risk (at least 2 factors, n 33) Imatinib vs. Allogeneic SCT for CML-AP Patients

Imatinib vs. Allogeneic SCT for CML-AP Patients:

Allo-HSCT confers significant survival advantages for high- and intermediate-risk patients with AP-CML compared with IM treatment Outcomes of two therapy is equally good in low-risk patients Limitations of study: Non randomised study Significant differences between two treatment groups Jiang Q et al. Blood 2011;117:3032-3040 Imatinib vs. Allogeneic SCT for CML-AP Patients

CML-AP patient (EW):

CML-AP patient (EW)

CML-AP patients (EW):

CML-AP patients (EW) Bone marrow aspiration and biopsy: Dry tap, but trephine was hypercellular. Bone marrow blast was 2% on imprint Bone marrow cytogenetic: 46,XX,t(9;22)(q34;q11.2)[1]/46,XX[4]

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Survival of CML patients with T315I mutations according to disease phase: Prior to ponatinib Jabbour et al Blood 2008

CML-AP patient (EW):

CML-AP patient (EW) Transplant donor status No sibling donor available No matched unrelated donor available What are treatment options for this patient Ponatinib Double Cord Blood transplant now Ponatinib followed by DCBT

Ponatinib in Patients with CML and Ph+ ALL Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I BCR-ABL Mutation: 2-Year Follow-up of the PACE Trial:

Ponatinib in Patients with CML and Ph+ ALL Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I BCR-ABL Mutation: 2-Year Follow-up of the PACE Trial ASH 2013 Abstract 650 JE Cortes, D-W Kim, J Pinilla-Ibarz, PD le Coutre, R Paquette, C Chuah, FE Nicolini, JF Apperley, HJ Khoury, M Talpaz, JF DiPersio, DJ DeAngelo, E Abruzzese, D Rea, M Baccarani, MC Müller, C Gambacorti-Passerini, S Lustgarten, VM Rivera, T Clackson, CD Turner, FG Haluska, F Guilhot, MW Deininger, A Hochhaus, TP Hughes, JM Goldman, NP Shah, and HM Kantarjian On behalf of the PACE Study Group

Ponatinib Phase 2 Study Responses at Any Time:

Ponatinib Phase 2 Study Responses at Any Time   CP-CML AP-CML BP-CML Ph+ ALL MCyR CCyR MMR MaHR* MaHR MaHR R/I to das/nil 56% 48% 31% 62% 32% 50% T315I 72% 70% 58% 61% 29% 36% Total ** 60% 54% 38% 61% 31% 41% Median time to response, months 2.8 2.9 5.5 0.7 1.0 0.7 *14 AP-CML patients with baseline MaHR and 1 AP-CML patient with no baseline MaHR assessment counted as non-responders **Total comprises all eligible patients treated with ponatinib. It excludes 5 patients (3 CP-CML, 2 AP-CML) who were non-cohort assigned (post-imatinib, non-T315I), but treated; all 5 achieved MCyR 34 JE Cortes et al; ASH 2013

Ponatinib Phase 2 Study PFS and OS in AP-CML:

Ponatinib Phase 2 Study PFS and OS in AP-CML 35 Criteria for progression in AP: death, development of BP, loss of hematologic response over 2 wks, or no reduction from baseline in % blasts on all assessments over 4 wks PFS at 2 years: 37% (median 15 months) OS at 2 years: 72% (median not reached) JE Cortes et al; ASH 2013

Ponatinib Phase 2 Study PFS and OS in AP-CML:

Ponatinib Phase 2 Study PFS and OS in AP-CML 36 Criteria for progression in AP: death, development of BP, loss of hematologic response over 2 wks, or no reduction from baseline in % blasts on all assessments over 4 wks (Cortes et al ASH 2013) PFS at 2 years: 37% (median 15 months) OS at 2 years: 72% (median not reached)

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  N=449 n (%) Data as of: 23 July 2012 (USPI) 03 Sep 2013 Median Follow-up [exposure] 12 months [340 patient-yrs] 24 months [578 patient-yrs] Category SAE AE SAE AE Cardiovascular 21 (5) 29 (6) 28 (6) 41 (9) Cerebrovascular 8 (2) 13 (3) 18 (4) 25 (6) Peripheral vascular 7 (2) 17 (4) 16 (4) 28 (6) Total Arterial Thrombosis 34 (8) 51 (11) 53 (12) 77 (17) Venous Thromboembolism 10 (2) 15 (3) 13 (3) 23 (5) Vascular Occlusion a Method 1 b 41 (9) 62 (14) 62 (14) 91 (20) Method 2 c 47 (10) 81 (18) 67 (15) 109 (24) 37 a Combined incidence of cardiovascular, cerebrovascular, peripheral vascular, venous thromboembolism events; b EMA press release, Nov 22, 2013; c FDA drug safety communication, Oct 31, 2013; SAE = AE reported as serious by the investigator, per standard criteria Ponatinib Phase 2 Study Incidence of Vascular Occlusive Events Over Time Cortes et al ASH 2013)

Ponatinib Phase 2 Study OS by Arterial Thrombotic Events:

Ponatinib Phase 2 Study OS by Arterial Thrombotic Events OS at 2 years: 73% with event (95% CI: 62,82) 69% without event (95% CI: 64, 74) All patients; OS data are similar for vascular occlusive events 38 (N=77) (N=372) 5 patients died of a grade 5 vascular event 5 additional patients died with vascular events possibly contributing to death Cortes et al ASH 2013)

Ponatinib Phase 2 Study Multivariate Analysis of Arterial Thrombotic AEs:

Ponatinib Phase 2 Study Multivariate Analysis of Arterial Thrombotic AEs 39 Risk factors significantly associated with arterial thrombotic AEs: Older age (p<0.0001) History of diabetes (p=0.0003) Higher dose intensity to time of first event (p=0.0009) History of ischemia (p=0.0087) Longer time since diagnosis (p=0.0228) Higher baseline neutrophils (p=0.0276) Higher baseline platelets (p=0.0466) Data are similar for vascular occlusive events Each 15 mg/day reduction in dose intensity results in a predicted reduction of ~40% in the risk of an arterial thrombotic event fit & 95% CI Cortes et al ASH 2013)

Ponatinib Phase 2 Study Impact of Dose Modification on Response:

Ponatinib Phase 2 Study Impact of Dose Modification on Response 40 149 CP-CML patients achieved MCyR by 12 mos Among patients who dose reduced after achieving response 97% (62/64) maintained MCyR 96% (51/53) maintained CCyR 92% (34/37) maintained MMR For additional information, see Poster 4007, Monday Dec. 9, 6-8pm Cortes et al ASH 2013)

CML-AP patient (EW):

CML-AP patient (EW) Transplant donor status No sibling donor available No matched unrelated donor available What are treatment options for this patient Ponatinib Double Cord Blood transplant now Ponatinib followed by DCBT

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Hehlmann et al ; Blood 2012

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Survival of CML-blast crisis patients: German CML studies I to IIIA Hehlmann et al, Haematologica 2008

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RH-56 years old female March 2008: Admitted with pneumonia and hypereukocytosis Splenomegaly -7 cm, no lymphadenopathy CBC: Hb 98 g/L, white cells 380x10 9 /L , platelets 153x10 9 /L, neutrophils 110.17x10 9 /L and blast 38%. Bone marrow : Hypercellular, 54% myeloblasts Case I –Blast crisis

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Immunophenotype: 54% of the blasts co-expressing CD7/CD13/CD33/CD34/CD38 Negative for CD117, CD123, HLDR. BCR-ABL/BCR: PB : 108% Bone Marrow : 65% CML-Blast Crisis (Case I)

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CT chest: Left and right lower lobe collapse consolidation and small pericardial effusion. Splenomegaly 12 cm Initial treatment: leukapheresis, hydroxyurea, antibiotics CML-Blast Crisis (Case I)

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CCR 20/20 Ph+ve 15/20 t(19;21 )

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Leukapheresis Imatinib Induction chemotherapy CCR 8/20 Ph + 0/20, t(19;21) CCR 5/21 Ph+ CCR

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Leukapheresis Imatinib Induction chemotherapy CCR CCR 5/21 Ph+ CCR 1 st Consolidation

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Leukapheresis Imatinib Induction chemotherapy CCR CCR 5/21 Ph+ CCR CCR 1 st Consolidation

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Leukapheresis Imatinib Induction chemotherapy CCR CCR 5/21 Ph + CCR CCR 1 st Consolidation 2 nd Consolidation No Bcr-Abl kinase domain mutations

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Leukapheresis Imatinib Induction chemotherapy Consolidation chemotherapy CCR CCR CCR Dasatinib

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Continue TKI Therapy Is TKI alone adequate to treat CML-BC Stem cell transplantation Further Treatment options

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Median survival: 19 months Median survival: 6 months Median survival: 3 months Imatinib in blast crisis patients

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Months after starting nilotinib therapy

Stem cell transplantation:

Stem cell transplantation HLA Typing A B C DRB1 Patient 0201 , 0206 1302, 3501 0303,0602 0408,1501 Donor 1 0201 1302,3501 03xx,06xx 0408,1501 Donor 2 02xx 13xx, 35xx 0404,1501 Donor 3 02xx 13xx, 35xx 0403,1501 Donor 4 2 13,35 0401,1501 Donor 5 2 13,35 0401,1501 International BM Donor Registry Search

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HLA Typing A B DRB1 Match Grade TNC x10 7 Patient 0201 , 0206 1302, 3501 0408,1501 4/6 CB 1 02xx,02xx 51xx,40xx 0408,1501 4/6 223 CB 2 2,32 14,35 0408,1501 4/6 198 Donor 3 02 xx,02xx 44xx,27xx 0408,1501 4/6 179 Donor 4 02 xx,02xx 51xx, 49xx 0408,1501 4/6 179 Donor 5 02xx,03xx 51xx,35xx 0408,1501 4/6 179 Donor 4 2, 2 50,27 0408,1501 4/6 139 Donor 5 2,11 27,35xx 0408,1501 4/6 138 Donor 6 02xx,1101 0702,35xx 0408,1501 4/6 137 Donor 7 02xx, 02xx 07xx,40xx 0408,1501 4/6 123 Donor 8 02xx,02xx 07xx,5001 0408,1501 4/6 111 Cord Blood Search Results

Pretransplantation Assessment of Mortality (PAM) score:

Pretransplantation Assessment of Mortality (PAM) score Variables Score Age 62 3 Donor type: Mismatched unrelated 4 Disease risk 8 (CP2) Conditioning chemotherapy 4 Serum creatinine <106 µ Mol/L 1 Serum ALT >49 U/L 2 DLCO >80% 1 FEV1 >80% 1 Total 24

Mortality following SCT according to PAM score:

Mortality following SCT according to PAM score Category Score range 2 years mortality 1 9 to 16 <25% 2 17 to 23 25 to 50% 3 24 to 30 50 to 75% 4 31 to 44 >75%

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EBMT score: 6

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Effect of HLA-A2 allele disparity on clinical outcome in hematopoietic cell transplantation from unrelated donors Y. Morishima et al Tissue Antigens ISSN 0001-2815 HLA-A2 allele mismatching involving HLAA*0201 and A*0206 was associated with a significant higher mortality rate than HLA-A2 allele matching, and Showed tendency to increase the risk of severe acute GVHD by multivariate analysis Thus, the combination of HLAA*0201 and A*0206 was confirmed non-permissive HLA mismatch in unrelated HCT

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Leukapheresis Imatinib Induction chemotherapy Consolidation chemotherapy CCR CCR CCR Dasatinib

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