CML in the PhilippinesPRISCILLA B. CAGUIOA MD

Conflict of Interest Disclosure● I have no personal or financial interests to declare:

● I have no financial support from an industry source at

the current presentation

Conflict of Interest Disclosure● I currently have, or I have had in the past two years, an

affiliation or financial interest with business

corporation(s):

● (1) Consulting fees, patent royalties, licensing fees: No

● (2) Research fundings: Yes, AstraZeneca

● (3) Others: No

Epidemiology

CML in the US 1

● 15% of cases of leukemia● Age adjusted incidence rate 1.8

per 100,000 per year● Death 0.3 per 100,000 per year● Median age at diagnosis 66● 1.1-1.4:1 MF ratio● 67.6% 5yr OS

CML in the PH 2

● 15%-20% of cases of leukemia● Age adjusted incidence rate● F: 0.81-1.08 per 100,000● M: 0.9-1.2 per 1000,000● Median age at diagnosis 60-65● 1.1:1 MF ratio

1 – National Cancer Institute SEER (Surveillance, Epidemiology, and End Results) Program2 – Globocan 2018

CML Around the Globe

NR – Not reported

US SEER ELN IACR PHIncidence 15% NR 15-20%ASR (per 100k) 1.8 0.69-1.39 0.86-1.14Median age 66 55 60-65Death 0.3 per 100k per yr 2% per yr NRM:F ratio 1.1-1.4:1 1.16:1 1.1:15yr OS 67.60% NR NR

Tertiary Hospital Experience● Median age at diagnosis is 37 years● MF ratio is 1.1:1

Age n11-20 1121-30 4231-40 5041-50 2751-60 2961-70 971-80 3

53% M(n = 91)

47% F(n = 81)

Tertiary Hospital Experience● Majority diagnosed at the chronic phase

97.67% CP

0.58% AP

1.75% BP

Presentation

European LeukemiaNet94% CP-CML3.5% AP-CML2.5% BP-CML

Spleen Size

36.6% massive splenomegaly

62%splenomegaly

20%normal

18%unknown

Diagnostic Work-up

● 100% underwent BM examination

● Only 89.5% had cytogenetic studies: 2 normal karyotypes (+) BCR-ABL on FISH

1 atypical translocation t(13;22)

The rest were Ph+

Co-morbidities

● 34.9% had co-morbid conditions

● Most common: HPN

T2 DM

Bronchial asthma

Thalassemia trait

Osteoarthritis

Co-morbidities● 5 patients with prior malignancy:

Non-Hodgkin Lymphoma Papillary thyroid carcinoma Colorectal carcinoma (n = 2) Mesenchymal chondrosarcoma

● 1 patient diagnosed with invasive ductal carcinoma IDCA diagnosis came 15 years after CML diagnosis Underwent MRM; currently on surveillance CML remains in MMR

Pregnancy on TKI

● 3 patients became pregnant during TKI treatment

2 on nilotinib; 1 on imatinib

TKI promptly discontinued

All with normal fetal and maternal outcomes

CML Complications

● Complications from hyperleukocytosis

2 male patients had priapism

● 3 patients progressed to blast phase 1 expired within 1 month of BP-CML (AML)

1 in remission (completed AML chemotherapy)

1 ongoing consolidation chemotherapy (pre-B cell

ALL)

Treatment Recommendations: NCCN

ENESTnd Trial 2010● Nilotinib versus Imatinib for newly diagnosed CML

Nilotinib600mg/d(n = 279)

Nilotinib800mg/d(n = 277)

Imatinib400mg/d(n = 280)

MMR at 12mos 44% 43% 22%CCyR at 12mos 78% 65% 65%Progression to AP or BP < 1% < 1% 4%CML-related death 0.36% (n=1) 0.36% (n=1) 1.43% (n=4)

ENESTnd 5yr Follow Up 2016● Nilotinib versus Imatinib for newly diagnosed CML

Nilotinib600mg/d(n = 279)

Nilotinib800mg/d(n = 277)

Imatinib400mg/d(n = 280)

MMR at 5yrs 77% 77.2% 60.4%Loss of MMR at any time 6% 7.3% 9.8%MR4 at 5yrs 65.6% 63% 41.7%MR4.5 at 5yrs 53.5% 52.3% 31.4%Progression to AP or BP n = 2 n = 3 n = 125 year EFS 95% 96.9% 92.6%5 year PFS 96.5% 98.3% 94.7%Deaths, all causes n = 18 n = 10 n = 22CML-related deaths n = 6 n = 4 n = 16

DASISION Trial 2016● Dasatinib versus Imatinib for treatment naïve CML

Dasatinib 100mg (n = 259)

Imatinib 400mg (n = 260)

BCR-ABL1 ≤ 10% at 3mos 84% 64%MMR at end of 5yrs 76% 64%MR4.5 at end of 5yrs 42% 33%5 year PFS 85% 86%5 year OS (p 0.1192) 91% 90%Acceleration to AP or BP 4.6% 7.3%CML-related Death 3.47% 6.53%ADE: Pleural effusion 28% 0.8%

BFORE Trial 2017● Bosutinib versus Imatinib for newly diagnosed CML

Bosutinib 400mg (n = 246)

Imatinib 400mg(n = 241)

MMR at 12mos 47.2% 36.9% (p 0.02)CCyR at 12mos 77.2% 66.4% (p 0.0075)Progression to AP or BP n = 4 (1.6%) n = 6 (2.5)Discontinued due to toxicity 12.7% 8.7%Grade ≥ 3 diarrhea 7.8% 0.8%Elevated ALT 19% 1.5%Elevated AST 9.7% 1.9%

PACE Trial 2018● Ponatinib for previously treated CML● >90% had received at least 2 TKIs (IM, N, B, D)

Clinical Endpoints(median time to response)

CP-CML(n = 267)

AP-CML(n = 83)

BP-CML(n = 62)

MCyR at 5yrs 60% (2.8mos) 49% 23%CCyR at 5yrs 54% (2.9mos) 31% 18%MMR at 5yrs 40% (5.5mos) 22% 13%MR4.5 at 5yrs 24%Overall survival 80% at 12mos

73% at 5yrs49% at 5yrs 9% at 3yrs

Progression free survival 90% at 12mos53% at 5yrs

22% at 5yrs Median PFS 3.7mos

Disease progression(median 6.4mos)

AP-CML, n = 5BP-CML, n = 4

Treatment Recommendations: NCCN

Omacetaxine in CML T315I MutationResponse to Omacetaxine in Pts With CML

Response, % CP(n = 62)

AP(n = 17)

BP(n = 15)

Hematologic CHR HI RCP

7777NANA

3529186

47207

27Cytogenetic MCyR CCyR Minor

44231621

666--

--------

Median survival, mos NR 19 2

Cortes J, et al. Blood. 2012;120:2573-2580. Slide credit: clinicaloptions.com

Omacetaxine After Failure of ≥ 2 TKIsResponse to Omacetaxine Treatment in Pts With CML

CP(n = 76)

AP(n = 35)

Median DoR, mosMedian cycles, n (range)Median duration of exposure, mos

12.56 (1-58)

8

52 (1-29)

2

Primary endpoint responses, %

MCyR: 18CCyR: 8

MaHR: 14CHR: 11

Median PFS, mos 9.6 3.6Median OS, mos 40.3 14.3Ongoing response, n 6 1

Cortes J, et al. Cancer. 2015;121:1637-1644. Slide credit: clinicaloptions.com

Treatment based on BCR-ABL1 mutation

● Availability of mutational analysis in Asia: Singapore

South Korea

Mutation Profile RecommendationY253H, E255K/V, F359V/C/I DasatinibF317L/V/I/C, T315A, V299L NilotinibE255K/V, F317L/V/I/C, , F359V/C/I, T315A, Y253H

Bosutinib

T315I Ponatinib, Omacetazine,alloHSCT, or clinical trial

Mutation Analysis

● Kinase domain mutations Best described mechanism of TKI resistance

Should be performed in patients failing TKI treatment

Detection of mutation should direct selection of

appropriate TKI based on known resistance patterns

● Method: Direct (Sanger) sequencing Low sensitivity

Detects mutations present in samples with ≥ 10-20% Ph+

cells

Assumes BCR-ABL1 value is ≥ 1%

Mutation Analysis

● Triggers for mutation testing: Failure to achieve milestone

Loss of response

● MUST be performed before stopping TKI treatment

● Pitfall: Mutations identified in only 50% of patients with

imatinib failure

Treatment Recommendations: ELN

Treatment: Our Experience● 13% still not on treatment● 150 patients on TKIs

65% started on Imatinib as first-line 35% started on Nilotinib as first line

● 32% required dose reduction due to adverse eventsAdverse Event n TKI

Cytopenia 14 5N, 4IJaundice and/or ↑ bilirubins 5 4N, 1ICutaneous reaction 7 2B, 5ISevere myalgia 3 2N, 1IGastrointestinal upset 19 17B, 2I

Grade ≥ 3 diarrhea 17 17B (100%)

Availability of TKIs● Imatinib and Nilotinib are approved by the Philippine

FDA

● Bosutinib, Ponatinib, and Dasatinib are available under

compassionate special permit

● Radotinib, Omacetaxine are not available

Healthcare System in the PH● Philippine Health Insurance Corporation

(PhilHealth)

● Private Health Maintenance Organization (HMO)

● Out of pocket

● Government Assistance Programs (PCSO)

● Patient Assistance Programs (Max Access

Solutions, OATH)

Molecular Monitoring● RQ-PCR

Only one available in PH

● Nested PCR

● Multiplex PCR

● Digital and DNA-based PCR

Response criteria: NCCN

Response criteria: ELN

Treatment Response: Our Experience● 75% remained on their initial TKI

● 25% shifted to second line TKIs due to disease progression

● Overall: 46% achieved MMRTreatment Response

113 maintained on 1st TKI61 achieved MMR13 CHR but never achieved MMR14 within 1 yr of initiation; all CHR but no RQ-PCR yet

27 are on their 2nd TKI8 achieved MMR11 never achieved MMR2 within 1 yr of initiation; CHR but no RQ-PCR yet

6 are on their 3rd TKI No one has achieved MMRMost within 1yr of 3rd TKI

2 on their 4th TKI Never achieved MMR both expired in Feb 2019

Treatment Free RemissionTFR rate in 11 trials: 38-61%

Treatment Free Remission

Challenges to TFR in the PH● Cost of RQ-PCR ~ 300USD

Minimum wage is only 236USD per month

Our experience:

100% of patients started on TKIs are still on treatment

● Patient reluctance

● Mutation analysis not available in PH

Outcomes● 5 year OS 89.6%

● Deaths: 5 patients (2.9% of all patients)

1 blast crisis

2 AP-CML

1 severe infection (Pneumocystis jirovecipneumonia)

1 unknown cause

Thank you