Adult ALL in Malaysia

Dr Tan Sen MuiDepartment of Haematology

Hospital AmpangMalaysia

I have no personal or financial interests to declare:

I have no financial support from an industry source at the current presentation.

Use the following slide to disclose any conflicts of interest

Form A: no conflicts of interest to declare.

대한혈액학회 Korean Society of Hematology

COI disclosureName of author ： Sen Mui TAN

Haematology service centers in Malaysia

Klang valley

Haematology service centers in Klang valley

Epidemiology

Average ~ 39 new cases annually

Cohort of ALL patients• 402 adolescent/adult ALL patients (≥ 12 years)• January 2007 till December 2018

Age Group Distribution of Newly Diagnosed ALL in Malaysia from 2007-2018

median: 30 year old

25.9%

40.8%

26.4%

7.0%

0

20

40

60

80

100

120

140

160

180

12-19 (Adolescent) 20- 39 (Young adult) 40- 59 (Adults) >60 (Elderly)

num

ber o

f cas

es

Age group

ALL subtype

B-ALL83%

T-ALL17%

Ph+21%

Ph-79%

High risk group based on -presenting count -flow cytometry analysis-cytogenetic study-clinical features: - CNS/extramedullary involvement etc.

High risk group: 49%

Ethnic Groups and Gender Distribution

Malay58.2%

Chinese27.1%

Indian12.4%

others2.2%

57%

43% Male

Female

Treatment

ALL Induction chemotherapy

• 91.2% of patient underwent induction chemotherapy

• Induction death: 8.6%• two frequent cause of induction death:

– infection– tumour lysis syndrome leading to multi-organ failure

Induction chemotherapy

• GMALL/BFM protocol: 72%• HyperCVAD regimen: 28%

• Ph+ ALL: HyperCVAD regimen + TKI prior allogeneic SCT

• Induction failure: 14.5%

Consolidation chemotherapy

• High risk patients• Non high risk patients on presentation but

having MRD along the way of treatment – transplant eligible – donor available– aim for TBI/Cy conditioning after good remission– avoid cranial irradiation prior SCT

Treatment outcomes

Treatment response

• Remission post induction 83%• Overall Remission 29.4%• Relapse 34.5%• Refractory 14.5%• Induction death 8.6%

OS

Median follow up, month (range)Median overall survival

2 years3 years5 years

13months16 months 34.1% 26.7% 22.6%

3 year OS = 26.7%

OS (months)

EFS

Median follow up, month (range)Median overall survival

2 years3 years5 years

11months11 months 26.2% 21.1% 16.7%

OS & EFS• overall survival at 3 years for all ALL patients: 26.7%

– T-ALL subgroup: 20.0%– B-ALL subgroup: 27.3%

• main reasons for such dismal outcome– disease relapse and refractory

• T-ALL: 53.2% • B-ALL: 46.0%

• main causes for disease relapse– High risk disease– High default rate

Stem cell transplantation (SCT)

• In general, intensive chemotherapy follow by SCT improved overall response

• Routine upfront alloSCT for very high risk/high risk group or with HLA-matched sibling

• About one third of our patients (28.4%) proceeded to allogeneic stem cell transplantation (alloSCT)

• For the last few years, we also upfront alloSCT for those who has MRD by flow cytometry analysis as supplement to the routine bone marrow study along the way of treatment

Overall Survival (OS) ALL Post Allogeneic SCT

Overall survival of B-ALL

Overall survival of T-ALL

Overall survival of B-ALL: Ph+ ALL

Overall Survival (OS) Post Allogeneic SCT[2007 - 2012 vs 2013 - 2018]

B & T - ALL B - ALL

Patients received Blinatumumab landed in Hospital Ampang

• Total cases: 10• Male:Female = 6:4• Age: 22.5 yr old

(18-46 yr old)• Ethic group:

• Malay - 6• Chinese - 2• Indian - 1• Dusun -1

• High risk:• presenting high TWDC - 5• refractory to induction - 2• early relapse - 4

• Persistence MRD positive - 5• Pre-B ALL: Ph neg: pos = 8:2

• extramedullary - 1• CNS involvement - 2• leukaemia cutis - 1

Patients received Blinatumumab landed in Hospital Ampang

• Lines of therapy prior Blinatumumab:• 3 lines 50%• 2 lines 30%

• Status of disease pre Blinatumumab:• CR1 with MRD positive - 30%• CR2 with MRD positive - 40%• Frank relapsed - 20%• Primary refractory - 10%

• Total cycle of Blinatumumab to each patient:• 1 cycle - 6• 2 cycles - 2• 4 cycles - 1• one patient stopped at day 8 due to neurotoxicity

Patients received Blinatumumab landed in Hospital Ampang

• Complications during Blinatumumab:• CRS (gd 1): 1• neurotoxicity: 1

• Post Blinatumumab outcome:• Achieved MRD negative and alloSCT - 6• Relapse/refractory post Blinatumumab - 3

• one salvaged with autoCART, one planned for autoCART as bridge for alloSCT & one BSC

• One patient stopped at day 8 due to neurotoxicity

• 2 patients relapsed post 1 cycle Blina: CD19+ blast

• 1 patient relapsed post 4 cycles Blina: CD19- & CD33/13/38+ blast

1st IACH Congress27-29 September 2018

Malaysian experience

• second-generation CD19-BBζCAR/lentivirus• From October 2017 to Nov 2018• 25 patients with r/r B-ALL

– compassionate use basis approved MOH Malaysia• 13 treated (11 MOH, 2 private)• 5 wait-list• 4 could not - too ill/ unable to produce CAR-T cells• 3 patients did not make it to referral

15 treated patients

• 8 - Ph+, 3 - CNS disease, 6 - relapsed after MRD alloSCT, 2 - primary refractory ALL (Blinatumumab)

• mean age: 34 (range 16 to 55 years)• mean number of relapses - 1.5• mean PB blast was 22% (range 0.04 to 84%) • mean ECOG was 0.9 (0-3)

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Day 0Day -1Day -2Day -3Day -4

mean CAR-T dose 1.1×106 cells/kg (0.25 - 4.3×106 cells/kg)

Results• 12 patients had evaluable outcome or completed at least 4-week follow-up

• 100% - B cell aplasia and leucopenia [78% (7) ≥ Grade 3]• 64% (7) - CRS(one with Grade 4 requiring ICU care) • 17% (2) - mild neuro-toxicity

• 75% (9) - CR at week 4 & 3/12 (5 MRD negative by FCM) – 2 relapsed at 6/12 & 10/12 respectively (3 autoCAR-T, one evolved CD19- blast)

• 4 patients had early death:– 3 sepsis (at Day 5, Day 7 & Day 14 after CAR-T)– 1 relapse at week 3 after CAR-T

• CAR-T cell expansion was observed among all evaluable patients:– mean maximum CAR-T count: 1175 million at 1 to 2 weeks post-Rx

(range 9- 5824 million)

D 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Tocilizumab

TWC 2.6 2.0 1.4 2.2 1.3 0.5 0.1 0.2 0.3 0.8 1.3 1.4 0.9 1.4

ANC 1.9 1.4 0.8 1.5 0.36 0.05 0 0 0 0 0 0.05 0.07 0.3

Patient MHMN

D 2 3 4 5 6 7 8 9 10 11 12 13 14 15Patient AAP

Tocilizumab

TWC 0.7 0.7 0.7 1.2 1.9 0.2 0.1 0.3 1.2 0 8.3 5.2 2.5 1.4

ANC 0.3 0.2 0.2 0 0 0.02 0.03 0 0 0 0.1 0.2 0.21 0.32

Cr 72 87 217 306 491 297 359 358 313

ALT 71 29 376 233 128 67 49 37

LDH 182 208 8552 4948 2541 1771 1319 1059

Seiz

ure

SLED

SLED

SLED

SLED

IL 6: 16,000

ICU

Feritin: 57,422 94,578 79,898

Conclusion• majority of our adult ALL patients

– high-risk group• ? any genetic predisposition• ? late presentation

• better treatment outcome can be achieved – improvement in patient’s awareness – treatment adherence

• advancement in laboratory help in– precise risk group stratification– MRD monitoring in tailoring treatment decisions

Acknowledgement • Dr Jameela Sathar & Ampang haematology team• Dr Leong Tze Shin & Dr Ong Tee Chuan • All the Haematologists and state hospitals provided

haematology service• All the patients

Thank you!