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The Development of Oral Arsenic Trioxide for Cancer Treatment: Academic Success,

Economic Implications and Global Perspectives

Yok-Lam Kwong

Department of Medicine Queen Mary Hospital

Hong Kong

Arsenic Medicinal use of arsenic has been known for centuries in China and medieval Europe

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Arsenicals in the treatment of leukaemia 1878: Boston City Hospital

“leucocythaemia” 1931: Boston City Hospital

chronic myeloid leukaemia 1937: JAMA

chronic myeloid leukaemia Since then, As2O3 was regarded as a standard treatment for leukaemia, there being few effective alternatives

As2O3 treatment of leukaemia Department of Medicine University of Hong Kong In the late forties to early fifties: a standard treatment for leukaemia Effective in suppressing white cells Cumulative toxicities included Skin pigmentation, chronic GI blood loss

Hong Kong Museum of Medical Sciences

Medical records in 1950

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Medical records in 1950

Liquor arsenicalis

Medical records in 1950

Oral As2O3 treatment

As2O3 treatment of leukaemia

As2O3 treatment was effective for different types of leukaemia, and may be related to an intrinsic toxicity of As2O3 to marrow cells

Blood. 1997 May 1;89(9):3487-8.

Resurgence of the use of As2O3 in China 1984 : Zhang TD. Ai Ling No. 1 1988 : Li et al. Treatment of lymphoma 1992 : Sun et al. Ai Lin 1 in acute

promyelocytic leukaemia (APL) 1997 : Chen et al. intravenous As2O3 in

APL

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Acute promyelocytic leukaemia

Hypergranular promyelocytes

Faggot cell

Faggot: Bundle of sticks or twigs

t(15;17) in acute promyelocytic leukaemia

Oral As2O3 Preparation of an oral formulation - In collaboration with the Division of Clinical

Pharmacology, Department of Medicine, and Pharmacy, Queen Mary Hospital

- Clinical trial started in 2000 for the treatment

of relapsed APL

Oral As2O3 for treatment of relapsed APL

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Oral As2O3 therapy in leukaemia

Blood. 2003 Jul 1;102(1):407-8.

0

50

100

150

200

250

300

350

400

200 400 600 800 1000 1200 1400 1600 1800 2000

CSF

ars

enic

(nm

ol/L

)

Plasma arsenic (nmol/L)

r = 0.74 p < 0.001

y=0.1771x+19.373

Arsenic penetrates the cerebrospinal fluid

Blood. 2008 Nov 1;112(9):3587-90. Pediatr Blood Cancer. 2011 Sep 2. [Epub ahead of print]

Oral As2O3 in pediatric patients

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0 20 40 60 80 100 120 Months

0

0.2

0.4

0.6

0.8

1.0

Leuk

emia

free

sur

viva

l

Blood. 2011 Oct 12. [Epub ahead of print]

Oral-As2O3 maintenance of 76 APL patients in CR1 Oral-As2O3 maintenance of 76 APL patients in CR1

0 20 40 60 80 100 120

Months

0

0.2

0.4

0.6

0.8

1.0

Even

t fre

e su

rviv

al

Blood. 2011 Oct 12. [Epub ahead of print]

Oral-As2O3 maintenance of 76 APL patients in CR1

Blood. 2011 Oct 12. [Epub ahead of print]

0 20 40 60 80 100 120 Months

0

0.2

0.4

0.6

0.8

1.0

Ove

rall

surv

ival

Oral-As2O3 for maintenance of 52 patients with APL in CR2 and beyond

Au et al J-Cin-Oncol 2011 (submitted)

0 20 40 60 80 100 120 140 Months

1.0

0.8

0.6

0.4

0.2

0

Ove

rall

surv

ival

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Oral-As2O3 for maintenance of APL in CR2 and beyond

0 25 50 75 100 125

1.0

0.8

0.6

0.4

0.2

0

Leuk

emia

free

sur

viva

l

Months

Au et al J-Cin-Oncol 2011 (submitted)

Oral-As2O3 for maintenance of APL in CR2 and beyond

Au et al 2011 (submitted)

0 20 40 60 80 100 120 140 Months

1.0

0.8

0.6

0.4

0.2

0

Ove

rall

surv

ival

Age ≤ 40 years

Age > 40 years

P = 0.01

Au et al J-Cin-Oncol 2011 (submitted)

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Different generations of As2O3 Oral Arsenic trioxide

Arsenic patent (Nature Medicine, October 2007) Arsenic patent (Nature Medicine, October 2007)

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2010 International Arsenic Union

Academic success 30 publications in international peer-reviewed journals

Patient management > 100 leukaemia patients successfully treated

Economic success IP rights and patents Global marketing

Societal impacts Humanitarian projects and global benefits

A success paradigm of medical research

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Acknowledgement Shanghai ZX Shen Hong Kong Prof D Todd Haematology team Versitech, University of Hong Kong Molecular genetics team Division of Clinical Pharmacology Pharmacy, Queen Mary Hospital Sidney Tam, Queen Mary Hospital S.K. Yee Medical Foundation Ruby and Minoo Master Charity Fund