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FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Children’s Hospital Stellenbosch University
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FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Mar 26, 2015

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Page 1: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

FROM POTASSIUM ARSENATE TO IMATINIB

MESYLATEA short story of 140 years

Prof. Cristina Stefan MD PhDPediatric Oncologist

Tygerberg Children’s HospitalStellenbosch University

Page 2: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.
Page 3: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.
Page 4: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.
Page 5: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Content of presentation

History of CML Case presentation Overview CML Treatment

Page 6: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

CML

First form of leukemia to be recognized as a distinct clinical entity

1844 Donne-hematological changes 1845 Bennet attributed the

hematological changes to”presence of purulent matter”

Virchow –acknowledged the description of CML by Bennet in 1845 in Edinburgh

1889 Ebstein difference ac/chronic

Page 7: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

CML 1960 Nowell and Hungerford –Ph

chromosome This was also the first specific

chromosomal abnormality associated with a human malignancy

Mutual translocation between chromosomes 9 and 22;the resultant fusion gene(bcr-abl)produced an activated tyrosine kinase (activity of CML cell)

Page 8: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

CML

CML-relative rare malignancy in childhood 2-3%

Ph chromosome-balanced translocation between long arms of chromosomes 9 and 22(t9;22)(q34;q11) resulting in the fusion of BCR and ABL genes

BCR-ABL encodes a 210 kilodalton ,which is found in >90% of childhood and adult CML

Page 9: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

PATIENT Z.A. 13YR FEMALE

Referred from Delft HC

1 day history : * Sore throat* Pleuritic chest pain* Dry cough* Stomach ache

Page 10: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

OE : Pale but not ill. T = 36.8oC

Palpable liver (3cm), spleen (8cm)

and generalised lymphadenopathy

CNS, CVS, RS, ENT = Normal

Prov. diagnosis : Inf Mono

P) :Amoxil & discharged

Page 11: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

A few days later: CXR : RLL opacification & hilar nodes

? Pneumonia ? TB

FBC : WCC = 393.17 X 109/Hb = 9.8 g/dMCV = 82.7 FLP = 1364 X 109/

Page 12: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

New Finding :

Pan-systolic murmur (L) parasternal

Radiates to pre cordium and backPainful (L) shoulder+ Liver 2cm Spleen 8cm

D : ? RF ? PTB ? Malignancy

ASOT/ECGESR/ADNAseB/C

Page 13: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Splenomegaly

+ fever Infections (HIV, Hep, Malaria)

Sarcoidosis, systemic diseases

Malignancies

+ lymph -

adenopathy

Leukaemia, Lymphoma

+ purpura Septicaemia

ALL

+ anaemia Leukaemia

Thalassaemia, Sickle Cell D,

+ ascites Malignancies

Portal hypertension

Causes for Splenomegaly (examples)

Page 14: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

ACUTE

• Normo or macrocytic anaemia

or WCC Platelets

CHRONIC

•Hb (n) slightly •WCC ++•Platelets

Diagnosis : CML

Page 15: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

ACUTESymptoms related to

bone marrow infiltration/suppression

or WBC Hb Platelets

Organ infiltration> Spleen> Liver> Glands

CHRONICSymptoms related to

hypermetabolism• Weight loss• Lassitude• Anorexia• Night sweets• Gout or renal

impairment Organ infiltration

>spleen – frequently massive

Bruising/bleeding : abn platelet function

LEUKAEMIA

Page 16: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

CLINICAL PRESENTATION

WCC > 50 X 109/L Hb = normal P = normal or or Splenomegaly CHRONIC PHASE (4-5 years) : stable

counts ACCELERATED PHASE : Resistance to

therapy/months BLAST CRISIS

Page 17: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

CML: develops CML: develops when…..when…..

Single , pluripotential, hematopoietic stem cell

Acquires a Ph chormosome Carrying the BCR-ABL fusion gene Develops a proliferative advantage Allows Ph(+) clone to displace

residual normal hematopoiesis.

Page 18: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

CMLCML

20% of newly dx cases of leukemia in adults Etiology: uncertain/irradiation Median age at presentation: 53y M/F ratio: 1.2:1 Sx: fatigue, anorexia, weight loss or

asymptomatic Ex: massive splenomegaly, elevated WCC Course of disease is characteristically

triphasic

Page 19: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Chronic phase:Chronic phase:

< 5% blast < 20% basophils < 30% blasts plus promyelocytes

in PB/BM Platelet count > 100 x 109/L

Page 20: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Accelerated phase Accelerated phase (AP):(AP):

10-19% blasts in PB/BM Blast + promyelocytes >30% Basophils > 20% Persistant thrombocytopenia ( <100)

or thrombocytosis (>1000) Increasing spleen size Cytogenetic evidence of clonal

evolution

Page 21: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Blast phase ( BP):Blast phase ( BP):

Blast > 20% in PB Extramedullary blast proliferation Large foci of clusters of blasts in

BM

WHO, PATHOLOGY AND GENETICS, p 20-23 & NEJM, vol. 346, no. 9. Feb 9, 2003, p 646-647

Page 22: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Molecular Molecular Pathophysiology:Pathophysiology:

Dx of CML is usually based on the detection of Philadelphia (Ph) chromosome

Mechanism by which Ph is first formed and the time required for progression to disease is unknown

Speculation: 1. close proximity of BCR and ABL during

interphase may favour translocation2. 76-kb duplicon on (9) near ABL and (22)

near BCR may be implicated in translocation

Page 23: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.
Page 24: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

CML – a Disease Linked to a Single Molecular Abnormality

CML Proliferative disorder of hematopoietic stem cells Well-characterized clinical course

Philadelphia (Ph) chromosome Unique chromosomal abnormality

Bcr-Abl tyrosine kinase A single molecular abnormality that causes

transformation of a hematopoietic progenitor into a malignant clone

Page 25: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

CML - prognosis (median survival years)

No treatment (3 yrs)

Hydroxyurea (4 yrs)

Imatinib mesylate – median not reached (at least 5 years and probably much more)

Transplant – cure but significant mortality and morbidity

Page 26: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

CML - treatment

Imatinib mesylate (Gleevec) Allogeneic transplantation Hydroxyurea

Page 27: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

History

1865-2011 Potassium arsenate (Fowler’s

solution)-Lissauer 1865 Boston City Hospital-first to study

scientifically Radiotherapy –Pussey 1902 Busulphan -1953 Hydroxyurea ,interferon

alpha ,cytosine arabinoside

Page 28: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Gleevec

May 10,2001 -only 3 years after the initiation of the phase 1 study in CML, US FDA approval

The regulatory review of Gleevec set the record -14 weeks-for the fastest approval of any cancer drug in HISTORY

Page 29: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

GLEEVEC

FDA approval of the drug as front line therapy for newly dg CML in adults

May 2003 US FDA approved the use of Gleevec for the Rx of patients >3 years old with Philadelphia positive (Ph+)CML in chronic phase whose disease has recurred after SCT or who are resistant to interferon alpha (IFN)therapy

Page 30: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Mechanism of action

In the untreated state bcr-abl protein has an open pocket accesible to ATP; this facilitates transfer of a phosphate from ATP to a tyrosine residue on a target substrate molecule

The activated molecule is then released to interact with downstream effector molecule, which can promote oncogenesis

Page 31: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

GLEEVEC

Imatinib inhibits this process by competing with ATP for the kinase pocket ,thereby preventing phosphorilation of substrate and effector molecules

Page 32: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.
Page 33: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Mechanism of action

Page 34: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

GLEEVECTHE PROMISE CONTINUES

Inhibit certain protein tyrosine kinases implicated in oncogenesis

Inhibits bcr-abl and blocks proliferation and growth of tumour cells expressing bcr-abl or v-abl

Potent inhibitor of two cell-surface protein tyrosine kinases(the platelet derived growth factor receptorPDGF-R and the stem cell factor receptor)

Page 35: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

How Should One Treat a Newly Diagnosed Pediatric

Patient With CML?Goal in Pediatric Therapy

Has Been Cure Rather Than Palliation

Page 36: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

IMATINIB MESYLATE

Paucity of data in patients <18 years with Ph+

No broad consensus on the use of Gleevec in children with CML (Thornley,Med Pediatr Oncol 2003)

No evidence that is curative , long term effects remain to be determined

Well tolerated and cytogenetic and molecular remissions can be achieved in a significant percentage

Page 37: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

IMATINIB

Effective in children with CML in late chronic and advanced phase and in relapse after SCT (F Millot et al-Leukemia 2006)

Multicentric phase 2 study-30 children from 8 European countries-complete hematological response in 8(80%)of the 10 chronic phase and in 6(75%)advanced phase

Page 38: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Cytogenetic reponse (dissapearance of Ph chromosome +BM cells(60%)in chronic phase and 29% in advanced phase

Reduction of bcr-abl ratio to<10-4 in 50% in chronic phase

12 months survival 95%in chronic phase and 75% advanced phase

Page 39: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Accelerated phase

Peripheral basophils >20%, thrombocytopenia <100X109, progressive splenomegaly or karyotypic evolution (chromosomal abnormalities in addition to a single Ph chromosome)

Page 40: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

RESPONSE TO THERAPY

Haematological response –sustained in >80% (Millot-2006)

Cytogenetic response (disapearence of Ph chromosome) >60%

Very low levels of bcr-abl transcript >50%

12 months survival >95%

Page 41: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

RESPONSE TO THERAPYRelapse after SCT for CML

Complete hematologic response 71% Complete cytogenetic remission 42% The degree of molecular response

predicts disease progression in adults receiving Gleevec but such an effect remains to be determined in children

Page 42: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Pharmacokinetics,dose

Rapidly absorbed –oral administration, max concentration 2-4h

T1/2 14,8h Millot et al –the dose equivalent to 400-

600mg in adults induced side effects of similar types to those observed in adults

None required discontinuation for toxicity

Page 43: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Dosage and administration 260-340mg/sqm/day Once daily/daily dose split into 2 doses Treatment-to be continued as long as

there is no evidence of progressive disease or unacceptable toxicity

Increase dose in disease progression(at any time),failure to achieve satisfactory hematologic response >at least 3 months

Page 44: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Dosage

Failure to achieve a cytogenetic response after 6-12 months of treatment

Loss of a previously achieved hematologic or cytogenetic response

Water/apple juice(50ml for 100mg tablet)

Page 45: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Clinical data

Few pediatric studies Champagne et al-2004 14 pediatric

patients(3-20y) Millot et al

Page 46: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.
Page 47: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Mechanism of resistance

Different mechanisms: overexpression of bcr-abl, development of point mutations in the kinase domain bcr-abl, mutations in the activation loop of the kinase domain, preventing the closed/inactivated conformation change of abl needed for imatinib binding

Increase dose 400-800mg/day

Page 48: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

DISCUSSION

Scant data regarding Gleevec in children with CML

COG –phase 1 study 31 patients < 22 y Ph+ treated with Imatinib

Treatment safe with complete cytogenetic response (12 patients)

Page 49: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Precautions

Neutropenia Bone marrow suppression Edema Hepatotoxicity Renal toxicity Cardiac toxicity Drug interactions

Page 50: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.
Page 51: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.
Page 52: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.
Page 53: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

Summary slide (in a nutshell)

1-What is CML? 2-How common ? 3-How do patients present? 4-Age group 5-How do you make the dg? 6- How many phases CML? 7-How do you treat? Options?

Page 54: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.
Page 55: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.

My colleagues at Tygerberg Hospital:

Page 56: FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Childrens Hospital.