FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years Prof. Cristina Stefan MD PhD...

FROM POTASSIUM ARSENATE TO IMATINIB

MESYLATEA short story of 140 years

Prof. Cristina Stefan MD PhDPediatric Oncologist

Tygerberg Children’s HospitalStellenbosch University

Content of presentation

History of CML Case presentation Overview CML Treatment

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

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)

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

PATIENT Z.A. 13YR FEMALE

Referred from Delft HC

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

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

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/

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

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)

ACUTE

• Normo or macrocytic anaemia

or WCC Platelets

CHRONIC

•Hb (n) slightly •WCC ++•Platelets

Diagnosis : CML

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

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

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.

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

Chronic phase:Chronic phase:

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

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

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

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

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

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

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

CML - treatment

Imatinib mesylate (Gleevec) Allogeneic transplantation Hydroxyurea

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

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

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

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

GLEEVEC

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

Mechanism of action

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)

How Should One Treat a Newly Diagnosed Pediatric

Patient With CML?Goal in Pediatric Therapy

Has Been Cure Rather Than Palliation

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

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

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

Accelerated phase

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

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%

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

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

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

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)

Clinical data

Few pediatric studies Champagne et al-2004 14 pediatric

patients(3-20y) Millot et al

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

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)

Precautions

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

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?

My colleagues at Tygerberg Hospital: