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: