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FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years

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. Content of presentation. History of CML Case presentation Overview CML Treatment. CML.

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FROM POTASSIUM ARSENATE TO IMATINIB MESYLATE A short story of 140 years

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

  2. Content of presentation • History of CML • Case presentation • Overview CML • Treatment

  3. 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

  4. 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)

  5. 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

  6. PATIENT Z.A. 13YR FEMALE Referred from Delft HC 1 day history : * Sore throat * Pleuritic chest pain * Dry cough * Stomach ache

  7. 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

  8. A few days later: CXR : RLL opacification & hilar nodes ? Pneumonia ? TB FBC : WCC = 393.17 X 109/ Hb = 9.8 g/d MCV = 82.7 FL P = 1364 X 109/

  9. New Finding : Pan-systolic murmur (L) parasternal Radiates to pre cordium and back Painful (L) shoulder + Liver 2cm Spleen 8cm D : ? RF ? PTB ? Malignancy ASOT/ECG ESR/ADNAse B/C

  10. Causes for Splenomegaly (examples)

  11. Diagnosis : CML

  12. LEUKAEMIA

  13. 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

  14. CML: develops 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.

  15. CML • 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

  16. Chronic phase: • < 5% blast • < 20% basophils • < 30% blasts plus promyelocytes in PB/BM • Platelet count > 100 x 109/L

  17. Accelerated phase (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

  18. 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

  19. Molecular 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: • close proximity of BCR and ABL during interphase may favour translocation • 76-kb duplicon on (9) near ABL and (22) near BCR may be implicated in translocation

  20. 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

  21. 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

  22. CML - treatment • Imatinib mesylate (Gleevec) • Allogeneic transplantation • Hydroxyurea

  23. 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

  24. 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

  25. 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

  26. 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

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

  28. Mechanism of action

  29. 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)

  30. How Should One Treat a Newly Diagnosed Pediatric Patient With CML?Goal in Pediatric Therapy Has Been Cure Rather Than Palliation

  31. 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

  32. 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

  33. 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

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

  35. 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%

  36. 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

  37. 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

  38. 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

  39. 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)

  40. Clinical data • Few pediatric studies • Champagne et al-2004 14 pediatric patients(3-20y) • Millot et al

  41. 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

  42. 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)

  43. Precautions • Neutropenia • Bone marrow suppression • Edema • Hepatotoxicity • Renal toxicity • Cardiac toxicity • Drug interactions

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