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Prof. Cristina Stefan MD PhD Pediatric Oncologist

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Prof. Cristina Stefan MD PhD Pediatric Oncologist Tygerberg Children’s Hospital Stellenbosch University




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

6 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

7 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)

8 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

9 1 day history : * Sore throat * Pleuritic chest pain * Dry cough
PATIENT Z.A. 13YR FEMALE Referred from Delft HC 1 day history : * Sore throat * Pleuritic chest pain * Dry cough * Stomach ache

10 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

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

12 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

13 Causes for Splenomegaly (examples)
+ fever Infections (HIV, Hep, Malaria) Sarcoidosis, systemic diseases Malignancies + lymph - adenopathy Leukaemia, Lymphoma + purpura Septicaemia ALL + anaemia Leukaemia Thalassaemia, Sickle Cell D, + ascites Portal hypertension

14 Diagnosis : CML ACUTE Normo or macrocytic anaemia  or WCC
 Platelets CHRONIC Hb (n) slightly  WCC  ++ Platelets  Diagnosis : CML

15 LEUKAEMIA ACUTE Symptoms related to bone marrow infiltration/suppression  or  WBC  Hb  Platelets Organ infiltration > Spleen > Liver > Glands CHRONIC Symptoms related to hypermetabolism Weight loss Lassitude Anorexia Night sweets Gout or renal impairment Organ infiltration >spleen – frequently massive Bruising/bleeding : abn platelet function

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

17 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.

18 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

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

20 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

21 Blast phase ( BP): Blast > 20% in PB
Extramedullary blast proliferation Large foci of clusters of blasts in BM WHO, PATHOLOGY AND GENETICS, p & NEJM, vol. 346, no. 9. Feb 9, 2003, p

22 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


24 CML – a Disease Linked to a Single Molecular Abnormality
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 [slide 2] CML: a Disease Linked to a Single Molecular Abnormality CML is a clonal proliferation of a malignant hematopoietic progenitor cell. The disease has been studied extensively and is characterized by defined clinical stages and prognostic factors. The efficacy and safety outcomes from a number of treatment regimens are well documented.1-3 In 1960, an aberrant chromosome that is unique to this disease was identified in bone marrow cells from patients with CML. Termed the Philadelphia (Ph) chromosome, it is a shortened chromosome 22 resulting from a reciprocal translocation, t(9;22)(q34;q11), between the long arms of chromosomes 9 and 22.4,5 The Ph chromosome, which is present in 95% of patients with CML, produces an abnormal, constitutively activated Bcr-Abl tyrosine kinase that is linked to malignant transformation.6,7 Thus, the Bcr-Abl kinase is an attractive target for rational drug design. References 1. Sawyers CL. Chronic myeloid leukemia. N Engl J Med ;340: 2. Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid leukemia. N Engl J Med ;341: 3. Pasternak G, Hochhaus A, Schultheis B, et al. Chronic myelogenous leukemia: molecular and cellular aspects. J Cancer Res Clin Oncol ;124: 4. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science. 1960;132: 5. Rowley JD. Letter: a new consistent abnormality in chronic myelogenous leukemia identified by quinicrine fluorescence and Giemsa staining. Nature. 1973;243: 6. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the p210bcr/abl gene of the Philadelphia chromosome. Science ;247: 7. Heisterkamp N, Jenster G, ten Hoeve J, et al. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990;344:

25 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

26 CML - treatment Imatinib mesylate (Gleevec) Allogeneic transplantation

27 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

28 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

29 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

30 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

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


33 Mechanism of action

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)

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

36 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

37 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

38 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

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

40 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%

41 RESPONSE TO THERAPY Relapse 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

42 Pharmacokinetics,dose
Rapidly absorbed –oral administration, max concentration 2-4h T1/2 14,8h Millot et al –the dose equivalent to mg in adults induced side effects of similar types to those observed in adults None required discontinuation for toxicity

43 Dosage and administration
mg/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

44 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)

45 Clinical data Few pediatric studies
Champagne et al pediatric patients(3-20y) Millot et al


47 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 mg/day

48 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)

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




53 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?


55 My colleagues at Tygerberg Hospital:


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