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PBL – problem 12 Chronic Myeloid Leukaemia

PBL – problem 12 Chronic Myeloid Leukaemia. Dr Guy Lucas, MRI, 2009. Chronic Myeloid Leukaemia. What is it? Epidemiology Clinical features at diagnosis Laboratory features Cytogenetics/Molecular biology Imatinib and other treatments. Chronic Myeloid Leukaemia. What is it?.

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PBL – problem 12 Chronic Myeloid Leukaemia

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  1. PBL – problem 12Chronic Myeloid Leukaemia Dr Guy Lucas, MRI, 2009

  2. Chronic Myeloid Leukaemia • What is it? • Epidemiology • Clinical features at diagnosis • Laboratory features • Cytogenetics/Molecular biology • Imatinib and other treatments

  3. Chronic Myeloid Leukaemia • What is it? Chronic myeloproliferative disorder, characterised by increased neutrophils and Philadelphia Chromosome NB Clonality

  4. Chronic Myeloid Leukaemia • Epidemiology Chronic myeloproliferative disorder 700 cases per year in UK Median age 55 years Male:Female 1.4:1 Linkage with radiation

  5. PBL Problem 12: Abdominal Mass, ? Cause General Practitioner’s notes: Karen Silkwood, 37 year old lab technician at BNFL, who rarely attends surgery c/o abdominal pain for 4/7 Additional questioning establishes that she has lost 10lb in weight in the last six months without dieting. “I am hungry but feel full after a small amount of food.” The pain is constant but gradually increasing in severity. It is epigastric and left hypochondral, but she has also had some pain in the left shoulder.

  6. PBL Problem 12: Abdominal Mass, ? Cause General Practitioner’s notes: Karen Silkwood, 37 year old lab technician at BNFL, who rarely attends surgery c/o abdominal pain for 4/7 o/e Large tender left-sided abdominal mass What is the differential diagnosis for this mass?

  7. PBL Problem 12: Abdominal Mass, ? Cause What investigations would you do? Full blood count Routine Biochemical profile Abdominal Ultrasound Examination

  8. Chronic Myeloid Leukaemia • Clinical features - symptoms Asymptomatic in > 20% Fatigue Bleeding Weight loss Splenic discomfort/fullness (7% present with advanced disease)

  9. Chronic Myeloid Leukaemia • Clinical features - signs Splenomegaly (75%) Hepatomegaly (2%) Purpura (16%) Priapism (1% of males)

  10. Chronic Myeloid Leukaemia

  11. PBL Problem 12: Abdominal Mass, ? Cause What investigations would you do? Full blood count Routine Biochemical profile Abdominal Ultrasound Examination Haemoglobin 10.3 g/dl White Cell Count 210 x 109/l Platelets 490 x 109/l 23 cm Splenomegaly

  12. PBL Problem 12: Abdominal Mass, ? Cause How would you explain these results? What further investigations would you do to confirm your suspected diagnosis? Haemoglobin 10.3 g/dl White Cell Count 210 x 109/l Platelets 490 x 109/l 23 cm Splenomegaly

  13. Chronic Myeloid Leukaemia • Laboratory investigations Full blood count (WBC, Hb, Plts) Blood film examination Bone marrow aspirate and trephine Cytogenetic analysis of bone marrow

  14. Normal blood Chronic myeloid leukaemia

  15. Bone Marrow Biopsy

  16. Bone Marrow Biopsy

  17. The Philadelphia Chromosome

  18. Cytogenetics in CML t(9;22) present in 95% of CML variant translocation (nb 922) 9q deletions additional chromosomes +8, iso17q, +Ph, +19

  19. t(9;22) – BCR-ABL

  20. Intracellular Effects of BCR-ABL Downstream effects of BCR-ABL still not completely identified Leukaemogenesis in CML appears to be dependent upon functioning BCR-ABL Numerous pathways appear to be involved in malignant transformation

  21. Clinical CML (“blast crisis”) A major point in CML biology: genetic instability The abnormal stem cells continue to replicate, but undergo additional mutations. Most mutations have no effect or are disadvantageous but in the end a new clone inevitably emerges in which the ability to differentiate is lost.

  22. Chronic Myeloid Leukaemia • Initial Management • Establish diagnosis • Relieve symptoms • Natural history of disease • Chronic Phase • Transformation (Blast crisis) • Definitive therapy before transformation

  23. PBL Problem 12: Abdominal Mass, ? Cause In view of the high white cell count and tender splenomegaly, Karen is given intravenous hydration, analgesia, Hydroxycarbamide and Allopurinol. She is kept in over the week-end, and her splenic pain gradually settles. By Monday, the spleen is smaller and much less tender, and her White Cell Count has fallen to 108 x 109/l. She is discharged home on Hydroxycarbamide, Allopurinol and prn analgesia, to return on Thursday for the bone marrow results.

  24. PBL Problem 12: Abdominal Mass, ? Cause In view of the high white cell count and tender splenomegaly, Karen is given intravenous hydration, analgesia, Hydroxycarbamide and Allopurinol. She is kept in over the week-end, and her splenic pain gradually settles. By Monday, the spleen is smaller and much less tender, and her White Cell Count has fallen to 108 x 109/l. She is discharged home on Hydroxycarbamide, Allopurinol and prn analgesia, to return on Thursday for the bone marrow results.

  25. PBL Problem 12: Abdominal Mass, ? Cause In view of the high white cell count and tender splenomegaly, Karen is given intravenous hydration, analgesia, Hydroxycarbamide and Allopurinol. She is kept in over the week-end, and her splenic pain gradually settles. By Monday, the spleen is smaller and much less tender, and her White Cell Count has fallen to 108 x 109/l. She is discharged home on Hydroxycarbamide, Allopurinol and prn analgesia, to return on Thursday for the bone marrow results. • Immediate management • Impending splenic rupture • Leucostasis • Iatrogenic gout

  26. PBL Problem 12: Abdominal Mass, ? Cause In view of the high white cell count and tender splenomegaly, Karen is given intravenous hydration, analgesia, Hydroxycarbamide and Allopurinol. She is kept in over the week-end, and her splenic pain gradually settles. By Monday, the spleen is smaller and much less tender, and her White Cell Count has fallen to 108 x 109/l. She is discharged home on Hydroxycarbamide, Allopurinol and prn analgesia, to return on Thursday for the bone marrow results.

  27. PBL Problem 12: Abdominal Mass, ? Cause She returns to see the Consultant Haematologist on Thursday. She is feeling much better and no longer needing analgesia. The spleen is still palpable but much less tender and the White Cell Count 72.3 x 109/l. The bone marrow test has confirmed the diagnosis of Chronic Myeloid Leukaemia; in particular, the bone marrow cytogenetics shows the “Philadelphia Chromosome”, although molecular screening for BCR-ABL is not yet through.

  28. Chronic Myeloid Leukaemia • Initial Management • Establish diagnosis • Relieve symptoms • Natural history of disease • Chronic Phase • Transformation (Blast crisis) • Definitive therapy before transformation

  29. Chronic Myeloid LeukaemiaOptions Glivec (Imatinib)First line use TransplantationPotentially curative Toxic procedure Expensive HydroxycarbamidePalliative Simple, cheap InterferonProlongs life Not curative, side effects

  30. Glivec, Imatinib mesylate

  31. Mechanism of action of Imatinib (Glivec) Imatinib

  32. Imatinib

  33. Chronic Myeloid LeukaemiaOptions Glivec (Imatinib)First line use TransplantationPotentially curative Toxic procedure Expensive HydroxycarbamidePalliative Simple, cheap InterferonProlongs life Not curative, side effects

  34. Year Total Dead 1990-2000 960 357 1982-1989 365 266 1975-1981 132 127 1965-1975 123 122 Survival in Early Chronic-Phase CML 1.0 0.8 0.6 Proportion Surviving 0.4 0.2 0.0 0 3 6 9 12 15 Years From Referral University of Texas M.D. Anderson Cancer Center Database 1965-2005

  35. Year Total Dead Imatinib 276 14 1990-2000 960 357 1982-1989 365 266 1975-1981 132 127 1965-1975 123 122 Survival in Early Chronic-Phase CML 1.0 0.8 90% 0.6 Proportion Surviving 0.4 0.2 0.0 0 3 6 9 12 15 Years From Referral University of Texas M.D. Anderson Cancer Center Database 1965-2005

  36. Chronic-Phase CML – survival after 6 years 1.0 Imatinib 90% 0.8 Sibling BMT 70% 0.6 Unrelated donor BMT 54% Proportion Surviving 0.4 0.2 0.0 0 3 6 9 12 15 Years From Referral University of Texas M.D. Anderson Cancer Center Database 1965-2005 / IBMTR data

  37. NICE: Appraisal Imatinib is recommended as first-line treatment in the management of people with Philadelphia-chromosome-positive chronic myeloid leukaemia (CML) in the chronic phase.

  38. Performance of Top 10 Products Sales 2008 in US $m Diovan® (hypertension)5740 Glivec® (CML)3670 Zometa® (cancer complications)1382 Femara® (breast cancer)1129 Sandostatin® (acromegaly, carcinoid)1123 Neoral® (transplantation)956 Lucentis® (macular degeneration)886 Exelon® (Alzheimers) 815 Voltaren® (arthritis) 814 Lescol® (cholesterol)645

  39. Imatinib: some remaining questions Will imatinib ‘cure’ anyone? Have we got the dose right, and can we improve on imatinib? How do we treat patients failing on imatinib?

  40. Imatinib: some remaining questions Will imatinib ‘cure’ anyone? Have we got the dose right, and can we improve on imatinib? How do we treat patients failing on imatinib?

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