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SCIENCE MEETS MEDICINE: ACUTE PROMYELOCYTIC LEUKEMIA

SCIENCE MEETS MEDICINE: ACUTE PROMYELOCYTIC LEUKEMIA. Nancy Fuller, M.D. June 23, 2004. Objectives: Understand the history and presentation of Acute Promyelocytic Leukemia (APL) Be familiar with the major abnormalities and genetic factors Understand treatment and prognostic indicators

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SCIENCE MEETS MEDICINE: ACUTE PROMYELOCYTIC LEUKEMIA

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  1. SCIENCE MEETS MEDICINE:ACUTE PROMYELOCYTIC LEUKEMIA Nancy Fuller, M.D. June 23, 2004

  2. Objectives: • Understand the history and presentation of Acute Promyelocytic Leukemia (APL) • Be familiar with the major abnormalities and genetic factors • Understand treatment and prognostic indicators 4. Be amazed at the achievements gained with the interaction between basic sciences and clinical medicine.

  3. Disclosure: No outside sources of funding (and inside sources getting smaller all the time)

  4. 25 yo woman presented to clinic in May -3 week history of spontaneous bruising, increasing fatigue, and dizziness with minor exertion like climbing stairs. -1 nose bleed 3 weeks ago, none since; no bleeding from gums or per rectum

  5. PMH: previously healthy except for history of an eating disorder several years ago, now asymptomatic -on no meds; she had taken aspirin on a couple of occasions in the recent past because of headaches. -LMP 2 weeks before, heavier than usual -New sexual partner for past 6 weeks

  6. PE: slim young woman in NAD, VS normal HEENT: no petechia or bleeding Pulm: normal CV: II/VI murmur Abd: splenomegaly, no hepatomegaly Ext: multiple eccymoses especially over lower legs but also upper legs, arms. No petechia noted

  7. Labs: WBC: 2.4 (27% PMN, 23% lymph, 47% blasts, 2% NRBC H/H: 10.6/29 PLTS 18 K LFTs normal, INR 1.2 Fibrinogen 147 (165-400) D-Dimer greater than 18 (0-0.5)

  8. Differential: consistent with acute promyelocytic leukemia (atypical promyelocytes with folded or dumb-bell shaped nuclei; large granules, and Auer rods) Bone marrow: 100% cellularity, almost all promyelocytes

  9. Acute Promyelocytic Leukemia -First described in 1957: “a very rapidly fatal course of only a few weeks duration, a white blood cell picture dominated by promyelocytes, and a severe bleeding tendency due to fibrinolysis and thrombocytopenia” -”seems to be the most malignant form of acute leukemia”

  10. APL Most impressive features of APL: -occurence of a severe bleeding diathesis :up to 20-30% of patients died rapidly due to cerebral hemorrhage -large numbers of promyelocytic malignant cells found in marrow and peripheral blood with folded nuclei, azurophilic granules and Auer rods 1976: FAB nomenclature committee: M3

  11. APL -accounts for 10-15% of cases of AML -sometimes occurs after cytoxic treatment for other malignancies -median age 30; does occur in children and elderly

  12. APL Clinical management difficult because of the unpredictable onset of life threatening bleeding disorders; chemo exacerbates the bleeding diathesis. 2 major causes of bleeding: thrombocytopenia and fibrinogenopenia DIC vs primary fibrinolysis, or both? Features of both exist; etiology is unclear but 2 tumor cell procoagulants may be implicated

  13. APL Genetic abnormalities: -identified in the early 1980s: balanced translocation in long arms of chromosomes 15 and 17 t (15;17)

  14. APL Prognostic factors: intensity of thromobocyopenia, number of WBCs Low risk: WBC less than 10K plts greater than 40K Intermediate risk: WBC less than 10K plts less than 40K High risk: WBC greater than 10K

  15. APL Treatment initially: anthracyclines and platelet transfusions -main causes of poor outcome: failure to achieve remission due to resistance to chemo, and fatal hemorrhage By 1988: early mortality due to bleeding 15%, failure to enter remission 10%= 75% initial remission rate Relapse rate within 2 years: 35% = approximately 30-35% 2 yr survival rate

  16. APL SCIENCE MARCHES ON! Concept: certain agents can trigger a differentiating process in leukemic cells:malignant changes are not irreversible. -more than 100 hundred agents found that could induce terminal differentiation for certain types of cells

  17. APL In APL, all trans retinoic acid (ATRA) was found to be the most effective in vitro BUT: not available in Europe or US

  18. APL The Chinese Connection: 1985: Chinese researcher begins working with a French researcher in APL, resulting in a close collaboration between Paris and Shanghai, where ATRA could be manufactured. First patients treated in Shanghai with ATRA in 1987: No worsening of bleeding diathesis (as with chemo) Up to 95% remission rate!

  19. APL 1989: Tienammen Square; cessation of Franco-Sino cooperation -Roche agrees to make drug but only for French patients; trials begin in France.

  20. APL More science: -retinoic acid receptor alpha (RARA) located on long arm of chromosome 17 -APL: abnormal RARA receptor gene (called PML-RARA) Conclusion: APL is due to the fusion gene PML-RARA and manufacture of protein PML-RARA which represses the normal job of RARA in myeloid differentiation

  21. APL ATRA trials: very favorable results BUT: rapid relapse after remission Most favorable results: ATRA + chemo By 1992: treatment of APL without ATRA considered ‘unethical’

  22. APL Problems with treatment: • ATRA syndrome (aka RAS, LAS): fever, respiratory distress, 3rd spacing, renal failure; up to 25% of patients • Secondary resistance to ATRA: usually reverses after 6-12 months. Due to increase in cytochrome p450 catabolism of ATRA

  23. APL ARSENIC? 1995: Chinese researchers investigating arsenic treatment for various cancers find effectiveness in APL. -not useful as first line because of toxicity issues, but now can be used in relapse

  24. APL Current treatment recommendations: ATRA x 3-4, then add anthracycline til remission Consolidation tx: at least 2 courses of anthracycline, plus maintance ATRA Follow PCR for PML-RARA: positive result predicts relapse (follow for up to 5 years) Arsenic is indicated for relapsed patients, especially when treated with ATRA in past 12 months Relatively poor results with bone marrow trans

  25. APL Relapse occurs in 20-30% of patients, with rate dependent on risk levels initially (WBCs, platelets): Low risk: 98% 3 year relapse free survival Intermediate: 89% High: 70%

  26. APL Conclusions: -APL went from being “the most malignant form of leukemia” to being curable in at least 75% of patients -’the first model of a malignant disease to be treated by drugs targeted on an oncogenic event that alters the biologic process of the diseased cells’

  27. APL More to come? Other leukemias may be targeted in the same way :Gleevec for CML

  28. Selected references: Degos, L. The History of Acute Promyelocytic Leukemia. British Journal of Haematology, 2003, 122:539-553 -reads like a detective story! Tallman,M et al. Acute Promyelocytic leukemia: evolving therapeutic strategies. Blood, 2002, 99:759-767 Au, W et al. Oral arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia. Blood,102:407-408

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