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History of Acute Lymphoblastic Leukemia PowerPoint Presentation

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  • Slide 1 - INCTR 2004 Historical Aspects of Acute Lymphoblastic Leukemia www.inctr.org Ian Magrath
  • Slide 2 - INCTR 2004 Discovery of Leukemia Craigie and Bennett described a case of suppuration of the blood in 1845. Subsequently referred to the disease as leukocythemia Rudolph Virchow, also in 1845, described a similar case, but did not think this simply pus in the blood and related it to simultaneous splenic enlargement. Subsequently referred to the disease as Weisses Blut then suggested the term leukemia
  • Slide 3 - INCTR 2004 Importance of Bone Marrow Ernst Neumann (1855) discovered, in the course of an autopsy, that the bone marrow was dirty green-yellow in colour, instead of red, and could be the origin of the blood abnormalities Subsequently showed that the bone marrow is the origin of the normal cellular components of the blood. Implication: leukemia a systemic disease – surgery and radiation therapy palliative at best
  • Slide 4 - INCTR 2004 Classification 19th century: splenic and lymphatic 1900: cytochemistry confirms 4 main cell types - acute and chronic myeloid; acute and chronic lymphoid 1976: FAB classification based on morphology and cytochemical features. ALL divided into L1, L2 and L3 on purely morphological grounds 1975: recognition of T cell subtype which had a worse prognosis (Sen and Borella) – immunophenotypic classification Subsequent identification of various cytogenetic abnormalities Molecular classifications e.g. using PCR
  • Slide 5 - INCTR 2004 Treatment – Early Observations 1865: Lissauer reported response to “Fowler’s solution” (arsenious oxide) 1903: Response of leukemia to splenic radiation in chronic leukemia Accidents in first and second world wars led to recognition of effect of mustard gas on lymph nodes and bone marrow 1942: Gilman and Phillips gave mustard to mice, then patients with lymphoma with some response
  • Slide 6 - INCTR 2004 Treatment – Modern Era Sidney Farber attempted to treat leukemic blasts (cf. megaloblasts) with folic acid (identified in 1941, synthesized in 1946) and noted worsening Subsequently gave an antagonist (4-amino pteroylglutamic acid, aminopterin, synthesized by Seeger) to children and observed remissions lasting for several months (reported 1948)
  • Slide 7 - INCTR 2004 Treatment – Other Drugs 1949: ACTH, cortisone and prednisone 1940s and 1950s: Elion and Hitchings study purine metabolism and develop antimetabolites 6-MP and 6-TG 1953: Burchenal gave 6-MP to children with leukemia and introduced triple therapy consisting of 6-MP, antifolate and steroid (one long term survivor) 1959: Cyclophosphamide synthesized by Brock and shown active in ALL by Fernbach et al 1962: Vincristine shown to be active (Karon, Freireich and Frei)
  • Slide 8 - INCTR 2004 Discovery of Principles 1950s and 1960s, Lloyd law develops mouse leukemia (L1210) Skipper, Schnabel et al, apply mathematical models and demonstrate that cancer cells persist even when the mice are in CR Also showed dose response relationship Led to the notion that treatment must be continued after leukemia no longer detectable Showed (Law) that cells resistant to 6-MP may respond to MTX – multiple drugs may be better
  • Slide 9 - INCTR 2004 Combination Chemotherapy 1962: Freireich and Frei showed that the four available anti-leukemic drugs VAMP gave better results: VCR, MTX (amethopterin) 6-MP prednisone A few patients achieved long term survival
  • Slide 10 - INCTR 2004 Treatment – St Jude 1962: St Jude Hospital founded. First Director, Donald Pinkel Grappled with problem that although complete remissions could be achieved, only a small percentage of patients (<5%) achieved long term survival Identified obstacles to cure: drug resistance, meningeal relapse, toxicity, pessimism
  • Slide 11 - INCTR 2004 Total Therapy St Jude initiated the concept of treatment phases: Remission induction (usually three drugs) Intensification or consolidation (different drugs) Prevention of meningeal leukemia (CNS irradiation) Continuation therapy (6-MP and MTX) Treatment cessation after 2-3 years Objective - CURE
  • Slide 12 - INCTR 2004 CNS Prophylaxis Total therapy gave better but still poor results (7 of 41 children long term survivors): Pneumocystis pneumoniae developed in many (probably from cranio-spinal irradiation) Relapse in meninges still a major problem Used increased dose of cranial radiation; in 1967, 24cG, with IT MTX Dramatic improvement - 50% long term survival
  • Slide 13 - INCTR 2004 German Contributions 1965: Formation of Deutsche Arbeitsgemeinschaft für Leukämie Forschung und Behandlung in Kindersalter (38 hematological oncologists). Reihm used aggressive therapy with similar survival rate to St Jude (50%) 1970: Formation of Berlin-Frankfurt-Munster group – based on aggressive 8-drug therapy Late re-induction improves prognosis in all patients Poor response to prednisone in first week indicates very poor prognosis Progressive improvement on structure of treatment protocols
  • Slide 14 - INCTR 2004 Insights into Origins 1960: Peter Nowell and David Hungerford discover Philadelphia chromosome in CML 1960: Lymphocyte transformation demonstrated, leading to new insights into lymphoid cells 1973: Janet Rowley discovers that the Ph’ chromosome results from a 9;22 translocation 1970s: T and B lymphocytes discovered, leading to immunophenotyping of lymphoid neoplasms
  • Slide 15 - INCTR 2004 CALLA Emerges ALL associated with improved socioeconomic status – implications for strong environmental influence on cause. NB, rarity of ALL in Africa today. Age-specific association suggests subtypes are age and environment-related.
  • Slide 16 - INCTR 2004 Translocations in ALL Childhood , USA
  • Slide 17 - INCTR 2004 Further Progress Once significant survival rates being obtained, prognostic factors could be defined: WBC, age, many others, ploidy, DNA index, rate of response to therapy, karyotype, genotype Treatment tailored to risk group Demonstration of late effects of treatment, especially radiation: Cognitive, leucoencephalopathy, brain tumors Demonstration that IT prophylaxis sufficient for most patients Exploration of detection of minimal residual disease
  • Slide 18 - INCTR 2004 Five Year Survival Rates (SEER) 1992-8, 0-14 years Percent
  • Slide 19 - INCTR 2004 Treatment of Relapse Success related to timing and location of relapse (e.g., early, worse prognosis, extramedullary better prognosis) Demonstration that allogeneic transplantation effective, although role in treatment of relapse still under study, and recent data suggests not useful in treatment of patients with poor risk translocations
  • Slide 20 - INCTR 2004 The Future – Individual, Minimally Toxic Treatment Better separation of molecular subtypes and correlation with genetic and environmental factors, and treatment results Exploration of alternative therapies in very high risk patients (NB. L3, BL therapy) Maximal simplification of therapy in low risk patients (few in India) – avoidance of acute and late toxicity Correlation of therapy (type, duration) with molecular response Use of pharmacokinetics and pharmacogenomics in guiding therapy Use of therapy targeted to molecular lesions

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