Historical Aspects of Acute Lymphoblastic Leukemia

1. Historical Aspects of Acute Lymphoblastic Leukemia www.inctr.org Ian Magrath INCTR 2004

2. 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 INCTR 2004

3. 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 INCTR 2004

4. 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 INCTR 2004

5. 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 INCTR 2004

6. 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) INCTR 2004

7. 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) INCTR 2004

8. 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 INCTR 2004

9. 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 INCTR 2004

10. 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 INCTR 2004

11. 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 INCTR 2004

12. 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 INCTR 2004

13. 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 INCTR 2004

14. 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 INCTR 2004

15. 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. INCTR 2004

16. Translocations in ALL Childhood , USA INCTR 2004

17. 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 INCTR 2004

18. Five Year Survival Rates (SEER) 1992-8, 0-14 years Percent INCTR 2004

19. 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 INCTR 2004

20. 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 INCTR 2004