INCTR

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

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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

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

5
Treatment Early Observations

• 1865 Lissauer reported response to Fowlers
  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

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)

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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)

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

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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

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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 (lt5) achieved long term
  survival
• Identified obstacles to cure drug resistance,
  meningeal relapse, toxicity, pessimism

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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

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

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

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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 922 translocation
• 1970s T and B lymphocytes discovered, leading to
  immunophenotyping of lymphoid neoplasms

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.
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Translocations in ALL
Childhood , USA
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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

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

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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