Therapy-Related Leukaemia What is it? Who has it? Are you sure? - - PowerPoint PPT Presentation

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Therapy-Related Leukaemia What is it? Who has it? Are you sure? - - PowerPoint PPT Presentation

Jul 20, 2023 209 likes •1.05k views

Therapy-Related Leukaemia What is it? Who has it? Are you sure? Robert Peter Gale MD, PhD, DSc (hon), FACP, FRSM Imperial College London UCLA Medical Center Celgene Corp Disclosure Celgene Corp Fusion Pharma StemRad Actuarial

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Therapy-Related Leukaemia

What is it? Who has it? Are you sure?

Robert Peter Gale MD, PhD, DSc (hon), FACP, FRSM Imperial College London UCLA Medical Center Celgene Corp

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Disclosure

Celgene Corp Fusion Pharma StemRad

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Thursday Friday Saturday Monday Actuarial ¡Probability ¡Anyone ¡ ¡Will ¡Hear ¡Your ¡Talk ¡ 100% ¡ 0 ¡

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Thursday Friday Saturday Monday Actuarial ¡Probability ¡Anyone ¡ ¡Will ¡Hear ¡Your ¡Talk ¡ 100% ¡ 0 ¡

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Secondary leukaemia OR second cancer?

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Me

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Me ¡

Likely ¡Outcome ¡

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Apoplexy

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Secondary or Therapy-Related Leukaemia

25%

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If a man will begin with certainties, he shall end in doubts, but if he will be content to begin with doubts, he shall end in certainties.

Francis Bacon

may

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Questions What is secondary or therapy-related leukaemia? Who has it? Can we diagnose it accurately?

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My 3 problems… Apophenia Conjunction fallacy Evolutionary drive to think you are right

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My 3 problems… Apophenia Conjunction fallacy Evolutionary drive to think you are right

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Apophenia The human tendency to perceive meaningful patterns within random data

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My 3 problems… Apophenia Conjunction fallacy Evolutionary drive to think you are right

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Are you intelligent OR rational?

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65 year old man with newly-diagnosed AML worked in a nuclear power facility for 30 years. His weekend hobby is making model airplanes using petroleum-based glues in a closed

  • workspace. A survey of his basement shows

high radon level. The mostly likely cause of his AML is…

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Radiation Radiation and benzene Radiation, benzene and radon

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Radiation Radiation and benzene Radiation, benzene and radon

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Radiation Radiation and benzene Radiation, benzene and radon

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Radiation Radiation and benzene Radiation, benzene and radon

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Radiation Radiation and benzene Radiation, benzene and radon Correct

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My 3 problems… Apophenia Conjunction fallacy Evolutionary drive to think you are right

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Questions What is secondary or therapy-related leukaemia? Who has it? Can we diagnose it accurately?

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Questions What is secondary or therapy-related leukaemia? Who has it? Can we diagnose it accurately?

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Secondary or Therapy-Related Leukaemia A leukaemia known to be caused by or contributed to by exposure to DNA- damaging (mutagenic) agents such as ionizing radiations, drugs or chemicals

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Typical Variables

Older age Antecedent haematologic disorder/MDS Anaemia, Decreased WBC, platelets Dysplastic bone marrow Cytogenetic abnormalities del(5/5q), del(7/-7q), del (3p), del(17p), t(18;21), t(3;21), t(8;21), t(x;11q23) Mutations EVI1, AML1/2, MLL, NRAS, FANC, XPD, NQ01

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But….

None of these features is unique to secondary or therapy-related leukaemia

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Some Exposures Implicated in Therapy- Related Leukaemia

Ionizing radiations DNA-alkylating drugs Topoisomerase-2-inhibitors Benzene Radon Smoking Formaldehyde

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Anti-Cancer Drugs Linked to Leukaemia

Alkeran Busulfan Cyclophosphamide Chlorambucil Cisplatin Doxorubicin Etoposide Melphalan Mitoxantrone Nitrogen mustard Nitrosoureas Thiotepa

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Caveats Not all anti-cancer drugs cause therapy- related leukaemia Not all exposures to relevant drugs cause therapy-related leukaemia

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If you see someone with leukaemia exposed to one of these agents does they have therapy-related leukaemia?

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Problems with these analyses

They reflect associations, not cause-and- effect The calculations assume you know who has secondary or therapy-related leukaemia Associations refer to cohorts not individuals

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Questions What is secondary or therapy-related leukaemia? Who has it? Can we diagnose it accurately?

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Why are statistics important?

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To understand God's thoughts we must study statistics for these are the measure of his purpose

Florence Nightingale

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The science of medicine is uncertainty. The art of medicine is probability.

Sir William Osler.

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The science of medicine is uncertainty. The art of medicine is probability.

Sir William Osler.

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How do epidemiologists view causation?

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Probability of Causation

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Variables Needed to Calculate Probability

  • f Causation

Agent Dose Schedule Age at exposure Gender Interval from exposure to leukaemia Potential confounders (prior cancer, genetic disorder, smoking etc.)

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Variables Needed to Calculate PC

Agent Dose Schedule Age at exposure Gender Interval from exposure to leukaemia Potential confounders (prior cancer, genetic disorder, smoking etc.)

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A-Bombs and Leukaemia

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Variables Needed to Calculate PC

Agent Dose Schedule Age at exposure Gender Interval from exposure to leukaemia Potential confounders (prior cancer, genetic disorder, smoking etc.)

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CML after A-Bombs

Males Females

ERR

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Probability of Causation

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Probability of Causation 45% (95% CI, 25, 65%)

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Limitations In clinical setting we rarely have data needed to calculate a PC We lack statistical programs to calculate PC for exposures other than radiation

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PC Calculation

100 75 50 25

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Consequently, it is best to use estimates such as likely, possible, unlikely which encompass uncertainty rather than a binary (Y/N) with no expression of uncertainty

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PC Calculation

100 Likely Possibly Unlikely

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Why is any of this important?

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Why is uncertainty important Mis-labeling someone as having therapy-related leukaemia can result in a fatal physician error No therapy because the situation is hopeless or a transplant because nothing else will work

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Questions What is secondary or therapy-related leukaemia? Who has it? Can we diagnose it accurately?

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What is the difference between an estimate and a guess?

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How tall is Bob Gale?

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1 m 2 m

Estimate

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Is Bob Gale’s wife beautiful?

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Compared to what? How can I know, I’ve never seen her? Guess

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Aging is not a battle, it’s a massacre.

Phillip Roth

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Age and Cancer Risk

Males Females

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Age distribution of AML

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Second or New Cancer

Shared genetic risk (known and unknown) Shared environmental exposure (known and unknown) Field cancerization Increasing age Surveillance bias

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New Cancers in People with a 1st Cancer

Curtis NCI Monograph

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Cancer Risks Lifetime risk males Lifetime risk females 2nd Cancer 43% 39% 10-15%

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Given this confounding and imprecision we can only estimate whether leukaemia developing after a prior cancer is therapy- related.

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Questions What is secondary or therapy-related leukaemia? Who has it? Can we diagnose it accurately?

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It ¡is ¡uncertain ¡everything ¡is ¡uncertain ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡Blaise ¡Pascal

¡

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Esce dalla porta e rientra dalla finestra

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Uranium Ion Paths

Durante Health Phy 2012

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1 Gy γ or photon radiation 1000 single-strand breaks 500 damaged bases 40 double-strand breaks 150 DNA-protein cross-links

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Radiation-Induced Translocations