Clinical Causation Analysis: Potential Causation of AML from Isotretinoin Exposure

This document was prepared during the acute phase of my wife’s AML diagnosis and treatment, for the consideration of her treating physicians. It is reproduced here in full, exactly as written and submitted, because it directly demonstrates a body of work referenced elsewhere in this portfolio: the capacity to build a rigorous, well-sourced clinical argument under emotionally extreme circumstances, communicate it clearly to specialists, and have that argument taken seriously enough to shape treatment review. The treatment rationale developed here was reviewed and accepted by both Drs. Westervelt and Perry and shaped the treatment plan going forward, though it was never fully utilized as Amy passed away from complications of the current protocol before this ATRA based plan could proceed.

Definitions

For the purposes of this discussion, the following terms are defined as follows:

Alkylating Agent: An organic or chemical compound that transfers or combines alkyl groups to other molecules in a process known as alkylation — commonly a subtype of antineoplastics. [Edit, May 23, 2007: Further research has shown that isotretinoin is not an alkylating agent, but is in the same family of antineoplastics, and is classified as miscellaneous, as its exact mechanism of action is still not fully known.]

Antineoplastics: Drugs that combat or inhibit the development of tumors. Also known as noncovalent DNA-binding drugs, or cytotoxic drugs.

Cytotoxic Drug: Any drug that inhibits or prevents the function of cells — drugs “toxic to cells.” Includes drugs used to treat cancers and some skin conditions.

Standard timeframe from exposure to presentation

“Treatment with alkylating agents has been associated with increased risks of MDS and tAML; a preceding MDS is observed in over 70% of patients who develop therapy-related AML. Typically, t-AML occurs 5–7 years following treatment, and risk is related to cumulative alkylating drug dose,” and “the mean latency period after onset of treatment is approximately 6 years.” Patients exposed to radiation in Japan saw presentation of AML approximately 5–7 years after exposure.

Isotretinoin/tretinoin as cytotoxic drug and potential alkylating agent

Isotretinoin is an antineoplastic and cytotoxic drug, and potentially an alkylating agent, used in both the treatment of severe acne and in the treatment of APL (AML M3), with an exact mechanism of action that remains unknown but works through alteration of DNA transcription. In cases of immunosuppression, DNA transcription may be reversed into RNA transcription, resulting in genetic alterations including additions, inversions, and deletions of chromosomes. Immunosuppression, including neutropenia, is a known side effect of isotretinoin/tretinoin.

Furthermore, isotretinoin/tretinoin contains a known carcinogen as one of its component active ingredients — butylated hydroxyanisole — which has a chemical structure similar to compounds found in the active ingredients of benzene (2-butoxyethanol), a common ingredient in paints; painters have one of the highest occurrences of AML of any profession.

Known links from isotretinoin/tretinoin to development of lupus

Lupus, an autoimmune disorder, has been linked to the use of isotretinoin/tretinoin, and lupus, like AML, is associated with the addition, inversion, or deletion of chromosomes. The cytotoxicity of isotretinoin/tretinoin is certainly capable of creating the chromosomal abnormalities found in AML or MDS. Given that “an abnormal number or structure of chromosomes, or both, are readily evident in approximately 75 percent of cases” of AML, one out of four patients will not have the underlying chromosomal abnormalities readily evident — meaning the absence of chromosomal abnormalities in cytogenetics is not necessarily indicative that a patient does not have a form of tAML or secondary AML related to chromosomal abnormalities found in MDS, or related to treatment with isotretinoin/tretinoin.

Amy Wilhoite’s background and usage of isotretinoin/tretinoin

Amy Wilhoite was exposed to tretinoin (ATRA) in the form of Retin-A topical gel at the highest commercially available dose, 0.1%, from 1997 through 2000, when she began a five-month course of isotretinoin (Accutane) at a varied dosage based on lab reports (45mg in the 1st and 3rd month, 60mg in the 2nd, 4th, and 5th month — equivalent to the same dosage she would have received had she been receiving isotretinoin as a chemotherapy drug: 55mg). Approximately six years later, coinciding precisely with the timeframe established above, she was diagnosed with AML.

Questions regarding future treatment and current diagnosis

• Given the above, is it safe to assume this is the likely cause of her AML, and if so, does this have any influence on treatment decisions?
• Similarly, is it possible she has a form of secondary, or tAML?
• Do her cytogenetics need to be further reviewed and researched in light of this information?
• I’ve read in numerous places that a cytotoxic or toxic agent given in small doses often corrects problems caused by the same toxin/cytotoxin in large doses (radiation, arsenic, cyanide, for example). If true, would treating her with ATRA, or as though she had M3 (APL), be worth considering?

Additional information — added May 23, 2007

At the time of this document’s original creation, we were not aware of any chromosomal abnormalities. We are now aware that Amy has an abnormality of t(11;19)(q23;p13.1) — also known as MLL (Multi-Lineage Leukemia, or Mixed Lineage Leukemia). Depending on her exact DNA, this would be classified as MLL-ELL or MLL-MEN.

We contacted a specialist on this particular abnormality at the University of Chicago — more for treatment questions than anything else — who has published work with another researcher unequivocally stating that this particular abnormality is always the result of prior treatment. I found several other sources stating it is almost always the result of prior treatment. The only treatment of any kind Amy has ever had is Accutane, and the only treatment she had that fits the timeframe for presentation of secondary AML also fits exactly when her Accutane treatment occurred. For the record, the specialist felt that Amy’s current treatment “is both appropriate and state of the art.”

Following Dr. Perry’s suggestion when first presented with this information in late April, I conducted extensive research over the following weeks on retinoid- or ATRA-based secondary leukemias. I found several studies indicating a sharp increase in tAML patients resulting from APL treatment with ATRA over the prior decade — fitting the timeframe for tAML presentation perfectly, since ATRA only began being used in APL treatment in the early 1990s (1993 was the earliest reference I could find), and is considered responsible for the high cure rate of APL patients. The studies indicated that between 5–10% (8.53% in one large study) of APL patients receiving ATRA therapy were presenting with a form of tAML. Most of these patients presented with a change of the 11th chromosome — the same as Amy — though most presented with 11;17 (the faulty chromosome in APL), with the rest presenting with 11;23, the same family as Amy’s abnormality.

In 80–90% of tAML cases, the patient presents with MDS first, though it often goes undiagnosed — the 11;23 chromosome is indicative of MDS. Though differing prognoses exist for each of the many 11;23 abnormalities, none are very favorable; with Amy’s particular abnormality, median lifespan is 6 months from presentation of disease. (In her case, looking back, we could identify potential disease presentation as early as November 2005 — meaning she had done exceedingly well, all things considered, by the time of this writing.) In tAML, MDS often lasts only a couple of months before evolving to AML, though in some cases it can remain for years — more common among non-tAML patients transitioning from MDS to AML.

Sources

Source material included: Cancer Epidemiology and Prevention, Third Edition (Colditz, Samet, Whittemore; Oxford University Press, 2006); Williams Hematology, Seventh Edition (Lichtman, Kipps, Kaushansky, Beutler, Seligsohn, Prchal; McGraw-Hill, 2006); Cancer Medicine 7 (Kufe, Frei, Bast, Hait, Hong, Pollock, Weichselbaum, Holland; B.C. Decker, 2006); Accutane (Isotretinoin Capsules) Side Effects & Precautions documentation (August 2005); the MD Anderson Manual of Medical Oncology (Kantarjian, Wolff, Koller; McGraw-Hill, 2006); and Lexi-Comp’s Drug Information Handbook for Oncology (Solimando; Lexi-Comp, 5th Edition, July 2005), along with additional peer-reviewed and clinical reference sources on isotretinoin, lupus, and chromosomal cytogenetics.

Related: Clinical Reasoning Under Pressure — An email response written during the acute phase of my wife’s AML treatment: explaining why a well-intentioned alternative treatment recommendation was medically contraindicated, to a lay audience, without condescension or dismissiveness.