Thursday, July 26, 2007

Secondary leukemia

While collecting a fax off the machine the other day I stumbled across a report on an old patient of mine. I had treated her about 10 years ago for follicular lymphoma but now she had developed acute myeloid leukemia. It is becoming apparent that the successful treatments for various cancers, themselves leave secondary cancers in their wake. Thinking back over my career of 35 years of treating cancer patients, the numbers are beginning to mount up.

I can remember another woman of a similar age who developed her secondary leukemia five years after the lymphoma treatment. There was a woman with splenic marginal zone lymphoma who developed her leukemia after chlorambucil. This is the only time I have seen chlorambucil responsible. There was a man with an autoimmune condition, Wegener's granulomatosis, who developed first myelodysplastic syndrome (MDS) then acute myeloid leukemia (AML) after cyclophosphamide, and another woman with systemic lupus erythematosus who had a cyclophosphamide induced acute leukemia.

It is well established that cytotoxic drugs can cause both MDS and AML. The alkylating agents - mustine, cyclophosphamide, melphalan, thiotepa, chlorambucil and busulphan are well known to do so. Often they cause a loss of all or part of chromosomes 5 and 7, and the type of leukemia is usually difficult to treat and frequently fatal. Less well known is the fact that another type of cytotoxic drug, those that act as topoisomerase inhibitors (such as adriamycin and etoposide)can also cause leukemia, though these drugs induce chromosomal translocations like t(8;21), t(15;17) and inv 16.

In my experience cyclophophamide is more likely to induce leukemia than other cytotoxic drugs. This is paradoxical because it is less likely to induce permanent bone marrow damage than the others. Perhaps the others do not allow partially damaged cells to survive.

There is also some suggestion that the type of tumor being treated might influence whether or not secondary leukemias occur. We know that MDS and AML can occur with other lymphomas and leukemia even if no treatment is given. Myeloma is associated with MDS. In the 1980s I reported 20 patients with various B cell malignancies who developed MDS or AML without any treatment. I have seen AML develop in CLL patients twice; on both occasions the patient had received no treatment for the CLL. I have seen three patients who developed chronic myeloid leukemia (CML) to complicate their CLL even though they had had no treatment for their CLL.

The patient who had Wegener's Granulomatosis had a brother with kidney cancer. The woman with systemic lupus erythematosus was treated at the same time as another with the same diagnosis, only this woman was treated with plasma exchange rather than cytotoxic drugs. She developed kidney cancer.

To me this all suggests a genetic tendency to develop multiple disorders of the blood and immune systems. Treatment toxicity may synergize with this.

Why some patients develop secondary cancers and others do not, despite having teh same disease and the same treatment is a mystery. It is agood subject for research.

8 comments:

Jenny Lou said...

Terry,
would you consider Melanoma as a secondary cancer to CLL? My husband had a dx of melanoma 1 year after treatment with FCR and 2 1/2 years after dx of CLL. I figured it was because of the T-cells not working properly. Maybe it is a "side" cancer of CLL.

Anonymous said...

So, do you think those who have taken FCR are at risk for future cancers? FCR is quite common now.

Terry Hamblin said...

Not in the sense that it is induced by DNA damaging drugs. It is a feature of the immune deficiency of CLL, which can be made worse by treatment. Melanoma is similar to mouse tumors induced by UV light in that it is commonner in individuals whose immunity is suppressed.

Terry Hamblin said...

Is secondary cancer commoner after FCR? We will have to wait and see. I have always considered it a possibility, but we will need long term follow-up to know one way or the other. I'm not jumping to conclusions.

Anonymous said...

Is this a case of do it and you die.

Don't do it and you die.

Jim McVey said...

It seems to me that the importance of knowing ones deletions has assumed a more necessary requirement than ever before. Maybe it has always been so, but was not so readily available as it is today.

I remember when I was first diagnosed 97- 99 and had gained a little experience of CLL, the patient was more conscious of WBC counts, HGB, HCT, Platelet, and ANC. I know in those days deletions were not mentioned.

Perhaps you could comment on the need to know of ones deletions. I am sure it is something that the local Oncologist/Hematologist does not discuss too much, mine doesn’t.

I believe the rule is, that one should have a FISH done before a contemplated treatment change.

Steve Grice said...

My wife had a desmoplastic malignant melanoma pop up within a few days of her being diagnosed with CLL. Is this type melanoma associated with CLL, sun abuse when younger, or something else? On dx her white count was already 40 so she had the CLL for a while. She has good progs de13q14, cd38-, mutated 4.1%, b2m 1.75, stage 1, but with a ZAP70 of 65-70%. She is worried that treatment when required will trigger another melanoma. Where can she find more info about DMM? We have not had much luck on the internet. Gentle treatment that doesn't hit the T cells too hard or hit it hard and get out (PCR of Fcr) - Any thoughts on that?

Terry Hamblin said...

http://path.upmc.edu/cases/case378/dx.html gives a description of desmoplastic melanoma beginning
"Desmoplastic melanoma is a term first used by Conley in 1971 to describe a variant of melanoma characterized by a dermal spindle cell population in a background of abundant collagen. Eight years later, Reed and Leonard used the term desmoplastic neurotropic melanoma to describe desmoplastic melanomas with nerve infiltration. Although desmoplastic melanoma may arise de novo, it is most commonly associated with other types of melanoma, mainly lentigo maligna. Like lentigo maligna, desmoplastic melanoma occurs in older individuals, most commonly in the sixth decade of life, and has a slight predilection for males (male-to-female ratio 1.75:1) (5). Lesions are most often located on sun-exposed skin of the head and neck but can also be located on the trunk or extremities."

Like other melanomas, UV light is a likely culprit and immunodeficincy may play a part.

It is likely that further immuosuppressive treatment will increase the likelihood of relapse and recurrence.