Secondary MDS and acute leukemia

As patients with CLL live longer they are experiencing a higher risk of secondary malignancy. The well known risk is of Richter's transformation in which an aggressive lymphoma supervenes. It seems that most cases are related to the immune defect that is present in CLL and that at least half are due to an inability to control the EB virus. However, it has come to light that patients who have autologous transplants have at least an 15% chance of developing MDS or AML. This is similar to what is found for patients with breast cancer and non-Hodgkin's lymphoma, and seems to be related to the chemotherapy used to induce remission or to condition the patient for the transplant. Moreover, patients treated with FCR or even plain fludarabine also have an increased risk of developing MDS or AML.

Why is it that some patients can receive this sort of chemotherapy safely and others are at risk of a second malignancy. The answer lies in the genes.

Despite the human genome having been sequenced, it is clear that everyone differs slightly from everyone else. These differences are due to polymorphisms. Some of us are blood group A, some B, some AB and some AB. We have different versions of a gene for blood groups. All differences between individuals have such an origin. Big ears, blue eyes, no ear lobes, red hair? All down to our genes. Some of these differences are due to a single amino-acid substitution in a protein. The best known is sickle cell disease. Here the substitution of a valine for a glutamic acid at position 6 in the beta chain of hemoglobin is sufficient to cause a crippling disease. However there are hundreds of similar substitutions in the hemoglobin molecule. Many of them cause no ill health whatsoever, but others cause various malfunctioning of the hemoglobin molecule.

Every other protein in the body is susceptible to the same sort of damage. I remember being astonished to discover when I was a junior doctor that the enzyme glucose-6-phosphate dehydrogenase has at least 160 different polymorphisms and that most don't cause a disease. In patients likely to develop MDS or AML after chemotherapy the polymorphisms mainly affect the enzymes concerned with DNA repair or toxin metabolism. Theoretically it should be possible to screen for these polymorphisms before administering cytotoxic drugs. We just need a little more time to be sure we fully understand all the mechanisms. I will write some moreabout the specific mechanisms as I study them, but here is something about gluthathione-S transferase:

A good example is the enzyme glutathione S-transferase (GST), which is involved in the detoxification of carcinogens such as alkylating agents and epoxides by catalyzing their conjugation to glutathione. It has been postulated that deficiency of this enzyme might be associated with a greater risk of MDS. Both GST M1 and GST T1 genes have a “null” variant allele in which the entire gene is absent. Chen et al found an odds ratio of 4.3 (95% CI, 2.5-7.4) for the GSTT1 null genotype and this was confirmed by Sasai et al who found that in individuals with the GSTT1 null genotype the odds ratio for disease risk were raised to 2.65 (95% CI 1.27-5.52) for de novo MDS, 4.62 (95% CI 1.48-14.4) in therapy related AML and 2.94 (95% CI 1.07-8.07) in AML with trilineage dysplasia.

On the other hand Davies et al found the GSTT1 null genotype similarly distributed in MDS patients as in a healthy population, but an odds ratio of 2.0 (95% CI, 1.3-3.1) for the GSTM1 null genotype in patients with AML/MDS compared with controls. Subsequently, three groups have demonstrated that the double null GSTT1/GSTM1 genotype to be overrepresented in Caucasian, Asian and Hispanic patients with primary and secondary MDS, AML and aplastic anemia.