New research from the Swedish medical university Karolinska Institutet shows that hydroxyurea, one type of cytotoxic treatment for chronic myeloproliferative blood disorders, does not increase the risk of developing acute leukemia, as had previously been suspected. Rather, it is the disease itself that mainly increases this risk. Another new study by the same group of researchers shows that mortality from chronic myeloid leukemia has decreased sharply since the approval of the drug Imatinib as a standard treatment in Sweden in 2001.
Both studies are published in the scientific periodical The Journal Clinical of Oncology, and offer hope to a small but severely affected patient group, according to the group.
Every year in Sweden, some 450 people fall victim to a group of bone marrow diseases collectively called chronic myeloproliferative diseases (polycythemia vera, essential thrombocythemia and primary myelofibrosis). The diseases are characterised by an increased risk of thrombo-embolism and haemorrhage, symptoms that the cytotoxic and/or radioactive phosphorus treatments given are designed to reduce. At the same time, it has long been known that high-doses of some of these cyto-reductive treatments make it more likely that the slowly progressive chronic blood disease will transform to an acute, life-threatening leukemia. Doctors have therefore been urged to exercise caution when treating patients, particularly the young.
In the first of the present studies, scientists at the Department of Medicine (Solna) carried out a case-control study in which people who developed acute leukemia after a myeloproliferative disease were compared in terms of the treatment they had received with matched patients with myeloproliferative disorders who did not develop acute leukemia. What they discovered was that the greatest risk factor in the development of acute leukemia in the studied patient cohort was the disease itself. 25 percent of the patients who developed acute leukemia were never exposed to cytotoxic therapy. People with myeloproliferative disease are 35 times more likely to develop acute leukemia than the general population. This risk rises further after 15 years of observation.
"The standard treatment for patients over 60 with chronic blood disease has long been the cytotoxic agent hydroxyurea, and with this treatment we see no increase in risk caused by the medication," says principal investigator Professor Magnus Björkholm. "However, the risk did increase somewhat if the patients also received high doses of other types of cytotoxic drugs so called alkylating substances, or radioactive phosphorus. Our findings are of considerable significance to patients, particularly young patients, who have been treated with drugs that cause more adverse reactions and are more expensive than hydroxyurea."
In the second of the two studies, the group studied survival rates for patients who had been diagnosed with chronic myeloid leukemia, a blood disease that strikes between 80 and 90 patients every year in Sweden. The only curative treatment available today involves blood stem cell grafts from a suitable donor, but the procedure is hazardous and available for only a minority of patients. As of November 2001, however, it has been possible to retard the disease using the drug Imatinib, something that the new study concludes greatly increases the chances of survival.
The study included all cases of chronic myeloid leukemia recorded in the Swedish Cancer registry between 1973 and 2008, a total of 3,173 patients with a mean age of 62. Survival improved with each calendar period with the greatest improvement between 1994-2000 and 2001-2008. Between 1973 and 1979, the disease was associated with an almost 80 per cent increase in mortality compared with the normal population; the corresponding figure for the 2001-2008 period was 20 per cent. At the same time, the up-front use of Imatinib increased from 40 per cent in 2002 to 84 per cent in 2006 for the entire patient group. The worst prognosis was found in the oldest patient group (79-plus), of whom the researchers could ascertain that only 18 per cent had been administered imatinib as initial therapy.
"What characterises chronic myeloid leukemia tumour cells is a genetic defect that gives rise to the constant formation of certain cells, above all leukocytes," says Professor Björkholm, who also led this second study. "Imatinib inhibits the growth of the tumour cells, and as we can see in this study it has revolutionised the care of these seriously ill patients."
- M. Bjorkholm, A. R. Derolf, M. Hultcrantz, S. Y. Kristinsson, C. Ekstrand, L. R. Goldin, B. Andreasson, G. Birgegard, O. Linder, C. Malm, B. Markevarn, L. Nilsson, J. Samuelsson, F. Granath, O. Landgren. Treatment-Related Risk Factors for Transformation to Acute Myeloid Leukemia and Myelodysplastic Syndromes in Myeloproliferative Neoplasms. Journal of Clinical Oncology, 2011; DOI: 10.1200/JCO.2011.34.7542
- M. Bjorkholm, L. Ohm, S. Eloranta, A. Derolf, M. Hultcrantz, J. Sjoberg, T. Andersson, M. Hoglund, J. Richter, O. Landgren, S. Y. Kristinsson, P. W. Dickman. Success Story of Targeted Therapy in Chronic Myeloid Leukemia: A Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2008. Journal of Clinical Oncology, 2011; DOI: 10.1200/JCO.2011.34.7146
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