The perspective “Chronic myelogenous leukemia: current treatment options”1 provides a succinct, direct, and evenhanded approach to a complex topic, for which I congratulate the authors. I have a lone concern with the final aspect of the review, the dependence on age to determine the recommended treatment option.
As the authors state, scoring systems devised by Sokal and Hasford can be used to predict survival for individual patients receiving nontransplant therapy. Similarly, Gratwohl's scoring system estimates survival after allotransplantation; the reliability of this scoring system was recently confirmed by the International Bone Marrow Transplant (IBMT) Registry.2 Advanced age is a poor prognostic factor for all patients, whether they undergo transplantation or receive nontransplant therapies. The other variables used in these scoring techniques are necessary to estimate outcome.
Recipient age may influence outcome in adults undergoing allogeneic transplantation for chronic myelogenous leukemia (CML) to a lesser degree than is commonly thought. Bolwell recently summarized relevant data and concluded that the inclusion of pediatric patients (grouped with young adults) in many studies has led to the impression that older adults fare far more poorly with transplantation than do younger adults.3 He found only a slightly higher risk of transplantation-related mortality in older compared to younger adults. Data from Seattle4 and our own center,5 among others, indicate that conventional allogeneic transplantation can be performed safely in older patients. Data from the same institutions suggest that transplantation less than 6 months4 and 3 months5 from diagnosis can further improve results, including in older patients.
Thomas et al's original report of allogeneic transplantation in CML found a direct relationship between mortality rate and interval from diagnosis to transplantation and an association between older age and longer interval from diagnosis to transplantation.6Delaying transplantation in older patients contributes to a higher mortality rate. The fact that every study does not demonstrate a significant influence of this interval on outcome does not prove a lack of influence any more than studies that fail to demonstrate an adverse influence of older age prove the absence of an adverse affect. These studies are not appropriately designed to detect the absence of such differences.
Last, results at specific institutions, often with large patient numbers, are clearly better than overall IBMT Registry results. Many studies with favorable results have included large numbers of patients and have utilized similar approaches. Using targeted busulfan and cyclophosphamide, the Seattle group reports one-year transplantation-related mortality rates of approximately 10% and rare relapses. Institutions with poor results should consider referring patients to centers consistently achieving favorable results.
We can all agree that the decision can best be made by a well-informed patient; that patient depends on clinicians to provide an accurate, fair, and complete description of his or her options.
Age and chronic myelogenous leukemia treatment algorithm
Our recent perspective tried to balance the benefits and risks of treatment with STI571 (imatinib mesylate) against the benefits and risks of early allogeneic stem cell transplantation (SCT) for patients with chronic myelogenous leukemia in chronic phase. Dr Copelan feels that we have ascribed undue importance to age in guiding decision-making. Regarding transplantation, he refers to published and unpublished data from single centers in which the transplantation-related mortality (TRM) does not differ greatly between younger and older patients.
As noted, in both the Sokal and Hasford systems for estimating survival with nontransplant therapy, older age is a negative prognostic factor. Thus, older patients would more likely fall into their intermediate- and high-risk categories. According to our algorithm, we would tend to favor transplantation options for these patients.
In all published series of unrelated allogeneic SCTs, including single-institution studies, age is indisputably the most important factor in predicting survival. In the Seattle experience, age over 50 years was associated with a greater than 60% mortality rate at 2 years after transplantation.1-1 In patients under age 50 receiving transplants within the first year of diagnosis, the 5-year survival rate was 74%. The HLA sibling transplantation experience is a bit more complicated and may relate in part to the conditioning regimen. In particular, the use of busulfan and cyclophosphamide, as opposed to cyclophosphamide and total body irradiation, may have a lower mortality rate. Whether this will also apply to unrelated transplantations is unknown. But this may account for some of the variability reported by individual centers.
Despite this, even sibling transplantations carry a significant mortality rate in the first 2 years following transplantation. For a Sokal or Hasford low-risk patient of older age, for whom median survival with nontransplantation therapy may approach 10 years, we would be less likely to consider transplantation as initial therapy. Ultimately of course, the final decision will be the patient's.