Neoplasia as a Late Complication of Bone Marrow Transplantation

Abstract & Commentary

Source: Kolb H, et al. Ann Int Med 1999;131:738-744.

This large, retrospective study included more than 1000 patients from 45 European centers who received a bone marrow transplant before December 1985 and had already survived more than five years. Only these long-term survivors were analyzed because of the expected high incidence of transplant-related complications and recurrence of the original disease during the first five years after transplant. After adjusting for age and sex, outcomes were compared with controls from two European registries.

There were 53 malignant tumors diagnosed representing an overall 3.8-fold higher incidence than in the matched controls. The most commonly diagnosed cancer was nonmelanoma skin cancer, representing a 10-fold increase in the standardized incidence ratio. However, patients were at an even higher risk for thyroid cancer, esophageal cancer, and head and neck cancer. Cases of carcinoma in situ of the cervix, glioblastoma, and Hodgkin’s disease also appeared to be increased but the numbers were small (5, 3, and 2 patients, respectively).

With data collected until March 1996, deaths from these secondary malignancies occurred in 10 patients. All but two of these deaths were attributable to either a brain tumor or a squamous cell carcinoma of the aerodigestive tract (oral cavity, larynx, esophagus, and anus). Unfortunately, recurrence of the original tumor and chronic graft-vs.-host disease (GVHD) were still the most common causes of death. A new malignant neoplasm was responsible for only 11% of the deaths in patients surviving more than five years after their transplant. AIDS was the cause of death in five patients.

Of the potential risk factors evaluated for the development of secondary malignancies, immunosuppressive therapy was found to be the most significant. The actual presence of chronic GVHD attained statistical significance only if it was severe. Neither prophylaxis of GVHD nor the presence of acute GVHD appeared to be risk factors. On the other hand, older patient age was associated with increasing risk. Comparisons of conditioning regimens demonstrated no increased neoplastic risk associated with the addition of total body irradiation to chemotherapy.

COMMENT by Kenneth W. Kotz, MD

This study characterizes the late occurrences of secondary malignancies after a bone marrow transplant. The actual risk for a secondary malignancy may be greater than suggested by this study. First, age itself was suggested to be a risk factor, and the relatively young population studied (median age, 21 years) may be different than the age of patients for whom bone marrow transplants are currently offered. Second, with a median follow-up of 10.7 years (range, 5-22.1 years), the relative contribution from the conditioning regimen may increase with time. For example, radiation-induced solid tumors typically occur more than 10 years after treatment. Data regarding other life-threatening, non-neoplastic conditions such as myelodysplastic syndrome were not presented.

Immunosuppressive therapy was shown to be the most important risk factor for development of a new malignancy. Maneuvers to decrease the requirement for immunosuppression would potentially decrease the incidence of secondary malignancies. However, primary disease recurrence and GVHD remain the most important causes of death, as they accounted for the majority of deaths in these patients who had already survived five years. How these long-term problems will be affected by newer approaches to the prevention and treatment of GVHD is unknown.

Although we can demonstrate an increased risk of cancer after bone marrow transplantation, no data exist regarding screening or prevention in this setting. Nevertheless, with the increased risk for nonmelanoma skin cancer, carcinoma in situ of the cervix and aerodigestive tract tumors, it would seem prudent to educate patients about avoidance of harmful ultraviolet radiation, appropriate use of sunscreens, the importance of yearly gynecologic evaluations, and smoking cessation. In light of the data presented, regular examination of the head and neck, including the thyroid, would be reasonable as well.

The actuarial risk for a malignant neoplasm increased from 3.5% at 10 years to 11.5% at 15 years and may continue to rise. However, many of these neoplastic transformations were not life-threatening. Therefore, while clinicians need to be aware of the late neoplastic complications described in this study, death from the underlying illness and GVHD remain the greatest cause of mortality even five years after the bone marrow procedure. However, it is encouraging that so many patients are surviving, and for so long.

Secondary neoplasia after bone marrow transplantation:

a. is the most common cause of death in patients who survive at least five years after transplant.

b. is associated with an increased risk in patients on immunosuppressive therapy.

c. is most commonly a secondary leukemia.

d. occurred in 53% of patients in this study.