Patients With Sickle Cell Disease at Increased Risk for Hematologic Cancers, Especially Leukemia

As the treatment of patients with sickle cell disease (SCD) has improved, patients are now living to an age at which the risk of developing cancer increases. Previous small case studies and surveys suggested that people with SCD have an increased risk for cancer, but whether this risk is higher than the general population has not been demonstrated.

In a Letter to the Editor published in Blood, Ann Brunson, MS, of the Center for Oncology and Hematology Outcomes Research and Training in the Division of Hematology and Oncology at the University of California Davis School of Medicine, and co-authors shared findings from a long-term, population-based study suggesting that patients with SCD are at increased risk of developing hematologic malignancies – particularly leukemia – compared with the general California population.

Using the California Patient Discharge Data and the Emergency Department Utilization databases from the Office of Statewide Health Planning and Development, the researchers identified patients with SCD from the Registry and Surveillance System for Hemoglobinopathies project; cancer diagnoses were obtained and confirmed from the California Cancer Registry (1988-2014).

Between 1991 and 2014, 6,423 patients with SCD were observed for a total of 141,752 person-years, with a median follow-up of 22.2 person-years (range not reported). Among those patients, 115 were diagnosed with a first primary cancer at a median of 46 years old (range not reported).

Compared with the general California population, patients with SCD appeared to have a lower incidence of developing any type of cancer (standardized incidence ratio [SIR] = 0.80; 95% CI 0.66-0.96; p values not reported), including a 38 percent reduced risk of developing a solid-tumor cancer. However, patients with SCD had a 72 percent increased risk of developing a hematologic malignancy (see TABLE). Specifically, patients with SCD had a more than two-fold increased risk of developing leukemia. The researchers also observed a higher risk for acute myeloid leukemia (SIR=3.59; 95% CI 1.32-7.82) and a “borderline” increased risk for chronic lymphocytic leukemia (SIR=4.83; 95% CI 1.00-14.11).

“The increased incidence of leukemia suggests a role of high cellular turnover (bone marrow in this instance) and chronic inflammation in leukemic pathogenesis,” the authors noted. “[This finding also] implies that mutations commonly seen in acute leukemia and myelodysplasia might be seen with greater frequency in patients with SCD.”

On the other hand, the decreased risk of solid-tumor cancers in this patient population could be explained by the “sickling” of the red blood cells. Mouse models of solid-tumor cancers and sickled red blood cells suggest that these cells block blood vessels surrounding the tumor, “acting as anti-angiogenic agents and inhibiting solid tumor formation,” the authors explained.

Certain patient factors appeared to be associated with a higher risk for developing hematologic malignancies: Female patients with SCD had a nearly three-fold increased risk for leukemia (SIR=2.84; 95% CI 1.14-5.84), and adolescents and young adults (15-39 years old) were more than three times as likely to develop leukemia (SIR=3.37; 95% CI 1.24-7.33), compared with the general population.

Patients classified as having severe SCD (defined as an average of 3 or more emergency department visits per year) had a four-fold increased risk for leukemia (SIR=4.41; 95% CI 1.91-8.70). Even among those with less severe SCD, the risk of leukemia was increased by 54 percent (SIR=1.54; 95% CI 0.42-3.95).

Hydroxyurea was the sole U.S. Food and Drug Administration-approved therapy for SCD during the study period, and the researchers did not observe a higher risk of leukemia after the drug was approved in 1998, “suggesting that the increased risk of leukemia is not related to hydroxyurea.” Further studies are needed to confirm the findings in a larger population and to identify factors associated with leukemia risk in patients with SCD, the authors concluded.

The study is limited by its use of hospital-admission and emergency-department data, which may have led to an exclusion of healthier patients with SCD, particularly children. In addition, data on other covariates, including socioeconomic status, “which could impact cancer incidence rates,” were not available.

The authors report no conflicts.


Brunson A, Keegan THM, Bang H, et al. Increased risk of leukemia among sickle cell disease patients in California. Blood. 2017 August 22. [Epub ahead of print]

TABLE. Standardized Incidence Ratios (SIRs) for Cancer Among Patients in California With Sickle Cell Disease*
  Observed Cases Expected Cases SIR 95% CI
All cancers 115 143.70 0.80 0.66-0.96
Solid tumor 76 123.25 0.62 0.49-0.77
   Breast 16 29.73 0.54 0.31-0.87
   Respiratory 16 13.13 1.22 0.70-1.98
   Digestive system 16 22.18 0.72 0.41-1.17
   Urinary system 8 6.06 1.32 0.57-2.60
   Female genital 5 11.63 0.43 0.14-1.00
   Male genital 6 16.71 0.36 0.13-0.78
Hematologic tumor 31 18.03 1.72 1.17-2.44
   Lymphoma 15 10.38 1.45 0.81-2.38
   Leukemia 12 5.17 2.32 1.20-4.05
      ALL 3 1.64 1.83 0.38-5.35
      CLL 3 0.62 4.83 1.00-14.11
      AML 6 1.67 3.59 1.32-7.82
*Adjusted for age, gender, race/ethnicity, and time.

ALL = acute lymphocytic leukemia; CLL = chronic lymphocytic leukemia; AML = acute myeloid leukemia