Sickle Cell Disease and Cancer Risk

The issue of cancer risk in patients with sickle cell disease (SCD) continues to attract the attention of researchers and clinicians despite having been studied fairly extensively.

Early studies, based primarily on case reports and survey-type studies, generally showed an increased risk of cancer overall. Later studies, several published about a decade ago, expanded the research into population-based investigations.

A study of more than 7,500 British patients with SCD showed a twofold greater risk of any type of malignancy, including multiple types of hematologic malignancies and several solid cancers. A California-based study involving 6,400 patients suggested that patients with SCD had a lower overall risk for cancer compared with the general population, but a 72% higher risk of leukemia and a 38% lower risk of solid malignancies. A case-control study involving 1,300 patients with SCD showed no increased risk of cancer overall or for solid malignancies but a marginally higher risk of hematologic malignancies.

Elusive Proof

“On the basis of epidemiologic studies, I would say there appears to be an increased malignancy risk in sickle cell disease,” Vijay Sankaran, MD, PhD, of Harvard Medical School and Boston Children’s Hospital, told MedPage Today. “I think the extent to which there is an increased malignancy risk remains not so well established.”

“There have not been a lot of studies other than case reports and extensive population studies,” he added. “As kind of a genetic epidemiologist, I would say the burden of proof remains to be shown.”

Interest in the cancer link was piqued again when clinical trials of the SCD gene therapy lovotibeglogene autotemcel (lovo-cel, Lyfgenia) were put on hold after one patient developed leukemia and another developed myelodysplastic syndrome. Within a month, the manufacturer, Bluebird Bio, announced that an investigation showed that the gene therapy was “very unlikely” to be the cause.

The FDA lifted the hold 3 months later and subsequently approved both lovo-cel and exagamglogene autotemcel (exa-cel, Casgevy) as the first two gene therapies for SCD. Labeling information for lovo-cel includes a boxed warning about a potential malignancy risk.

“There was a lot of concern [about cancer risk] given the malignancies that were seen in the gene therapy trials,” said Sankaran. “When the trials were halted, that got a lot of attention, and there was certainly a lot of worry.”

A recent a systematic review of investigations into cancer risk in SCD, involving 24,000 patients worldwide, showed “highly variable” risk estimates. Nonetheless, the analysis showed an overall increased risk of malignancy in both SCD and thalassemia, particularly hematologic malignancies (and especially myeloid leukemia in patients with SCD).

Another recent study examined the relationship between sickle cell trait (SCT) and cancer risk. Overall, the results showed that SCT did not have a significant association with cancer. The data suggested a lower risk of leukemia compared with SCD and a trend toward an increased risk of kidney cancer.

Earlier this year, investigators examined the evidence of SCD as a cancer predisposition syndrome and concluded, “Strikingly, the relative risk of cancer in SCD is much lower than most cancer predisposition syndromes and closer to those conferred by common variations.”

“Sickle cell disease and cancer predisposition syndrome share some similarities,” the authors continued. “Nevertheless, differences are substantial, with the main one being the lower relative risk of malignancy in individuals with sickle cell disease than in those with cancer predisposition syndrome.”

“Absolute risk of malignancy is low in individuals with sickle cell disease, but clinicians should be aware of this rare event,” they added.

The totality of evidence, thus far, has yet to make a convincing case for an increased cancer risk in patients with SCD, said Sana Saif Ur Rehman, MD, of Washington University in St. Louis, who treats adults with SCD.

“I don’t think our patients are at any higher risk at baseline than the general population,” she told MedPage Today. “I think there used to be some concern about hydroxyurea use and whether that can cause cancer or increased predisposition for cancer, but that was well refuted. There was a concern about one of the gene therapies, but they sequenced the genome of the person who got the leukemia, and it wasn’t because of the gene therapy insertion.”

Both gene therapy and stem cell transplantation involve high-dose chemotherapy, “so I do worry about that situation. If things don’t go the right way, yes, you are at higher risk. But I would say that if at baseline there is no chemotherapy, no hydroxyurea or transfusion therapy, I don’t think there’s an increased risk of cancer per se.”

Role for Clonal Hematopoiesis?

The search for a causative link between SCD and cancer has led to clonal hematopoiesis as one potential explanation. Clonal hematopoiesis occurs when acquired mutations cause some blood stem cells to multiply faster than others to form distinct populations or clones.

A few years ago, Sankaran and colleagues reported no differences in the frequency of clonal hematopoiesis in patients with SCD and a control group. Recent advances in techniques to assess clonal hematopoiesis have provided a different perspective. For example, a recent study using a more sensitive assay showed a four times higher odds ratio for clonal hematopoiesis in two large cohorts of children with SCD than in a matched control group.

In another recent study using a highly sensitive assay, investigators compared onset of clonal hematopoiesis in 3,885 patients with SCD (all age groups), 3,398 with SCT or normal hemoglobin, and 188 patients with beta thalassemia. The results showed that clonal hematopoiesis occurred significantly more often in SCD and at a younger age.

The clonal hematopoiesis was driven primarily by mutations in the DNA damage response and repair pathway, also found in leukemias that occur in patients with SCD. The investigators concluded that the findings suggest a biological connection between SCD and leukemia warranting further study.

“These are important observations that we need to follow up on,” said Sankaran. “What remains to be fully understood is whether that actually translates into an increased risk of malignancy. None of the studies have been able to say definitively that can lead to a malignant clone at a higher rate.”