After Chemo, Risk of Tx-Related Blood Cancer Higher Than Thought

Kristin Jenkins

December 20, 2018

Patients treated with chemotherapy for a solid tumor are at much higher risk than was previously thought of developing a highly lethal blood cancer as a result of that treatment.

A research team from the National Cancer Institute (NCI) says that the relative risk of this late effect — therapy-related myelodysplastic syndrome or acute myeloid leukemia (tMDS/AML) — is exponentially higher than was supposed.

The new findings come from an analysis of longitudinal US cancer registry and treatment data for 700,612 patients who received chemotherapy between 2000 and 2013.

In that timeframe, the use of known leukemogenic agents, particularly platinum compounds, in initial chemotherapy has increased exponentially, from 10% in 2000-2001 to 81% in 2012-2013, they note.

"We've known for a long time that the development of myeloid leukemia is a very rare adverse effect of some types of cancer treatments that damage cells," Lindsay Morton, PhD, lead author of the study and a senior investigator in the NCI's Division of Cancer Epidemiology and Genetics, commented in a statement.

"There have been many changes in cancer treatment over time, including the introduction of new chemotherapy drugs and drug combinations, but we didn't know what the risk of therapy-related leukemia looked like for patients since these changes were made."

The study found that, by 2014, tMDS/AML had developed in 1619 patients (0.23% of 700,612 patients) who had been treated with chemotherapy for a first primary solid tumor.

Although the cumulative incidence of tMDS/AML was less than 1% for most solid tumor types, the prognosis was poor, the authors note: median overall survival was only 7 months and 78% (1270/1619) of the patients died.

The report was published online December 20 in JAMA Oncology.

Risk Elevated in Many Tumor Types

The analysis showed that the relative risk of tMDS/AML was increased from 1.5-fold to more than 10-fold depending on the type of cancer treated and chemotherapy or chemoradiotherapy used.

The risk was observed in 22 of 23 solid cancer types, with the exception of colon cancer.

The relative risks for tMDS/AML were highest (>10) in patients receiving chemotherapy for cancers of the bone, soft tissue, and testes (standardized incidence ratio [SIR], 39.0, 10.4, and 12.3, respectively). These cancers were typically diagnosed in younger patients, the analysis showed.

For patients who received chemotherapy for cancers of the peritoneum, small cell lung, ovary, fallopian tube, and brain or central nervous system, the SIRs were elevated 5- to 9-fold.

For all remaining cancers, with the exception of colon cancer, the SIRs were elevated 1.5- to 4-fold.

For certain first primary tumor types, the analysis also showed that tMDS/AML risks were higher after chemoradiotherapy than with chemotherapy alone.

Expands Number of Survivors At Risk

These new data significantly expand the number of survivor groups at risk of tMDS/AML resulting from previous cancer treatment, the authors note.

Until now, the excess risk for tMDS/AML following chemotherapy has been established only for cancers of the lung, ovary, breast, soft tissue, testis, and brain/central nervous system, they note.

Previous studies of tMDS/AML have relied on a relatively small number of cases taken from case series and case-control studies, the researchers pointed out. The population-based data approach used in the current study made it possible to work with a much larger sample size using prospective data from long-term patient follow-up, they said.

"The most important message from this study is that, while advances in cancer treatment approaches have improved the prognosis for many types of cancer, the number of patients at risk of developing rare, therapy-related leukemia after cancer chemotherapy in the modern treatment era has markedly expanded," Morton said in an NCI statement.

"Assessments of treatment risks and benefits should balance these risks and other adverse effects of chemotherapy against potential gains in survival following treatment for the initial solid cancer," Morton added.

"Long-Awaited Study"

In an accompanying editorial, Shyam A. Patel, MD, PhD, of the Stanford Cancer Institute at Stanford University School of Medicine, California, said this "long-awaited study" provides oncologists with highly desirable information "because improved survival from primary cancers is associated with increased risk for secondary neoplasms later in life."

To date, he added, "there have been no risk-assessment models to guide therapeutic decisions about solid tumor chemotherapeutics that carry a high risk for secondary malignant neoplasms within the hematopoietic compartment."

The findings from the current study may change the way patients need to be screened and managed, Patel told Medscape Medical News. With the recent discovery of clonal hematopoiesis of indeterminate potential (CHIP), new ways to better stratify risk in patients receiving chemotherapy for solid tumors could help mitigate therapy-related hematologic damage, he said.

Certain subgroups of primary cancer survivors who live long enough to be at risk for therapy-related myeloid neoplasm will benefit from risk stratification.

This includes most patients with early stage, node-positive breast cancer treated with chemotherapy, Patel said.

On the other hand, patients diagnosed at an older age or those with more aggressive primary disease and a less favorable prognosis are unlikely to develop tMDS/AML. "A question that remains is [whether] the risk of tMDS/AML [is] associated with the use of poly (ADP-ribose) polymerase (PARP) inhibitors," said Patel.

"Future efforts should be focused specifically on patients who are at highest risk of tMDS/AML," he writes. "It is critical that risk assessment models for tMDS/AML consider the clonal evolution of subclinical mutations into overt, clinically apparent disease. Risk calculations should be dynamic because the chemotherapy armamentarium for solid tumors will likely change over the years. "

This study was funded by the National Institutes of Health, National Cancer Institute. Morton and co-authors, and Patel reported no relevant financial relationships.

JAMA Oncol. Published online on December 20, 2018. Full text, Editorial

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