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Chemotherapy, radiation may increase risk for subsequent acute lymphoblastic leukemia
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SAN DIEGO — Prior cancer treatment with chemotherapy, radiation or both was associated with an increased risk for subsequent acute lymphoblastic leukemia, according to findings presented at ASH Annual Meeting and Exposition.
ALL is traditionally not considered a treatment-related complication, but the risk for ALL among patients treated with chemotherapy and radiation for other cancers is not well known.
Thus, Remco J. Molenaar, MD, PhD, of Academic Medical Center in Amsterdam and Tausig Cancer Institute at Cleveland Clinic, raised the question of whether there is an elevated risk for ALL among patients who underwent a combination of chemotherapy or radiation.
“Spoiler alert, for those leaving — yes, there is,” he said.
Using the SEER database, Molenaar and colleagues looked at all patients with ALL who had been treated with radiotherapy, chemotherapy or combined modalities.
“Since 1973, almost 2 billion person-years of cancer data have been collected,” Molenaar said.
The current analysis included 4,851,222 eligible patients treated for a first cancer, including 821,004 who underwent radiotherapy alone, 571,035 who received chemotherapy alone, 488,930 who received a combination of the modalities and 2,970,253 who received neither.
“We cross-referenced these cases with about 2,000 ALL cases we found,” Molenaar said.
Among patients in the current analysis, 849 developed ALL, including 176 in the radiotherapy-only group, 137 treated with chemotherapy only, 106 in the combined-modality group, and 430 in the no-therapy group.
Patients who received no radiation or chemotherapy did not have an increased risk for subsequent ALL (standardized incidence ratios = 1; 95% CI, 0.91-1.1), whereas patients who received chemotherapy alone (SIR = 3.1; 95% CI, 2.59-3.67), radiotherapy alone (SIR = 1.49; 95% CI, 1.27-1.72) or both modalities combined (SIR = 3.10; 95% CI, 2.53-3.75) had an increased risk for ALL.
In multivariate analysis adjusting for age, gender, year of diagnosis, cancer type and treatment type, chemotherapy significantly increased risk for ALL compared with no treatment (HR = 1.51; 95% CI, 1.19-1.91). Similar outcomes were reported for radiotherapy alone (HR = 1.63; 95% CI, 1.33-1.99) and both modalities (HR = 1.98; 95% CI, 1.56-2.52) compared with no treatment.
These trends persisted among children with primary malignancies and through treatment eras. “In the most recent treatment group of 2005 to 2014, there is still a risk for developing ALL after chemotherapy and radiotherapy combined,” Molenaar said.
When the researchers broke down the findings by primary malignancy, they continued to observe these trends, particularly among patients with hematologic first cancers.
For example, treatment of a primary breast cancer with both modalities increased the risk for subsequent ALL (SIR = 3.49; 95% CI, 2.60-4.59). Treatment of acute myeloid leukemia with chemotherapy alone carried an even greater risk for subsequent ALL (SIR = 11.48; 95% CI, 6.27-19.25), as did treatment of multiple myeloma with chemotherapy alone (SIR = 7.44; 95% CI, 4.25-12.09) and treatment of multiple myeloma with both modalities (SIR = 14.41; 95% CI, 6.22-28.40).
“These risks were highest after treatment for hematologic cancer,” Molenaar said. – by Rob Volansky
Reference:
Molenaar RJ, et al. Abstract 900. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures : Molenaar reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
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Pinkal Desai, MD
We have always had a lot of interest in therapy-related disease. Myelodysplastic syndrome and AML are known therapy-related diseases, with detailed characterization of what cytogenetic and molecular phenotypes have a worse prognosis. ALL is not generally considered a therapy-related disease. We do see patients who have had previous AML who now have ALL, but it is unusual.
Any disease that is therapy-related is considered to be so at prognosis. In the world of myeloid therapy-related diseases, we tend to transplant these patients for exactly that reason.
ALL is different and, for the most part, if patients with ALL achieve a minimal residual disease-negative remission, the trend is to not transplant. If there is therapy-related subgroup of ALL that is proven to have a negative prognostic value, then that changes the classification. One of the interesting things about Dr. Molenaar’s abstract is that it does look like there’s an increased risk, but more so after hematologic diseases. We have to consider whether it’s possible this is really a biphenotypic leukemia from the beginning. After killing one of the clones or subclones, or the myeloid component, is the so-called second cancer a more lymphoid-like cancer?
With that in mind, one of the things to think about is whether this is all one disease: the AML in the first place, and then the ALL. It might be the same kind of stem-cell disorder that gives rise to two different leukemias down the line. However, the fact that researchers also saw increased risk in patients who had chemotherapy for nonhematologic malignancies still suggests that this is a true treatment-related disease.
One way I might suggest getting a clearer picture of this is to take the myeloid diseases out of the picture for the primary malignancies. If researchers continue to see the increased risk, that might be a very robust result showing that this is truly a therapy-related disease.
Sometimes when we see patients with ALL in the clinic, they have cytogenetic signals that look to be therapy-related. They have TP53 mutations and other signatures that are considered to be therapy-related. So, the phenomenon may exist, but how strong that signal is, and whether it truly impacts survival, is something we need to look at more closely before we have to think differently about these patients in a clinical setting.
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