Modifying Treatment Strategies for Patients With FL or DLBCL at Risk of Therapy-Related Transformation

Abhay Singh, MD, Cleveland Clinic, Cleveland, Ohio, discusses the need for modifications in treatments for older patients with follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL) who are at risk of transformation to therapy-related myeloid neoplasms, such as therapy-related myelodysplastic syndrome (tMDS) or therapy-related acute myeloid leukemia (tAML). 

Dr Singh speaks about modifications including but not limited to implementing molecularly screening, as well as tending to possible predictive factors. 

Transcript: 

Hi, my name is Abhay Singh. I'm one of the physicians in the Leukemia and Myeloid Disorders Program at the Cleveland Clinic. I'm here today to discuss one of our recent studies that was presented, titled Risk Factors Beyond Chemotherapy Exposure for Therapy-Related Myelodysplastic Syndromes and Acute Myeloid Leukemia Development in Lymphoma Survivors. That was a 15-year SEER-Medicare study.

As we know, many of the patients with lymphomas—indolent and aggressive, diffuse large B-cell lymphoma, and follicular lymphomas—undergo curative treatments, especially for diffuse large B-cell lymphomas. Then, they enter the period of survivorship. During the period of survivorship, they do well generally, but there's a small percentage of patients who can go on to develop this dreaded outcome called therapy-related myeloid neoplasms. They're usually therapy-related myelodysplastic syndromes and therapy-related acute myeloid leukemia together, they're called therapy-related myeloid neoplasms.

Now, not everyone who's exposed to this chemotherapy and radiation therapy for their primary treatment gets this diagnosis of tMDS or tAML. We started wondering if there could be any potential causes that augmented this risk of transformation to an upward myeloid malignancy. 

This was our motivation to start this study in lymphoma survivors. We looked at some of the risk factors that are pretty common, like age, chemotherapy exposure, radiation exposure, [and] smoking. We looked at several other factors, where there is some ambiguity regarding whether there's some sort of association with the development of therapy-related myeloid neoplasms. So, these were looking at history of autoimmunity, looking at [granulocyte-colony stimulating factor] (G-CSF) exposure, [and] obesity, among other things.

We conducted this study using a large population-based database called the [Surveillance, Epidemiology, and End Results] (SEER)-Medicare, and we looked at around 33,000 patients, including [those] both diffuse large B-cell lymphoma and follicular lymphomas. These patients were from the Medicare database, so the[ir] age[s] [were] 66 and above. We had a cutoff of 66 to 84 years. 

I think the primary takeaway from our analysis was that some of the risk factors that have been historically ambiguous in nature, in terms of being a risk factor, were pretty highly correlated in our analysis. So, these were prior histor[ies] of autoimmunity [which] increased the risk of development of therapy-related myelodysplastic syndrome and acute myeloid leukemia by threefold. Also, what was very intriguing was that the utilization of G-CSF, or granulocyte colony-stimulating factors, in these patients, increased the risk of therapy-related myeloid neoplasms as well. This was in a large, large number of patients. We have now conducted this study in several other cancer cohorts, including solid malignancies [and] several other blood malignancies, and these results are pretty consistent across the board.

This calls for [a] change in clinical application potentially because primarily in many of the cancers for neutropenic prophylaxis, G-CSF is widely used. Perhaps we need to order some of our clinical practices where we are molecularly screening the patients and making sure that there [are] no clonal hematopoiesis or preexisting leukemic mutations that are there that we might be potentiating by use of certain factors.

Another thing that needs to be clarified as well in the setting of autoimmunity is [whether it is] the autoimmunity itself that's driving escape of these clones or is it the immunosuppression that's used for these autoimmune condition treatments that [are] driving this progression to acute leukemia?

All in all, I think we already knew that chemotherapy and radiation therapy, the increased risk of therapy-related myelodysplastic syndromes and acute myeloid leukemia, but through our study there have been more data that suggest that there are several additional factors that contribute to this transformation to MDS and AML, those being autoimmunity and GCSF exposure. Thank you.

Source: 

Herr M, Singh A, Hahn T, et al. Risk factors beyond chemotherapy exposure for therapy-related myelodysplastic syndrome (tMDS) and acute myeloid leukemia (tAML) development in lymphoma survivors: A 15-year SEER-medicare analysis. Clin Lymph Myel and Leuk. Published online: September 2023. doi: 10.1016/S2152-2650(23)00983-7