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Lenalidomide Linked to Risk of Therapy-Related Myeloid Neoplasms

July 20, 2022

August 2022

Prior exposure to thalidomide analogs, particularly lenalidomide, was associated with an increased risk for TP53-mutated therapy-related myeloid neoplasms (t-MNs), according to research published in Blood. Data from a multivariable analysis of the mutational profile of 416 patients with t-MNs confirmed a significant association between TP53 mutations and prior exposures to thalidomide analogs (odds ratio [OR] = 3.14, 95% CI 1.60-6.18, p=0.0009). Further experiments showed a significant association with lenalidomide exposure.

Thalidomide analogs are predominantly used for the treatment of multiple myeloma (MM), with prolonged administration given as maintenance therapy.

“Our result might offer a personalized approach to reducing the risk of t-MNs,” said study researcher Koichi Takahashi, MD, PhD, of the University of Texas MD Anderson Cancer Center. “First, maybe patients with [MM] should be screened for clonal hematopoiesis. If the patients have TP53-mutated clonal hematopoiesis, our results suggest that the risk of t-MN might be mitigated by avoiding the use of lenalidomide.”

According to Dr. Takahashi, t-MNs are secondary myeloid malignancies – typically in the form of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) – that occur in patients previously treated with or exposed to cytotoxic chemotherapies or radiation therapy. The incidence of this is about 0.5% to 1% in patients with solid tumors.

“Fortunately, it is not a frequent complication for cancer patients; however, when it happens, it is devastating, and most of the time it ends up with a lethal clinical course,” Dr. Takahashi said. “Since many cancer patients are now living longer and receiving multiple lines of therapies, t-MNs are becoming a growing concern for cancer survivors. The problem is that it is difficult to predict the risk of t-MN development, and there is really no prevention for this.”

In the present study, researchers first examined the landscape of cancer gene mutations in t-MNs by searching their institutional database. Of the 416 patients with t-MNs, 40% had t-AML and 60% had t-MDS. About half (45%) had received prior treatment with chemotherapy alone, 17% with radiation alone, and 39% with both.

The median latency period from initial treatment exposure to t-MN diagnosis was 6.2 years. There was a significantly shorter latency period for t-AML than for t-MDS (5.0 vs. 6.4 years; p=0.0283).

The majority of patients (85%) had at least one gene mutation detected, and the most common were involved in DNA damage response (TP5=37%, PPM1D=19%).

In addition to the association found between TP53 mutations and prior thalidomide analog exposure, the multivariable analysis also showed an association with vinca alkaloids (OR=1.76, 95% CI 1.05-2.93; p=0.031) and a negative association with topoisomerase inhibitors (OR=0.49, 95% CI 0.26-0.91; p=0.023).

Dr. Takahashi and colleagues further investigated the association between TP53 mutations and lenalidomide because 92% of the thalidomide analog exposure in the study population involved lenalidomide. They used in vitro and in vivo mouse models to demonstrate that p53-mutant hematopoietic stem and progenitor cells (HSPCs) showed a competitive advantage over wild-type cells under lenalidomide treatment. This is likely the explanation for why TP53 mutations are enriched in patients treated with lenalidomide, Dr. Takahashi said.

“Interestingly, we found that pomalidomide, another thalidomide analog, does not provide the same level of selective advantage to p53-mutated HSPCs,” Dr. Takahashi said. “This provides a biological rationale that pomalidomide may not promote clonal selection of TP53-mutated HSPCs as the lenalidomide does, which might eventually lead to a reduced risk of t-MN development.”

Dr. Takahashi also noted that at the population level, lenalidomide clearly improved the survival of patients with MM.

“We do not want our result to be interpreted in a way that we should avoid using lenalidomide all along,” he said. “However, we want to point out that in a specific patient with TP53-mutated clonal hematopoiesis, it may increase the risk of t-MN and for those particular patients, switching to pomalidomide may be considered.”

Study findings need to be confirmed through clinical trials.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Sperling AS, Guerra VA, Kennedy JA, et al. Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms [published online ahead of print, 2022 May 5]. Blood. doi: 10.1182/blood.2021014956.


Perspectives

What happens when a therapy designed to treat cancer leads to the development of a different, aggressive form of hematologic malignancy instead? In this study, Sperling et al. evaluated the clinical features of 416 patients diagnosed with t-MNs based on the 2016 World Health Organization classification scheme and elucidated a mechanism by which lenalidomide seems to promote the development of t-MNs harboring TP53 mutations.1

Chemo- and radiation therapies induce clonal selection and expansion of pre-existing mutant HSPCs, thereby promoting the development of t-MNs enriched for TP53 and PPM1D mutations.1,2 Patients who develop t-MNs have a more aggressive disease presentation and experience inferior outcomes compared to those with de novo myeloid neoplasms. It is therefore critical to understand the mechanistic basis of t-MN development to modify existing therapeutic regimens and mitigate this risk.

Using clinical and genomic data from patients with t-MNs, the authors found a history of lenalidomide therapy was significantly associated with the presence of TP53 mutations before the initiation of therapy; not surprisingly, most of the patients who developed lenalidomide-associated t-MNs were originally diagnosed with MM.

Using mouse models of wild-type and TP53-mutant hematopoiesis, the authors found lenalidomide conferred a selective advantage to TP53-mutant HSPC clones by inducing CK1a degradation and P53-mediated apoptosis in wild-type but not TP53-mutant HSPCs. The mechanism for selection was unique to lenalidomide since other thalidomide family members, including pomalidomide and iberdomide, did not induce apoptosis in wild-type HSPCs. Moreover, this effect of lenalidomide was not observed on mouse HSPCs harboring mutations in other common clonal-hematopoiesis-associated genes (DNMT3A, TET2, ASXL1, EZH2, and PPM1D). Since proteasome inhibitors are also used to treat patients with MM, the authors performed several analyses to demonstrate TP53 mutations were significantly associated with lenalidomide but not proteasome inhibitor treatment.

Although these studies advance our understanding of the mechanisms driving the development of t-MNs, a number of important questions remain. For example, how should this information be used to modify therapy for patients being treated with lenalidomide? Should lenalidomide be eliminated from MM therapy, or should exposure time to lenalidomide-based therapy be limited by switching to another thalidomide during maintenance therapy? Can screening patients with MM for TP53-mutant clonal hematopoiesis before therapy is initiated assist with selecting patients for whom lenalidomide therapy is appropriate, or should the emergence of TP53-mutant clones be assessed during maintenance therapy?

While these questions underscore the need for more studies to assess the effect of changes in therapeutic strategies to treat MM, the current study is notable for elegantly demonstrating and reinforcing the notion that clonal selection and outgrowth of pre-malignant HSPC clones are significantly modulated by the interplay between genotype and extrinsic stressors including choice of therapy. We anticipate such knowledge will allow revision and tailoring of therapeutic designs to reduce the risk of t-MNs and improve patient outcomes.

Christopher Y. Park, MD, PhD
NYU Grossman School of Medicine
New York

Sohini Chakraborty, PhD
NYU Grossman School of Medicine
New York

Reference

  1. Sperling AS, Guerra VA, Kennedy JA, et al. Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms [published online ahead of print, 2022 May 5]. Blood. doi: 10.1182/blood.2021014956.
  2. Heuser M. Therapy-related myeloid neoplasms: does knowing the origin help to guide treatment? Hematology Am Soc Hematol Educ Program. 2016(1):24-32.

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