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Therapy-related myeloid neoplasms (t-MN) are secondary malignancies, such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).1 t-MN arise as a result of prior exposure to chemotherapy and/or radiation therapies (CRTs) for a primary condition. Generally, t-MN develop 3–7 years after exposure to CRTs and confer an adverse prognosis. Recent data suggest that t-MN may arise due to CRTs inducing clonal selection of preexisting mutant hematopoietic stem and progenitor cells (HSPCs).1
The thalidomide analogs lenalidomide and pomalidomide facilitate the degradation of Ikaros transcription factors IKZF1 and IKZF3.1 Lenalidomide has also been shown to promote the degradation of the protein kinase CK1α.1 Sperling et al.1 recently published an article in Blood suggesting that prior exposure to lenalidomide promotes the development of TP53-mutated t-MN, and we are pleased to summarize the key findings below.
A retrospective analysis was performed of data from 416 patients diagnosed with t-MN (based on the 2016 World Health Organization classification) at MD Anderson Cancer Center, US, between 2008 and 2019. A comparison was made with data from 1,021 patients with de novo MN who were diagnosed in the same time period.
Next-generation sequencing was used to detect somatic mutations in bone marrow (BM) and peripheral blood samples using a 300-gene panel (n = 156).
Immortalized mouse HSPC cell lines with an estrogen-inducible Hoxb8 transgene were generated using CrbnI391V knock-in mice.
Hoxb8 CrbnI391V;Rosa26-Cas9 cells were engineered to carry recurrent clonal hematopoiesis mutations using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system and treated with lenalidomide and pomalidomide.
Live, lineagelo, Sca1+, c-Kit+ (LSK) cells from CrbnI391V;Rosa26-Cas9 were virally transduced with concentrated lentiviruses encoding single-guide RNAs targeting Dnmt3a, Tet2, Asxl1, Trp53, Ppm1d, and Ezh2 genes, a tag-red fluorescent protein, and two control single-guide RNAs in parallel. Mutant cells were transplanted into lethally irradiated wild-type (WT) recipient mice and validated through next-generation sequencing and flow cytometry (Figure 1).
c-Kit+ cells were transplanted with donor marrow consisting of 20% CD45.2;Trp53−/−;CrbnI391V cells mixed with 80% CD45.1;CrbnI391V WT cells. Mice were then treated with dimethyl sulfoxide, lenalidomide 50 mg/kg, or pomalidomide 20 mg/kg.
Figure 1. Schematic of mouse model experiments to determine the selective advantage of HSPCs in the presence of thalidomide analogs
BID, twice a day; BM, bone marrow; HSPC, hematopoietic stem and progenitor cell; LSK, Live, lineagelo, Sca1+, c-Kit+; PB, peripheral blood; PO, taken orally.
*Adapted from Sperling, et al.1 Created with BioRender.com.
Competitive BM transplant experiments were carried out with Csnk1a1 heterozygous knock-out mouse cells and WT cells in the Crbn1391V background. Transplanted mice were treated with dimethyl sulfoxide , lenalidomide 50 mg/kg, pomalidomide 20 mg/kg, or iberdomide 20 mg/kg.
Of the 416 patients diagnosed with t-MN, a total of:
Statistically relevant patient characteristics are listed in Table 1.
Table 1. Characteristics of patients diagnosed with t-MN*
Characteristic, % (unless otherwise specified) |
All patients (N = 416) |
t-AML (n = 167) |
t-MDS (n = 249) |
p value |
---|---|---|---|---|
Median age (range), years |
68 (17–91) |
65 (17–89) |
69 (22–91) |
0.002 |
Median latency† (range), years |
6.0 (0.1–40) |
5.0 (0.1–40) |
6.4 (0.3–45) |
0.028 |
Median WBC (range), K/μL |
3.2 (0.1–267) |
3.8 (0.1–267) |
3 (0.2–85.7) |
<0.001 |
Median PLT (range), K/μL |
58 (3–895) |
41 (3–389) |
65 (6–895) |
0.002 |
Active primary malignancy |
15 |
7 |
21 |
<0.001 |
Cytogenetics‡ |
|
|
|
|
Del 5q/-5§ |
32 |
25 |
37 |
0.013 |
Del 7q/-7 |
34 |
20 |
43 |
<0.001 |
Inv 16/t (16;16) |
1 |
4 |
0 |
0.003 |
11q23 |
7 |
16 |
1 |
<0.001 |
t (15;17) |
1 |
2 |
0 |
0.036 |
t (8;21) |
1 |
2 |
0 |
0.036 |
PLT, platelet; t-AML, therapy-related acute myeloid leukemia; t-MDS, therapy-related myelodysplastic syndromes; WBC, white blood cell. |
At least one gene mutation was detected in 85% of patients with t-MN. The most common gene mutations detected were TP53 (37%), PPM1D (19%), TET2 (16%), DNMT3A (15%), RUNX1 (13%), ASXL1 (13%), and SRSF2 (10%). Comparison with the de novo AML and MDS cohort (N = 1,021) found that:
Complex karyotype was associated with prior exposure to platinum agents (odds ratio [OR], 1.88; 95% confidence interval [CI], 1.23–2.89; false discovery rate [FDR] = 0.052).
Abnormalities in chromosome 7 were associated with prior exposure to alkylating agents (OR, 1.64; 95% CI, 1.08–2.49; FDR = 0.057) and platinum agents (OR, 1.65; 95% CI, 1.06–2.57; FDR = 0.057).
Patients who received radiation therapy were more likely to harbor NPM1 mutations, splicing gene mutations, and normal karyotype.
Mutations in TP53 were associated with treatment with proteasome inhibitors (OR, 3.06; 95% CI, 1.52–6.15; FDR = 0.025), and thalidomide analogs (OR, 2.62; 95% CI, 1.36–5.05; FDR = 0.035). Multivariate logistic regression analysis also found TP53 mutations were more common in patients treated with thalidomide analogs (OR, 3.14; 95% CI, 1.60–6.18; p = 0.009) or vinca alkaloids (OR, 1.76; 95% CI, 1.05–2.93; p = 0.031), and less common in patients treated with topoisomerase inhibitors (OR, 1.76; 95% CI, 1.05–2.93; p = 0.031).
In patients treated with lenalidomide, TP53 mutations were associated with a longer duration of exposure.
In vivo and in vitro mouse models demonstrated that lenalidomide, but not pomalidomide, conferred a selective advantage to Trp53-mutant HSPCs.
This study also highlights the importance of genetic screening prior to initiation of treatment, to identify potential mutations that may exert selective pressure and to improve risk stratification.
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