The spectrum of hematologic neoplasms in patients with Li-Fraumeni syndrome

Li-Fraumeni syndrome (LFS) is a rare inherited disorder associated with germline pathogenic TP53 variants. The absence of the functional gene product, p53 protein, results in failure to activate programmed cell death in the appropriate context and leads to uncontrolled cell proliferation. LFS patients present with a high incidence of various malignancies, often at young ages. In contrast to the high occurrence rate of solid tumors, hematologic neoplasms in LFS patients are relatively rare and not systemically described. A few previous studies showed that leukemias developed in about 2%–4% of LFS patients, whereas lymphomas are less frequent, seen in approximately 2% of LFS patients.^1-3

This study explored the clinicopathologic spectrum of hematologic neoplasms in LFS patients. Eighteen patients with a well-established clinical diagnosis of LFS and confirmatory TP53 genetic testing as well as a hematologic neoplasm were included, spanning the time interval from 1/1/2000 through 8/5/2023. Their LFS diagnosis was further confirmed by our LFS Progeny Database and/or Clinical Cancer Genetics (CCG) team that runs the LFS program in our institution. Four previously reported patients (cases #1, 2, 6, 7 in that cohort)⁴ were included in this study. To the best of our knowledge, this is the largest cohort described to date.

The cohort included 12 (67%) women and 6 (33%) men. Their clinical history and hematologic diagnoses are presented in Table 1. All patients had a confirmed germline pathogenic variant of TP53 at MD Anderson Cancer Center and/or an outside institution, although the detailed nomenclature of TP53 germline mutation in 4 patients (cases #1, 8, 14, 18) tested at an outside institution was not available. All 18 patients had an extensive family history of malignancies (Supplementary Table 1). Seventeen (94%) patients had other malignant or pre-malignant neoplasms in additional to hematologic malignancy; 7 (39%) patients had one neoplasm and 10 (56%) patients had ≥2 neoplasms. The most common non-hematologic malignancies were breast cancer (9/18, 50%), sarcoma (8/18, 44%), and gastrointestinal tumors (5/18, 28%). The only patient without any other neoplasm (case #18) was diagnosed with B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) at the age of 11 years and died 4 years later.

The median age at diagnosis of the first malignancy was 32 years (range, 1–54 years) and the median age at diagnosis of hematologic neoplasm was 41 years (range, 11–73 years). The initial presenting hematologic neoplasms included myelodysplastic syndrome (MDS) (n = 10, 56%), “de novo” acute myeloid leukemia (AML) developing in patients without a prior history of MDS or other hematologic neoplasms (n = 2, 11%), B-ALL/LBL (n = 2, 11%), plasma cell neoplasms (PCN) (n = 2, 11%), T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) (n = 1, 6%), and myeloproliferative neoplasm (MPN) (n = 1, 6%). Fifteen (83%) hematologic neoplasms occurred after the diagnosis of other tumors. In the remaining 3 patients, 1 T-ALL/LBL (case #5) was diagnosed with a synchronous astrocytoma, 1 B-ALL/LBL (case #7) was followed by high grade dysplasia in a gastric adenoma, and another B-ALL/LBL (case #18) was diagnosed in a 11-year-old patient without any other malignancies.

At initial presentation of hematologic neoplasm, 11 (61%) patients had a history of exposure to chemotherapy or radiation therapy (“cytotoxic exposure”) for other tumors. This exposure occurred with a median interval of 111 months (range: 3–240 months) prior to the diagnosis of the hematologic neoplasm. All these 11 patients presented with a myeloid neoplasm, including 9 MDS and 2 “de novo” AML. Among 9 MDS cases, 4 developed secondary AML with a median interval of 9.5 months (range, 3–15 months). The 7 patients without a history of cytotoxic exposure included 1 MDS, 1 T-ALL/LBL, 2 B-ALL/LBL, 1 MPN, and 2 PCN. Among this group, 1 patient (case #18) presented initially with B-ALL/LBL, was treated with chemoradiation and developed MDS 43 months later.

Cytogenetic findings from bone marrow aspirate samples are summarized in Table 1 (detailed karyotype in Supplementary Table 2). Conventional cytogenetic analysis showed a complex karyotype in all MDS (n = 10), AML (n = 2) and T-ALL/LBL (n = 1) cases. The 2 B-ALL/LBL cases had a hypodiploid (case #18) and a possible hypodiploid (case #7) karyotype, respectively. The remaining 3 cases (1 MPN and 2 PCN) showed a normal karyotype. By conventional cytogenetic analysis, chromosome 17 alterations were seen in 4 MDS, 2 B-ALL/LBL, 1 AML, and 1 T-ALL/LBL cases. Fluorescence in situ hybridization (FISH) or microarray-based comparative genomic hybridization (aCGH) results were available for 10 neoplasms, showing monosomy 17 and/or loss of one TP53 allele in 6 neoplasms. Incorporating conventional cytogenetic and FISH/aCGH data, 9 patients had TP53 deletion at cytogenetic level (monosomy 17 or loss of TP53 signal).

Targeted next generation sequencing (NGS) data from bone marrow aspirate samples were available for 17 cases (Table 1). Three patients showed an additional somatic TP53 mutation besides the germline TP53 mutation (cases #4, 9, 10). Of the 14 patients with detailed information on germline TP53 variants, 10 (71%) germline mutations occurred in the DNA binding domain (exons 5–8), including 2 in exon 5, 2 in exon 6, 5 in exon 7, and 1 in exon 8. The remaining 4 germline mutations included 3 in exon 4 and 1 involving exons 10 and 11. Missense mutations were most common (n = 10, 71%), followed by frameshift (n = 3, 21%) and nonsense (n = 1, 7%). Among the missense mutations, TP53 p.R248Q was most common, detected in 3 patients (cases #3, 15, 17). Of the 4 patients without a detailed germline TP53 mutational profile, 3 (cases #1, 8, 14) had a TP53 mutation (possibly germline) detected by NGS. The remaining 1 case (#18) did not have material to perform the analysis.

In the newly published WHO and ICC classifications of myeloid neoplasms, great emphasis was placed on TP53 status, with a separate category of MDS/AML proposed to include cases with biallelic alterations of TP53. Integrating cytogenetic and molecular data, 14 cases in this cohort demonstrated a presumed biallelic TP53 alteration (Table 1) based on a high variant allele frequency of the mutant TP53 (cases #3, 6, 7, 13, 14, 15), two separate TP53 mutations (cases #4, 9, 10), or a TP53 mutation paired with a cytogenetic alteration involving the TP53 locus at chromosome 17p (cases #2, 3, 4, 5, 6, 7, 8, 10, 12, and 16). In the remaining 4 cases, 3 did not have FISH study performed for evaluation of TP53 deletion status, thus their biallelic TP53 status is uncertain. The remaining one case (#17) showed no TP53 deletion by FISH, arguing against biallelic TP53 alteration.

The treatment regimens and survival data for the hematologic neoplasms are summarized in Supplementary Table 3. Nine patients underwent stem cell transplant (SCT), including 5 MDS, 1 AML, 2 B-ALL/LBL, and 1 T-ALL/LBL. At the time of last clinical follow up, 9 (50%) patients died, including 5 MDS, 2 AML, 1 T-ALL/LBL, and 1 B-ALL/LBL. The median overall survival (OS) time from the diagnosis of the first malignancy was 198.0 months and the median OS from the diagnosis of the hematologic neoplasm was 28.8 months. To explore the prognosis of patients with MDS or AML, we compared the OS of these patients with TCGA cohort of AML patients stratified by using the European LeukemiaNet standardized system for cytogenetic risk.⁵ Only patients younger than 55 years were included to achieve a group of similar median age to this cohort. The analyses showed that the MDS/AML patients in this cohort showed a poorer OS than the TCGA AML patients with favorable cytogenetic risk (median, 19.7 months vs. not reached, p = .0002) and a similar OS to TCGA AML patients with intermediate cytogenetic risk (median, 19.7 vs. 27.0 months, p = .89) and those with unfavorable cytogenetic risk (median, 19.7 vs. 12.2 months, p = .60).

In contrast to previous studies which showed that hematologic neoplasms in LFS patients mainly occurred in children with B-ALL/LBL being the most common,² the majority of our cohort had myeloid neoplasms (MDS or AML) with a median age of 41 years. These discrepancies are potentially due to selection bias, as our institution is a tertiary referral cancer hospital with a predominant patient population of adults.

Both B-ALL/LBL patients in our cohort exhibited a low hypodiploid or pseudo-hyperdiploid karyotype, highlighting the association of a hypodiploid karyotype in B-ALL/LBL and alterations in TP53. This association is particularly notable for low hypodiploid B-ALL/LBL in children in up to 50% of whom with this karyotype are found to have LFS.⁶

In our cohort, 11 (61%) patients had a history of cytotoxic exposure, and all developed MDS/AML. Only one MDS patient (case #1) had no history of cytotoxic therapy. These findings highlight the strong association between exposure to cytotoxic treatment and subsequent development of MDS/AML. These findings have clinical implications regarding the follow-up of LFS patients receiving cytotoxic therapy, given the high risk of transformation to aggressive leukemia and poor prognosis.

In summary, in this largest cohort of predominantly adult LFS patients with hematologic neoplasms, MDS and AML were most common, frequently associated with a prior non-hematologic malignancy, a history of cytotoxic exposure, complex karyotype, and poor prognosis. Missense mutation was the most observed TP53 germline mutation, followed by frameshift mutation. Many of the myeloid neoplasms would fall into the category of neoplasms with biallelic TP53 alterations, additionally supporting the aggressive nature of these neoplasms seen in LFS patients.

The authors declare no conflicts of interest.

Not applicable.