AMP case report: Therapy-related acute myeloid leukemia in a patient with BRCA1-positive breast cancer and a DDX41 possibly germline variant

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Ejas Palathingal Bava, MD; Pooja Khonde, MD; Reger Mikaeel, PhD
Alexa Dickson, PhD; Eric Duncavage, MD; Kilannin Krysiak, PhD

August 2026—The 2022 World Health Organization and International Consensus Classification frameworks recognize several well-defined myeloid neoplasm categories that arise in the setting of inherited genetic predisposition. These entities are grouped according to associated clinical features and include myeloid neoplasms with germline predisposition in the absence of antecedent platelet abnormalities or organ dysfunction (e.g. CEBPA, DDX41, and TP53), those associated with inherited platelet disorders (e.g. RUNX1, ANKRD26, and ETV6), and disorders linked to underlying or potential organ dysfunction. The latter category encompasses a broad range of conditions, including GATA2 deficiency, SAMD9/SAMD9L–related disorders, telomere biology disorders, bone marrow failure syndromes, and Fanconi anemia.^1,2 Additionally, rare pathogenic variants in homologous recombination repair pathway genes (BRCA1, BRCA2, RAD51C, RAD51D), mismatch repair (MMR) pathway genes (MLH1, MSH2, MSH6), as well as other tumor suppressors (CDKN2A, NF1) predispose an individual to multiple solid cancers. Furthermore, cancer predisposition genes are strongly linked with multiple cancer diagnoses rather than a single cancer diagnosis over the lifetime of an affected individual.³

Importantly, multiple hereditary cancer syndromes characterized by defects in DNA damage response and repair pathways are associated with an increased risk of both solid malignancies and myeloid neoplasms. These syndromes involve genes such as CHEK2, BRCA1, BRCA2, MLH1, MSH2, MSH6, and PMS2.^4-6 Germline variants in these broad cancer predisposition genes may be overrepresented among patients with myeloid neoplasms who have a personal history of solid tumors, including those who develop therapy-related myeloid neoplasms.^6,7 In a study by Hein K, et al., germline pathogenic or likely pathogenic variants in cancer predisposition genes were seen in nearly one-fifth of patients with both a solid tumor and a myeloid neoplasm, including those with therapy-related myeloid neoplasms or myeloid neoplasms after prior cytotoxic therapy, supporting a low threshold to pursue germline testing in this population.⁸

Herein, we present an interesting case of therapy-related acute myeloid leukemia (t-AML) in a patient with a history of germline BRCA1-positive breast cancer and a DDX41 p.Q41* variant suspected to be of germline origin.

Case. A 65-year-old female with history of BRCA1 (NM_007294.4:c.68_69del, p.E23Vfs*17) germline pathogenic variant-positive right breast cancer diagnosed 12 years prior (invasive ductal carcinoma, estrogen receptor positive, progesterone receptor positive, HER2 negative, stage T1 N0) who is post-bilateral mastectomy, chemotherapy (cyclophosphamide, methotrexate, fluorouracil), and adjuvant anastrazole presented at an outside hospital with progressive pancytopenia (WBCs = 1.56 K/mcL; hemoglobin = 7.6 g/dL; platelets = 41 K/mcL). A bone marrow biopsy showed t-AML, with 26 percent blasts (Fig. 1A–B). The BRCA1 variant was confirmed germline in the outside hospital.

Molecular analysis was done using the MyeloSeq next-generation sequencing assay, a high-depth, tumor-only targeted sequencing panel designed to identify recurrent genetic variants in patients with myeloid neoplasms.⁹ MyeloSeq analysis was performed on bone marrow and showed variants in DDX41 NM_016222.4:c.121C>T, p.Q41* (VAF = 50 percent); DDX41 NM_016222.4:c.1574G>A, p.R525H (VAF = 18 percent); ASXL1 NM_015338.6:c.2385del, p.W796Gfs*22 (VAF = 18 percent); and KRAS NM_004985.5:c.57G>C, p.L19F (VAF = 16 percent) (Table 1). DDX41 p.R525H is the most frequent somatic variant observed in patients with germline pathogenic DDX41 variants. The DDX41 c.121C>T, p.Q41* variant (Fig. 1C), if germline, would be pathogenic. Due to the positions of the two DDX41 variants, this assay is unable to determine whether they are in cis (on the same chromosome) or in trans (on opposite chromosomes). Corresponding cytogenetics studies showed a 46,XX[20] karyotype with no aberrations detected by myelodysplastic syndrome or AML FISH panels. The immunohistochemistry stain for CD34 showed an increase in blasts (20 percent) in the bone marrow. Flow cytometry of the bone marrow specimen showed myeloid progenitor population with abnormal surface antigen expression consisting of CD45, CD34, HLA-DR (slightly decreased), CD38 (decreased), CD117, CD13, CD33, and CD123 (dim), without expression of CD11b, CD5, CD19, CD10, CD16, CD14, CD36, CD64, CD56, or CD7. Total non-erythroid cells expressing CD34 were present at 23 percent, representing increased myeloblast population (23 percent of total events).

This case was best classified as AML with myelodysplasia-related gene mutations, therapy-related by International Consensus Classification criteria, or AML, myelodysplasia-related, post-cytotoxic therapy based on the WHO-HAEM5. The overall constellation of variants was consistent with adverse risk AML by National Comprehensive Cancer Network guidelines. The patient was started on chemotherapy with daunorubicin and cytarabine induction.

After one and a half months, subsequent bone marrow biopsy showed markedly hypocellular bone marrow with pan-hypoplasia and no morphologic evidence of AML. Repeat MyeloSeq performed on the post-induction bone marrow specimen showed that previously identified variants in ASXL1, DDX41 p.R525H, and KRAS were not seen, consistent with variant clearance and measurable residual disease negative status at a sensitivity of at least 0.1 percent. The DDX41 p.Q41* variant was again detected (VAF = 49 percent) at near heterozygous allelic fraction, in the absence of morphological evidence of leukemia, and is also seen in the global population at low levels, which suggest it likely represents a germline variant (Table 1). The germline BRCA1 variant was again found in a heterozygous state on NGS testing of bone marrow specimen done by Tempus xT in the current encounter when the bone marrow was negative for measurable residual disease.

The proposed diagnosis was t-AML, with possibly germline DDX41 p.Q41* variant and history of germline BRCA1-positive breast cancer. The patient is being evaluated for bone marrow transplantation.

Discussion. This patient with t-AML likely has multiple cancer predisposition syndromes with established BRCA1 and putative DDX41 p.Q41* pathogenic germline variants. Longitudinal MyeloSeq molecular data shows that the persistent DDX41 p.Q41* variant likely represents a germline variant, which predisposes to myeloid neoplasms. In a study by Bannon SA, et al., 94 percent of patients with suspected DDX41 germline variant had confirmed germline DDX41 variant on germline testing on DNA extracted from cultured skin fibroblasts obtained from skin punch biopsy.¹⁰ The patient was referred for genetics counseling for further workup.

The DDX41 p.R525H is one of the most frequently acquired somatic variants affecting the second DDX41 allele in this setting, as in this case, and may be associated with more rapid progression to myelodysplastic syndrome/AML.¹¹ In patients with therapy-related myeloid neoplasms, germline variants coexist in 10 to 30 percent of cases, mainly in genes related to BRCA1/2, TP53, CHEK2, and Fanconi anemia.¹² In a study of breast cancer patients who developed t-AML, germline variants were present in 21 percent of cases, mainly in BRCA1 (six percent), TP53 (six percent), BRCA2 (four percent), PALB2 (two percent), and CHEK2 (two percent). These findings support a contribution of inherited cancer susceptibility to the development of t-AML following breast cancer.⁶ This was observed as well in our patient, who presented with t-AML with a history of BRCA1-positive breast cancer. These variants may predispose to clonal hematopoiesis of indeterminate potential (CHIP), which is then naturally selected under cytotoxic pressure leading to t-AML. The association of t-AML with germline pathogenic variants and CHIP represents an emerging and promising field for developing preventive and monitoring strategies.¹³ Intriguingly, in a recent study by Korotev SC, et al., one family with another DDX41 germline pathogenic variant (c. 490 C>T [p.Arg164Trp]) had a coexisting BRCA1 germline pathogenic variant. The family members developed hematopoietic malignancies as well as solid tumors (colon, ovarian, prostate, spinal).⁷

There are many implications for this patient of having a DDX41 germline variant. Approximately half of DDX41 carriers develop myeloid malignancies in their lifetimes, underscoring the need for genetic counseling of the individual with consideration for cascade testing of family members.¹⁴ Moreover, germline pathogenic variants in DDX41 are relatively prevalent in the general population (approximately one in 429 individuals), a factor that may warrant consideration when developing guidelines for the selection of unrelated adult donors for hematopoietic stem cell transplantation (HSCT).¹¹ The unrecognized use of related transplant donors with the same germline variant has led to donor-derived myeloid neoplasms, emphasizing the need for increased awareness and recognition of germline predispositions to myeloid neoplasms. Furthermore, patients with pathogenic DDX41 germline variants frequently develop acute graft-versus-host disease after allogeneic HSCT unless they receive post-transplant cyclophosphamide.¹⁴ Although our testing cannot definitively differentiate between somatic and germline variants, the persistent near-heterozygous allele fraction and disease clearance strongly warranted recommendations for follow-up genetic counseling and germline testing for our patient and any potential related donor. Germline testing of the patient for DDX41 should be prioritized, and hence the patient has been given a kit for germline testing for DDX41. If confirmed that the DDX41 variant is germline, then cascade testing for family members is relevant to further address cancer predisposition risk in the family.

We note that DDX41 p.Q41* is a reasonably common germline variant and has not been previously reported as somatic.¹¹ Genetic counseling and consideration for germline testing is recommended for potential carriers of the BRCA1 variant in family members. Through tailored management and regular surveillance, individuals with BRCA variants can reduce cancer risk or identify malignancies at earlier, more treatable stages.¹⁵

Here, we present an intriguing patient with t-AML, as well as a history of germline BRCA1-positive breast cancer and a DDX41 p.Q41* possibly germline variant. This case contributes to the emerging understanding of the relationship between t-AML with a history of solid tumor and predisposing germline variant(s), as well as CHIP, offering insight into potential preventive and monitoring strategies for these patients. Our observations may further support the findings of previous studies, to follow up patients with solid tumor with germline predisposition for development of t-AML, as well as to offer germline genetic testing to all patients who develop therapy-related leukemia after breast cancer, to enable primary prevention for at-risk relatives and guide care for survivors of therapy-related leukemia.^6,12

This case report helps to create awareness of the benefits of germline testing for DDX41 in suspected cases as well as its implications for bone marrow transplantation in order to address the barriers to germline testing.

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2. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703–1719.
3. Shevach JW, Xu J, Snyder N, et al. Established cancer predisposition genes in single and multiple cancer diagnoses. JAMA Oncol. 2025;11(10):1222–1230.
4. McNerney ME, Godley LA, Le Beau MM. Therapy-related myeloid neoplasms: when genetics and environment collide. Nat Rev Cancer. 2017;17(9):513–527.
5. Ramachandra C, Challa VR, Shetty R. Constitutional mismatch repair deficiency syndrome: Do we know it? Indian J Hum Genet. 2014;20(2):192–194.
6. Churpek JE, Marquez R, Neistadt B, et al. Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia. Cancer. 2016;122(2):304–311.
7. Korotev SC, Cheng JX, Haribabu Y, et al. Overall cancer risk in people with deleterious germline DDX41 variants. Haematologica. 2025;110(9):2076–2090.
8. Hein K, Chowdhuri SR, Dinardo C, et al. Landscape of germline pathogenic/likely pathogenic mutations involving DNA repair genes in solid tumor patients with antecedent or subsequent myeloid neoplasms. Hemasphere. 2023;7(S3):e9942105.
9. Slade MJ, Ghasemi R, O’Laughlin M, et al. Persistent molecular disease in adult patients with AML evaluated with whole-exome and targeted error-corrected DNA sequencing. JCO Precis Oncol. 2023;7:e2200559.
10. Bannon SA, Routbort MJ, Montalban-Bravo G, et al. Next-generation sequencing of DDX41 in myeloid neoplasms leads to increased detection of germline alterations. Front Oncol. 2021;10:582213.
11. Cheloor Kovilakam S, Gu M, Dunn WG, et al. Prevalence and significance of DDX41 gene variants in the general population. Blood. 2023;142(14):1185–1192.
12. Baranwal A, Hahn CN, Shah MV, Hiwase DK. Role of germline predisposition to therapy-related myeloid neoplasms. Curr Hematol Malig Rep. 2022;17(6):254–265.
13. Jerez J, Hernandez C, Hill CN. Understanding therapy-related AML: genetic insights and emerging strategies for high-risk patients. Front Hematol. 2025;4:1609642.
14. Nagata Y. Molecular pathophysiology of germline mutations in acute myeloid leukemia. Int J Hematol. 2024;120(4):417–426.
15. Petrucelli N, Daly MB, Pal T. BRCA1– and BRCA2-associated hereditary breast and ovarian cancer. In: Adam MP, Bick S, Mirzaa GM, et al., eds. GeneReviews. University of Washington. Sept. 4, 1998. Updated March 25, 2026. www.ncbi.nlm.nih.gov/books/NBK1247

Dr. Palathingal Bava and Dr. Khonde are fellows in molecular genetic pathology; Dr. Mikaeel is a laboratory genetics and genomics fellow; Dr. Dickson is a clinical variant scientist; Dr. Duncavage is professor of pathology and immunology and division chief, genomic and molecular pathology; and Dr. Krysiak is associate professor of pathology and immunology and associate medical director of the cytogenomics and molecular pathology laboratory—all at Washington University School of Medicine in St. Louis, Mo.

Test yourself

Here are three questions taken from the case report. Answers are online now at www.amp.org/casereports and will be published next month in CAP TODAY.

1. Germline variants in which of the following genes may be associated with increased risk of both myeloid and solid malignancies?

a. BRCA1/2.

b. CHEK2.

c. MLH1.

d. All of the above.

2. Which of the following statements is false?

a. DDX41 p.R525H is one of the most frequently acquired somatic variants affecting the second DDX41 allele.

b. DDX41 p.R525H may be associated with less rapid progression to myelodysplastic syndrome/acute myeloid leukemia.

c. In patients with therapy-related myeloid neoplasms, germline variants coexisted in 10 to 30 percent of cases.

d. Germline variants in BRCA1/2 are seen in many breast cancer patients who developed therapy-related acute leukemia.

3. Which of the following statements is false?

a. All DDX41 carriers develop myeloid malignancies in their lifetimes.

b. Germline pathogenic variants in DDX41 are relatively prevalent in the general population.

c. Patients with pathogenic DDX41 germline variants frequently develop acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

d. Inherited cancer susceptibility contributes to the development of therapy-related AML following breast cancer.