February 2024 Clinical Case of the Month
Title: Acute Myeloid Leukaemia 20 years after HCT
Submitted by Felipe Peña Muñoz. Clinical Hematology Department, Institut Catala d’Oncologia–Hospitalet, Barcelona, Spain
Physician's expert perspective: Montserrat Arnan Sangerman. Clinical Hematology Department, Institut Catala d’Oncologia–Hospitalet, Barcelona, Spain
A 50-year-old woman, initially diagnosed with AML M4 in 2003, received induction therapy with cytarabine + daunorubicin (7+3) and consolidation with mitoxantrone + cytarabine, achieving complete remission (CR). She had allogeneic stem cell transplant MAC MRD from her 7 years older brother (37y.o.) on 06/03/03 without further complications, maintaining CR with full donor chimerism, finishing hematological follow-up on May 2021.
In addition, her 13 years older sister was diagnosed with AML in February 2016 with 55-year-old, received induction treatment, achieved complete response, and received RIC MMUD HSCT in July 2016.
In October 2023, our patient presented with spontaneous bruising and gingival bleeding. Laboratory tests revealed WBC 12.31 x10E9/L, blasts 20%, Hb 113 g/L and platelets 11 x10E9/L. Peripheral blood smear showed medium sized blasts and Auer's rods. Bone marrow aspirate showed 33% blasts, CD34+/CD117+/CD7+ by flow cytometry. FLT3 ITD/TKD, NPM1, IDH1/IDH2 WT. Karyotype 46XY and chimerism 100%. With these findings, AML was confirmed on donor bone marrow cells.
Reviewing the 2003 and current 2023 NGS results, as well as her sister's AML diagnosis NGS, it was found that they share a single CEBPA C.917G>C VAF mutation: 47.93% classified as VUS by germline and not investigated. Other CEBPA mutations detected by Panel 2023 were discarded as germline mutations.
Considering the available results, the CEPBA mutation presented in the 3 siblings by NGS and previous data described in the literature, familial AML with germline predisposition is considered, although to our knowledge this specific mutation has not been reported in previous cases. To date, the brother has not developed acute leukaemia or any other hematological malignancy.
Considered as de novo AML (on donor´s bone marrow) and previous treatment 20 years ago, she started treatment with cytarabine + daunorubicin (7+3) achieving CR with negative MRD after 1st induction.
As of February 2024, all three siblings are alive and disease-free.
Expert perspective by Montserrat Arnan Sangerman:
Hereditary predisposition to myeloid neoplasms is more common than previously thought. However, relapse of leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) arising in cells of donor origin in the transplant recipient, so-called donor cell leukemia (DCL), is a rare pathologic entity.
In this family, unexpectedly, a VUS-type mutation is identified. This VUS mutation found in the 3 siblings of this family with this family history of AML underscores the need for further studies to support its pathogenicity. Familial segregation analysis can provide very useful data to reclassify this VUS CEBPA mutation.
Furthermore, in this case, the fact that the donor remained healthy makes it imperative to study the presence of other mutations in the donor. In the absence of these mutations, it would indicate that this single mutation is probably not sufficient for leukemogenesis. Although another important question is the impact of the patient's microenvironment, which in our described case could also explain the development of AML in the recipient and not in the donor.
The present case raises an important question regarding the need for donor selection, reporting and follow-up.
References:
- Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J. Mutation of CEBPA in familial acute myeloid leukemia. New England Journal of Medicine. 2004 Dec 2;351(23):2403–7. doi:10.1056/nejmoa041331
- Pabst T, Eyholzer M, Haefliger S, Schardt J, Mueller BU. Somatic CEPBA mutations are a frequent second event in families with germline CEPBA mutations and familial acute myeloid leukemia. Journal of Clinical Oncology. 2008 Nov 1;26(31):5088–93. doi:10.1200/jco.2008.16.5563
- Nanri T, Uike N, Kawakita T, Iwanaga E, Mitsuya H, Asou N. A family harboring a germ‐line n‐terminal C/EBPΑ mutation and development of acute myeloid leukemia with an additional somatic c‐terminal C/EBPΑ mutation. Genes, Chromosomes and Cancer. 2009 Dec;49(3):237–41. doi:10.1002/gcc.20734
- Snaddon J, Smith ML, Neat M, Cambal‐Parrales M, Dixon‐McIver A, Arch R, et al. Mutations of cebpa in acute myeloid leukemia FAB types M1 and M2. Genes, Chromosomes and Cancer. 2003 Mar 11;37(1):72–8. doi:10.1002/gcc.10185
- Tawana K, Rio-Machin A, Preudhomme C, Fitzgibbon J. Familial CEBPA -mutated acute myeloid leukemia. Seminars in Hematology. 2017 Apr;54(2):87–93. doi:10.1053/j.seminhematol.2017.04.001
- Xiao H, Shi J, Luo Y, Tan Y, He J, Xie W, et al. First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation. Blood. 2011 May 12;117(19):5257–60. doi:10.1182/blood-2010-12-326322
Future Clinical Case of the Month
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