Angioimmunoblastic T‐cell lymphoma after acute myeloid leukemia: Alleged common pathogenesis. A case report and literature review

Abstract The genomic landscape of AITL is characterized by mutation of epigenetic modifiers. This gene expression pattern resembles myeloid diseases and shows a potential role for hypomethylating agents as possible therapy for AITL.


| CASE PRESENTATION
Here, we describe the presence of angioimmunoblastic T-cell lymphoma (AITL) in a 75-year-old woman who 10 years ago had acute myeloid leukemia (AML) with mutation in the gene encoding nucleophosmin 1 (NPM1).
In 2008, she was diagnosed with AML (FAB M5), MLL-(mixed-lineage leukemia) negative, NPM1-positive, normal karyotype, with infiltration of central nervous system. The patient achieved a complete remission (CR) after 2 cycles of cytarabine and anthracycline given in the standard 3 + 7 regimen, and posterior intermediate-dose cytarabine. She also received six doses of triple intrathecal chemotherapy: cytarabine, methotrexate, and hydrocortisone. Subsequently, the patient underwent autologous stem cell transplantation with busulfan and cyclophosphamide (BuCy) as conditioning regimen. The patient remained in remission since then, with a very good quality of life and without any other therapy.
In 2016, the patient started with low platelet count at about 80 000 to 100 000/mm 3 , so a bone marrow aspiration was done. The patient was diagnosed with myelodysplastic syndrome with multilineage dysplasia secondary to previous chemotherapy (therapy-related myeloid neoplasm by WHO), with del 5q associated. From 2016 to 2019, her disease remained stable. She was asymptomatic, did not receive any treatment, and no transfusion support was needed.
In 2019, she presented with a 2-month history of progressive lymphadenopathy in right axilla associated with skin lesions of the type purple infiltrative nodules of 2-3 cm large in thoracic region ( Figure 1). She did not have hepatoesplenomegaly nor B symptoms. She had mild anemia and thrombopenia, with normal LDH and no hypergammaglobulinemia. PET-CT scan showed abnormal activity in the skin extending from the right arm through both supraclavicular regions, the back, and the lumbar region. It also showed intense and homogeneous hypermetabolic activity (SUV 14) at both cervical ganglionar regions, right axilla and right paratracheal region. There was hypermetabolic lymphadenopathy in right groin, with several lymph nodes, 40 mm in longest diameter (SUV 21). There was no hepatic or splenic involvement.
The skin biopsy showed a diffused dense infiltrate of small to medium-sized neoplastic lymphocytes with irregular nuclei, evident nucleoli, and occasional clear cytoplasm located in the dermis and subcutaneous tissue. There was associated vascular hyperplasia with prominence of endothelial cells. The neoplastic infiltrate was accompanied by a polymorphous inflammatory background composed of reactive lymphocytes, plasma cells, and histiocytes. Tumor cells expressed pan-T-cell antigens (CD3 and CD5) and showed the immunophenotype of normal T follicular helper (TFH) cells (CD10, BCL6, and PD1). There were focal expanded follicular dendritic cell networks highlighted by CD21 and also Epstein-Barr virus (EBV)-positive cells. These EBV-positive cells are typically B cells, often with CD30 expression, and are seen in nearly 95% of nodal AITL cases. 3 The histologic diagnosis was cutaneous involvement of T-cell lymphoma with TFH phenotype suggesting angioimmunoblastic T-cell lymphoma (AITL). Figure 2A.
In the bone marrow biopsy, there was no evidence of infiltration by lymphoma. Molecular studies of the bone marrow identified a clonal TET2 somatic mutation. The TET2 mutation was present in virtually almost all the bone marrow cells (variant allele frequency [VAF], 43.13%). In addition to this epigenetic modifier, MLL and NPM1 were also mutated.
The patient is currently in complete remission after six cycles of chemotherapy with cyclophosphamide, doxorubicin, prednisone, and brentuximab vedotin. 4 The follow-up after completion of therapy is only of 2 months. The study by Odejide et al 2 defined the first genetic landscape of AITL, describing TET2 as the most frequent mutation, presenting in 76% of AITL. DNMT3A was the second most frequently mutated gene (33%) followed by IDH2 (20%). 2 TET2 and DNMT3A have been described in myeloid neoplasms and in clonal haematopoiesis. In AITL, TET2 mutations were found not only in the tumor cells but also in hematopoietic stem cells, suggesting that early TET2 during hematopoiesis could lead to the development of AITL. 6 In the present case study, TET2 is mutated with a high VAF, which suggests an early event in pathogenesis.

DISCUSSION
It is also important to consider the use of busulfan in this patient, as it can cause genetic mutations and the development of second malignancies. Busulfan is commonly used in hematopoietic stem cell transplant setting as it has both myeloablative and antitumor properties. This alkylating drug is cytotoxic to proliferating tissues, and therefore, it can also cause several adverse events. The most common significant toxicity of busulfan is sinusoidal obstruction syndrome, neurotoxicity, and interstitial pneumopathies. 7 Alkylating agents such as busulfan can cause second malignancies in which deletion of chromosome 5 and 7 is very frequent, and they usually appear 5-10 years after primary cancer.
The development in the same patient of acute myeloid leukemia with mutation in NPM1 and angioimmunoblastic T-cell lymphoma with mutation in the RHOA gene was previously described in the literature. 8 The common origin of these two hematologic neoplasms can be explained by a highrisk CHIP (Clonal hematopoiesis of indeterminate potential) characterized by overlapping mutations in epigenetic modifiers such as TET2. 8

| CONCLUSION
The development of acute myeloid leukemia with mutation in NPM1 and angioimmunoblastic T-cell lymphoma, in the same patient, could be linked by a common pathogenesis.
Further studies are needed to elucidate the role of these genetic alterations in AITL pathogenesis and eventually develop molecularly targeted therapies to treat this aggressive disease.