Myeloproliferative and lymphoproliferative malignancies occurring in the same patient: a nationwide discovery cohort

Holst, Johanne Marie; Plesner, Trine Lindhardt; Pedersen, Martin Bjerregård; Frederiksen, Henrik; Møller, Michael; Clausen, Michael Roost; Hansen, Mette Halskov; Hamilton-Dutoit, Stephen; Nørgaard, Peter; Johansen, Preben; Eberlein, Tobias Ramm; Mortensen, Bo; Mathiasen, Gustav; Øvlisen, Andreas Kiesbye; Wang, Rui; Wang, Chao; Zhang, Weiwei; Ommen, Hans Beier; Stentoft, Jesper; Ludvigsen, Maja; Chan, Wing C.; Inghirami, Giorgio; d’Amore, Francesco

doi:10.3324/haematol.2019.225839

Cited by 23 publications

(20 citation statements)

References 33 publications

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“…Most recently, a nationwide case series of 83 Danish MPN patients concurrently or subsequently diagnosed LPD was presented: 32% presented aggressive lymphomas, 53% CLL or large granular lymphocyte leukemia and 10% peripheral T‐cell lymphomas, especially angioimmunoblastic lymphoma . Male‐to‐female ratio (1.08) and median age at MPN diagnosis (71 years) were similar to those reported by large MPN registries.…”

Section: Discussionsupporting

confidence: 61%

Lymphoproliferative disorders in patients with chronic myeloproliferative neoplasms: A systematic review

et al. 2018

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Patients with a Ph-negative myeloproliferative neoplasm (MPN) may harbor or develop lymphoproliferative disorders (LPD), however, the clinical and molecular determinants of MPN and LPD co-occurrence are still uncertain. To systematically pool the available knowledge, we conducted a scoping review of literature published since January 2005 and analyzed single-patient clinical data from 50 papers reporting 214 individuals harboring both MPN and LPD. Patients had been diagnosed essential thrombocythemia (44%), polycythemia vera (29%), or myelofibrosis (23%) at a median age of 67 years (26-94): half of them incurred a LPD after a median of 72 months from MPN diagnosis, while in 20% the LPD diagnosis was antecedent or synchronous. Patients mainly incurred indolent LPD, particularly chronic lymphocytic leukemia (CLL), while aggressive lymphomas and multiple myeloma were a relevant portion of the LPDs occurring in the follow-up of MPN. CLL was preferentially diagnosed in PV patients and was associated with a very high male-to-female ratio, as well as an older age at MPN diagnosis. On converse, multiple myeloma was rarely reported in PV patients and was preferentially diagnosed in female patients not harboring the JAK2 V617F mutation. Based on the 46 cases reporting follow-up data, median survival after MPN diagnosis was 96 months. This thorough review of published evidence confirms that LPD are relevant clinical events in the history of MPN patients. Controlled studies are needed to better refine individuals at higher risk of developing LPD, to support surveillance programs and to avoid therapies possibly favoring LPD.

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Section: Discussionsupporting

confidence: 61%

Lymphoproliferative disorders in patients with chronic myeloproliferative neoplasms: A systematic review

et al. 2018

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“…A recent study also described patients with MPNs preceding AITL, but clonal relatedness was not shown. 29 In the literature, both patients with MNs preceding AITL 3,7,18,20 and patients with MNs developing after AITL 19,30 have been reported, although in only rare cases was a clonal link clearly demonstrated between the 2 neoplasms. Given that both scenarios have been reported, it may be that due to our sample size, we only identified patients who developed MNs following their AITL with confirmed clonal relationships.…”

Section: Discussionmentioning

confidence: 99%

Clonal hematopoiesis in angioimmunoblastic T-cell lymphoma with divergent evolution to myeloid neoplasms

Lewis¹,

Petrova‐Drus²,

Huet³

et al. 2020

Blood Advances

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TET2 and DNMT3A mutations are frequently identified in T-cell lymphomas of T follicular helper cell origin (TCL-TFH), clonal hematopoiesis (CH), and myeloid neoplasms (MNs). The relationships among these 3 entities, however, are not well understood. We performed comprehensive genomic studies on paired bone marrow and tissue samples as well as on flow cytometry–sorted bone marrow and peripheral blood subpopulations from a cohort of 22 patients with TCL-TFH to identify shared CH-type mutations in various hematopoietic cell compartments. Identical mutations were detected in the neoplastic T-cell and myeloid compartments of 15 out of 22 patients (68%), including TET2 (14/15) and DNMT3A (10/15). Four patients developed MNs, all of which shared CH-type mutations with their TCL-TFH; additional unique genetic alterations were also detected in each patient’s TCL-TFH and MN. These data demonstrate that CH is prevalent in patients with TCL-TFH and that divergent evolution of a CH clone may give rise to both TCL-TFH and MNs.

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“…3). Interestingly, co-existence of myeloid disorders such as CMML and AITL have been described, at a higher frequency than expected 40,91,92 . Both malignancies share common ancestral mutations in TET2 and/or DNMT3A, while disease specific mutations result in the emergence of the AITL (RHOA, TCR signaling) or myeloid disease (NPM1) 93 (Fig.…”

Section: Aitl Mutational Hierarchymentioning

confidence: 95%

New preclinical models for angioimmunoblastic T-cell lymphoma: filling the GAP

et al. 2020

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Mouse models are essential to study and comprehend normal and malignant hematopoiesis. The ideal preclinical model should mimic closely the human malignancy. This means that these mice should recapitulate the clinical behavior of the human diseases such as cancer and therapeutic responses with high reproducibility. In addition, the genetic mutational status, the cell phenotype, the microenvironment of the tumor and the time until tumor development occurs, should be mimicked in a preclinical model. This has been particularly challenging for human angioimmunoblastic lymphoma (AITL), one of the most prominent forms of peripheral T-cell lymphomas. A complex network of interactions between AITL tumor cells and the various cells of the tumor microenvironment has impeded the study of AITL pathogenesis in vitro. Very recently, new mouse models that recapitulate faithfully the major features of human AITL disease have been developed. Here, we provide a summary of the pathology, the transcriptional profile and genetic and immune-phenotypic features of human AITL. In addition, we give an overview of preclinical models that recapitulate more or less faithfully human AITL characteristics and pathology. These recently engineered mouse models were essential in the evaluation of novel therapeutic agents for possible treatment of AITL, a malignancy in urgent need of new treatment options. Angioimmunoblastic T-cell lymphoma: a challenging complex malignancy Clinical aspects Angioimmunoblastic T-cell lymphoma (AITL) belongs since 2016 after revision of the world health organization (WHO) classification to the nodal T-cell lymphomas with follicular helper T-cell (Tfh) phenotype 1. AITL is a rare, aggressive lymphoma with little treatment options. Overall survival is generally poor with a five-year median survival rate of 32% 2,3. It represents only 1-2% of the non-Hodgkin's lymphomas. However, AITL appears to be the most prevalent PTCL, representing up to 35% of the noncutaneous peripheral T-cell lymphomas 2,4-6. AITL pathology develops late in life with a median age at onset of 59-65 years and patients display a generalized lymphoadenopathy 7,8. Seventy percent of the patients have bone marrow involvement and unfortunately early stage detection of AITL is very uncommon (10%) 9. Disease symptoms resemble closely an infection inducing immunologic hyper-activation (fever, rash, loss of weight, hemolytic anemia 2,5) (Fig. 1). AITL has particular clinical and pathological features, associated with splenomegaly, hepatomegaly and enlarged lymph nodes showing effacement of normal architecture and appearance of endothelial venules 3 (Fig. 1). Other typical clinical manifestation of AITL are cutaneous lesions also called skin rash in 20-50% of the patients and accumulation of abdominal ascites 5,10-13. These patients often test positive for autoimmunity including detection of rheumatoid factor, anti-smooth muscle, and nuclear autoantibodies 14. They also present a general increase in immunoglobulins called hypergammaglobulemia (30%) 7,12 .

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Myeloproliferative and lymphoproliferative malignancies occurring in the same patient: a nationwide discovery cohort

Cited by 23 publications

References 33 publications

Lymphoproliferative disorders in patients with chronic myeloproliferative neoplasms: A systematic review

Lymphoproliferative disorders in patients with chronic myeloproliferative neoplasms: A systematic review

Clonal hematopoiesis in angioimmunoblastic T-cell lymphoma with divergent evolution to myeloid neoplasms

New preclinical models for angioimmunoblastic T-cell lymphoma: filling the GAP

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