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Resolving the diagnostic dilemma of T-cell clonal expansion after hematopoietic stem cell transplantation in T-cell lymphoma patients by TCR-gamma next generation sequencing

Bone Marrow Transplantation volume 54, pages 159–163 (2019)Cite this article

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Peripheral T-cell lymphomas (PTCLs) are rare tumors in Western countries, representing about 10% of all non-Hodgkin’s lymphomas (NHL) [1]. Despite their pathobiological [2] and clinical heterogeneity [3], T-cell malignancies are considered as clonal disorders that arise from the expansion of committed lymphoid cells at different differentiation stages, the neoplastic clones varying in different patients due to the unique T cell receptor (TCR) gene rearrangements that occur during T-cell differentiation [4]. Thus, clonality assessment of TCR is often used for both diagnostic purposes (i.e., for identification of clonal populations within a reactive non-neoplastic milieu) and minimal residual disease monitoring (i.e., for the early recognition of a given clone during patients’ follow-up). In practice, TCR gamma (TRG) genes are commonly studied, being the first ones to be rearranged during T-cell development and thus being indicative of TCR editing in most instances. By contrast, TCR alpha (TRA), TCR beta (TRB), and TCR delta (TRD) are usually studied in case TRG analysis fails [5]. To date, polymerase chain reaction (PCR) based techniques are commonly adopted for clonality assessment [4, 5].

The prognosis of PTCL patients is overall dismal; therefore, autologous or allogeneic stem cell transplantation (ASCT or allo-SCT, respectively) is widely used as either part of a standardized procedure or within clinical trials [6,7,8]. Particularly, allo-SCT, though not part of the standard first-line approach yet, is considered a potentially curative option. It is well known that the long-term efficacy of allo-SCT relies primarily on graft-versus-tumor (GVT), which partly overlaps with graft-versus-host disease (GVHD). The balance between these two reactions is strongly influenced by the immunological reconstitution. Both B- and T-lymphocytes are involved in this process, and, more recently, adequate thymic function measured by quantification of T-cell receptor excision circles (TRECs) has been correlated with balanced immune reconstitution and reduced risk of infections [9]. In daily clinical practice, the immune reconstitution is usually evaluated with quantitative assessment of CD3+, CD4+, CD8+, CD19+, CD56+, and CD16+ cells on peripheral blood at least every 3 months during the first year after allo-SCT. The speed of immune reconstitution is strongly associated with several factors, being fastest in allo-SCT from a HLA-identical sibling donor [10]. It is well known that during the first year after allo-SCT the majority of patients have a polyclonal IgG repertoire, similar to that of healthy controls, while serum IgM repertoires remain oligoclonal for a long time after transplant [11]. The same phenomenon is observed in terms of T-cell reconstitution, which is often characterized by dominance of oligoclonal T cell populations, reflecting specific antigen-driven immune responses [12]. The latter phenomenon is a major caveat on the use of TCR rearrangement for relapse assessment, as the presence of a clonal TCR not necessarily means presence of overt disease recurrence. As a consequence, in daily clinical practice, conventional imaging techniques (e.g., CT scan and PET), together with molecular chimerism on peripheral blood lymphocytes and neutrophils, are used to confirm complete remission (CR) and to rule out a graft rejection.

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Acknowledgements

The authors are grateful to Dr. Ying Huang, Dr. Jeff Panganiban, Dr. Kasey Hutt, Dr. Jeffrey Miller, and Dr. Michael Klass for their kind technical assistance and Invivoscribe Technologies Inc for financial support.

Funding

The study was in part supported by Research and Development, Invivoscribe Technologies, Inc., San Diego, CA, USA; Centro Interdipartimentale per la Ricerca sul Cancro “G. Prodi” BolognAIL; RFO (Prof. Piccaluga); AIRC (Prof. Piccaluga IG 2013 N.14355); and FIRB Futura 2011 RBFR12D1CB (Prof. Piccaluga).

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Authors and Affiliations

  1. Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy

    Pier Paolo Piccaluga & Anna Gazzola

  2. Istituto Euro-Mediterraneo di Scienza e Tecnologia (IEMEST), Palermo, Italy

    Pier Paolo Piccaluga

  3. Jomo Kenyatta University of Agriculture and Technology, Juja, Kenya

    Pier Paolo Piccaluga

  4. Hematology Unit, Ospedale Santa Croce e Carle, Cuneo, Italy

    Davide Rapezzi

  5. Chair of Hematology, Division of Hematology and Stem Cell Transplantation, Brescia University, Brescia, Italy

    Michele Malagola

  6. Hematology and Hematopoietic Stem Cell Transplant Center, AORMN, Pesaro, Italy

    Giuseppe Visani

  7. Research, Innovation and Statistics Department. A, Lacassagne Cancer Center, Nice, France

    Andrea Gallamini

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  1. Pier Paolo Piccaluga
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Correspondence to Pier Paolo Piccaluga.

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Piccaluga, P.P., Rapezzi, D., Gazzola, A. et al. Resolving the diagnostic dilemma of T-cell clonal expansion after hematopoietic stem cell transplantation in T-cell lymphoma patients by TCR-gamma next generation sequencing. Bone Marrow Transplant 54, 159–163 (2019). https://doi.org/10.1038/s41409-018-0268-4

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