Lymphopenia a simple prognostic factor in lymphoma and other cancers: why not use it more as a guide?

The role of lymphocytes has largely been studied in the context of their function as positive regulators of the immune response. They are essential for host defense against infections and inflammation, as well as being the vital effector cells in cancer surveillance [1]. In a multicenter study involving 5141 patients, reported in 1998, lymphopenia was first recognized as a significant poor prognostic factor in patients with advanced Hodgkin lymphoma (HL) [2]. An absolute lymphocyte count (ALC) of fewer than 600 cells/mm² or a differential count of fewer than 8% lymphocytes in the peripheral blood was identified as one of seven significant parameters included in the proposed prognostic scoring system, indicative of an inverse correlation with freedom from disease progression in these cases [2].

Subsequent studies, which analyzed the significance of lymphopenia in a variety of different malignancies such as diffuse large cell lymphoma (DLCL) [3] at the time of diagnosis and relapse [4], breast cancer [5], and other advanced carcinomas and sarcomas [6], all confirmed an association between lymphopenia and inferior prognosis. Furthermore, in patients with relapsed DLCL, a higher ALC at relapse was associated with a better response to treatment with Revlimid, an immune-modulatory drug used in some of the treatment schedules for lymphoma [7].

In this issue of Leukemia and Lymphoma, Castillo et al. evaluate, for the first time, the significance of lymphopenia, defined as a lymphocyte count of <1000 cells/mm³, as a prognostic factor for survival in patients with peripheral T-cell lymphoma, unspecified type (PTCLU) [8]. They studied 69 patients, and compared the prognostic significance of the International Prognostic Index (IPI) and the Prognostic Index for PTCLU (PIT) scores and the occurrence of lymphopenia in these individuals. In a multivariate analysis performed in this cohort of patients, lymphopenia evident at the time of disease presentation was obviously associated with a worse overall survival (OS).

The reasons for the association of lymphopenia with a worse survival in cancer patients have, surprisingly, still not been well studied, and the underlying mechanism of this association remains incompletely understood. This phenomenon appears to be associated with an increased risk of complications, including febrile neutropenia, anemia requiring red blood cell transfusions, and thrombocytopenia necessitating platelet transfusions [9,10]. These associations, although resulting in an adverse outcome, are still insufficient to explain the negative impact on OS and progression-free survival (PFS) reported in the different malignancies.

Ray-Coquard et al. investigated the clinical significance of lymphopenia in patients with newly diagnosed diffuse large cell lymphoma, hormone resistant metastatic breast cancer, and untreated soft tissue sarcoma [6]. In the latter study, lymphopenia was noted to be an independent prognostic factor for overall survival, and was related to tumor as well as host characteristics such as total tumor burden, metastatic sites involved, or patient age [6]. Based on the above, ALC may be regarded as a surrogate marker of host immune status, implying that the intrinsic immune response is inadequate, enabling tumor growth.

The biological background and explanation for these clinical observations still need to be clarified and better understood [3]. First, there is a need to identify whether the lymphopenia is a result of impaired differentiation of lymphocyte progenitors due to the expression of immune inhibitory molecules on the tumor cell such as PD-1 ligand, or to the production and secretion of cytokines such as transforming growth factor-β (TGF-β) by the tumor cells themselves. Alternatively, it could also be related to enhanced apoptosis of the lymphocytes present in the tumor itself, which may be linked to chronic activation of these cells, resulting in up-regulation of death receptors on the cell surface [11,12]. Second, it is noteworthy that most of the above studies did not perform subanalysis of lymphocyte subsets, in an attempt to define which lymphocyte subpopulations are most frequently depleted in these cases. In this regard, Ray-Coquard et al. reported that the observed lymphopenia was not restricted to a particular lymphocyte subset, but involved CD4, CD8, CD19, and CD56 positive lymphoid cells [9]. On the other hand, Plonquet et al. noted that higher absolute natural killer (NK) cell counts were indeed associated with eventual clinical outcome [13]. Thus, it is evident that the results are still somewhat controversial, and further investigations are needed to advance better understanding on all these issues.

Obtaining data on the ALC is a simple and reproducible laboratory procedure which can easily be acquired routinely by all, and is a reliable prognostic marker at diagnosis and in some instances of relapse in other types of diffuse large cell lymphoma [4]. Based on the data reported here by Castillo et al., ALC can also be readily applied in cases with PTCLU.

Nevertheless, it should be remembered that lymphopenia is still an open field for investigation, and an improved understanding of the mechanisms involved would certainly contribute to improving future treatment strategies, which will probably employ more combinations of different types of immunotherapy, in an attempt to avoid some of the recognized and more serious toxicities of more aggressive combination chemotherapy regimens currently in use for the treatment of this type of lymphoma.