Large granular lymphocyte (LGL) proliferation typically follows a chronic course during which major features are cytopenia and immune abnormalities. Elevated numbers of LGL were reported in a few cases following allogeneic stem cell transplantation (allo-SCT). In this report, we present a retrospective analysis of LGL cases that occurred following allo-SCT in a cohort of 201 consecutive patients transplanted over a period of 7 years. Six cases were identified and LGL expansion occurred more frequently following a reduced fludarabine and anti-T lymphocyte globulin-based preparative regimen (4 cases/49), than after a conventional myeloablative regimen (2 cases/152). Expansion of LGL was seen between 3 and 15 months following allo-SCT. Hematopoiesis, with mild to severe cytopenia, was a favored target for LGL. Autoimmune manifestations including polyarthritis and hypergammaglobulinemia were also observed. LGL proliferation was observed in the context of chronic antigenic stimulation associated with recurrent viral infections especially CMV. Moreover, five out of these six high risk patients achieved a long-term complete remission concomitant or following LGL expansion. These data suggest that LGL might be a subset of effector lymphocytes which may participate to the graft-versus-tumor effect.
Large granular lymphocytosis was recognized as a distinct clinical entity more than 20 years ago, and this syndrome was characterized by lymphocytosis and tissue invasion.1 Some healthy individuals may have small circulating CD8+ T cells compatible with large granular lymphocytes (LGL) and expressing the CD57 glycoprotein determinant.2 LGL can be either oligoclonal or polyclonal,3 and can arise from a CD3+ T cell lineage or from CD3− NK cell lineage. T LGL proliferation follows a chronic course during which major features are neutropenia, anemia, bone marrow infiltration, mild splenomegaly and multiple immune abnormalities (polyclonal hypergammaglobulinemia presence of rheumatoid factor, autoimmune antibodies and circulating immune complexes).4,5 Persistently elevated numbers of CD8+CD57+ lymphocytes have been shown to be increased in a few cases after allogeneic stem cell transplantation (allo-SCT) with myeloablative conditioning regimens,6,7,8,9 or following solid organ transplantation.10 However, the clinical features of this entity in the allo-SCT setting are still sparse. LGL were shown to mediate a wide range of immunoregulatory functions. LGL, initially reported to down-modulate B cell differentiation and CD4+ T cell proliferation, inhibit the CD8+ T cell or NK cell cytotoxic activity.11,12,13,14 In contrast, they can also mediate a killer cell activity after non-specific activation, or develop a peptide-specific cytotoxicity.15 Our group recently reported the case of a chronic myeloid leukemia (CML) patient, for whom in vivo LGL expansion following allo-SCT was associated with a sustained complete molecular remission.16 In the present report, we performed a retrospective analysis of all LGL proliferation cases occurring following allo-SCT among 201 consecutive patients transplanted over a 7 year period in a single institution for different hematological and non-hematological malignancies. The aim of the study was to describe clinical features associated with LGL expansion following allo-SCT.
Patients and methods
Between January 1994 and January 2001, 201 consecutive adult patients received an allo-SCT at the Institut Paoli-Calmettes (Marseille, France), for different hematological and non-hematological malignancies. Among these patients, 152 patients were transplanted using a standard myeloablative preparative regimen. The remaining 49 patients received a reduced or so-called non-myeloablative regimen, according to a protocol ongoing since 1998.17 Briefly, the myeloablative regimens were based on an association of high-dose alkylating agents (cyclophosphamide, melphalan, busulfan) with, or without total body irradiation, whereas the reduced intensity regimen consisted of a combination of fludarabine, busulfan and anti-T lymphocyte globulin (ATG).17 Supportive care included antibacterial prophylaxis and oral digestive decontamination. Pneumocystis carinii prophylaxis included trimethoprim/sulfamethoxazole administered pre-transplantation, and as soon as the ANC exceeded 0.5 × 109/l. Prophylaxis against herpes simplex virus (HSV) included intravenous acyclovir. Allo-SCT patients in our center are submitted to peripheral blood counts at least once a week after initial discharge, and at least once a month within the first year. During this 7 year period, six patients were diagnosed with an LGL expansion in their peripheral blood and bone marrow, according to standard morphological and phenotypic criteria.18 Although few cases of LGL expansion below 2 × 109/l have been reported,19 only patients presenting a significant number of lymphocytes (>2 × 109/l) with LGL features were retained in this study as presenting a LGL expansion.20 Morphological analysis of LGL was carried out on peripheral blood mononuclear cells and marrow aspirates and was systematically reviewed by two independent pathologists (DS and CA). The following monoclonal antibodies were used for immunophenotyping according to standard procedures:21 CD2, CD3, CD4, CD8, CD14, CD16, CD25, CD28, CD45 RA, CD45 RO, CD56, CD57, anti-HLA-DR and a panel of commercially available anti-Vβ segments for clonality determination.
The major clinical features of the patients are summarized in Table 1. One of these cases (UPN 3) has been previously reported.16 Prior to allo-SCT, two patients (UPN 4 and 6) had received in the course of their disease an autologous peripheral blood stem cell transplantation. All donors were HLA-compatible siblings. Three donor–recipient pairs were sex-mismatched. Patients were assessed systematically twice a week for CMV infection using an antigenemia assay, in order to initiate ganciclovir pre-emptive therapy. Apart from patient UPN 6, all donor–recipient pairs were CMV seropositive prior to transplantation. At time of LGL diagnosis, all six patients were in full donor chimerism as assessed by FISH analysis on blood smears in sex-mismatched pairs, and VNTR analysis in other pairs. Patient UPN 6 received peripheral blood stem cells, whereas all other patients received a bone marrow graft. In addition, the bone marrow graft of patient UPN 1 was CD34+ immunoselected. The median number of CD34+ and CD3+ cells infused were 1.74 × 106/kg (range, 1.11 to 10.66 × 106/kg) and 18.96 × 106/kg (range, 0.04 to 509.70 × 106/kg), respectively. The median number of CD3+/CD4+, CD3+/CD8+ and CD3−/CD56+ cells contained in the graft were 9.35 × 106/kg (range, 0.03 to 304.74 × 106/kg), 7.35 × 106/kg (range, 0.02 to 178.55 × 106/kg) and 2.57 × 106/kg (range, 1.58 to 36.59 × 106/kg), respectively.
Higher frequency of LGL following reduced-conditioning regimens
During a 7 year follow-up period in this unicentric cohort study, we identified six patients with a significant LGL expansion, among 201 patients who underwent allo-SCT. The median time for LGL expansion following allo-SCT was 295 days (range, 75–450). In serial peripheral blood and bone marrow samples, abnormal lymphoid cells were mainly large in size, showing round to indented nuclei with coarse chromatin and azurophilic cytoplasmic granules (data not shown). Immunophenotypic analysis, revealed that these cells were CD8 and CD57 positive in all cases and oligoclonal in two cases (UPN 1 and 5). LGL were positive for CD2, CD3 and negative for CD16 and CD56. LGL were also dimly positive for the IL-2 receptor CD25. CD8+CD57+ LGL displayed the late activation marker HLA-DR and were CD45RA positive. CD28 expression was negative. These morphological and immunophenotypic features were consistent with LGL of T lineage in all cases. No specific features or differences in acute or chronic GVHD could be distinguished among these six patients with LGL expansion following allo-SCT as compared to other allo-SCT patients. Two patients (UPN 1 and 4) experienced cutaneous acute GVHD followed by a progressive chronic GVHD. One patient (UPN 3) developed a grade III acute cutaneous GVHD which rapidly responded to steroids in addition to cyclosporin A. Two patients (UPN 2 and 5) had de novo chronic GVHD (Table 2). At time of LGL diagnosis, one patient (UPN 2) was asymptomatic. The other most common symptoms at diagnosis were mild to severe peripheral blood cytopenia, noted in four patients. Two patients (UPN 3 and 5) experienced severe neutropenia associated with a septicemia. In addition, UPN 5 experienced a recurrent severe hemolysis. Although thrombopenia was also observed, no severe hemorrhagic events were diagnosed. At time of cytopenia, global hypoplasia was the major feature observed on bone marrow aspirates. In addition to peripheral cytopenia, associated co-morbid conditions for this cohort are shown in Table 3. Variable autoimmune manifestations were also noted. UPN 1 experienced a long-lasting painful diffuse polyarthritis with a positive rheumatoid factor, whereas UPN 6 had a histology proven granulomatous hepatitis concomitant with LGL diagnosis. Two patients (UPN 1 and 3) had a monoclonal and an oligoclonal hypergammaglobulinemia, respectively (Table 3). Finally and interestingly, four out of these six cases of LGL expansion occurred following a reduced conditioning regimen, whereas the two remaining cases (UPN 1 and 2) occurred following a myeloablative regimen.
LGL expansion is associated with viral infections
A viral infection was documented in four patients in this series (Table 2). Three patients (UPN 1, 3 and 4) experienced two close episodes of blood CMV infection as evidenced by positive blood antigenemia. These three patients rapidly responded to appropriate ganciclovir preemptive therapy. At time of CMV infection, no abnormal lymphoid cells were seen on peripheral blood smears from these patients. The median time between CMV infection and LGL expansion was 336 days (range, 66–339). None of these patients developed a CMV disease. Patient UPN 5 had severe recurrent oral and anal HSV infection, despite long periods of prophylactic acyclovir therapy. At time of LGL expansion diagnosis, none of the patients had a concurrent CMV infection. However, patient UPN 1 had a VZV reactivation concomitant with LGL expansion.
Treatments and outcome
At time of this analysis, the median follow-up for all six patients was 890 days (range, 331–1523) and the median follow-up following LGL proliferation was 429 days (range, 30–1341) (Table 3). Three patients (UPN 2, 4 and 6) have required no LGL specific therapy, and remain asymptomatic, with persistent circulating LGL in two cases. The three remaining patients (UPN 1, 3 and 5) have required therapy, either at initial presentation (UPN 3), or during subsequent follow-up (UPN 1 and 5). Long-lasting symptomatic polyarthritis required the initiation of corticosteroid therapy in patient UPN 1, with significant efficacy on clinical symptoms and decrease without complete disappearance of circulating LGL. LGL were also suspected to be responsible for the severe neutropenia and life-threatening septicemia undergone by patient UPN 3. Therefore, this patient received corticosteroids, G-CSF and 3 days of ATG (125 mg /day) which had little effect on the percentage of circulating LGL. The same held true for patient UPN 5, where the recurrent hemolysis responded poorly to corticosteroids and ATG (Table 3). All patients remain alive and are disease-free by all measurable criteria, with good quality of life. Patient UPN 5 relapsed at day 356 post allo-SCT. This patient had no more circulating LGL at time of relapse. LGL spontaneously disappeared in patient UPN 6, but are still persistent in the four remaining patients.
The aim of this retrospective study was to shed further light on the features of LGL expansion following allo-SCT. To our knowledge, this series constitutes one of the largest single-institution surveys on this group of allo-SCT patients. Although this study was not a case–control one, it suggests that the frequency of CD8+CD57+ expanded LGL after allo-SCT may be increased when using a reduced conditioning regimen, as compared to conventional myeloablative allo-SCT. Expansion of LGL could be documented between 3 and 15 months following allo-SCT. A wide variety of clinical and biological symptoms were encountered by these patients. Hematopoiesis, with one, two or three-lineage cytopenia, seems to be a favored target for LGL. Different autoimmune manifestations were also observed. LGL proliferation appears to be associated with long-term antigenic stimulation due to recurrent multiple viral infections especially CMV. Moreover, the long-term complete remission achieved by some of these high risk patients (UPN3, 4, 5 and 6) was concomitant or followed LGL expansion.
The immune reactions between donor-derived immunocompetent T lymphocytes and host-type tumor cells are considered to be the major anti-tumor agent in allo-SCT.22 However, anti-tumoral effector lymphocytes are not yet well characterized in the allo-SCT setting. In this report, we show that a subset of T cells with morphologic and phenotypic features of LGL, can target hematopoiesis inducing mild to severe cytopenia. We could not find any graft characteristic predictive of LGL expansion. The appearance of LGL in our series is likely to be the result of long-term stimulation by alloantigens and/or viral antigens. Although the median time between CMV infection and formal LGL expansion diagnosis was long (336 days), it is possible that latent LGL expansion could have been initiated after CMV infection before being diagnosed. This finding is in line with previous reports describing LGL as more frequent following viral infection, and chronic antigen-specific stimulation of CD8+ T cells due to HIV or CMV has been associated with LGL expansion.9,23,24 Interestingly, reduced conditioning regimens proved to allow engraftment following allo-SCT with minimal procedure-related toxicity.25 However, we recently showed that this setting is associated with an increased rate of viral infections.17,26 The latter was further confirmed by other investigators,27,28 and can explain the increased frequency of LGL following reduced conditioning regimens as compared to myeloablative regimens. Such recurrent viral infections can stimulate the generation of alloantigen-specific cytotoxic T lymphocytes (CTL) coincidental with the generation of virus-specific CTL.29 These CTL were shown to be cross-reactive for allogeneic and virus-infected syngeneic target cells.29 Furthermore, CTL clones have been isolated specific for a HLA-B8 restricted Epstein–Barr virus epitope and cross reactive with the allo-antigen HLA-B44.02.30
On the other hand, accumulating evidence suggests that LGL are equipped with different costimulatory molecules that might play a role in the cytotoxic mechanisms of LGL.31 Particularly, a dysregulation of Fas/Fas-L apoptotic pathway was shown to be involved in the pathogenesis of LGL expansion.31,32,33 Fas-L concentration can be useful as an indicator of LGL activity. Soluble Fas-L levels were not determined in the sera of the patients from the current study.
In our series, the clinical correlation between LGL expansion and sustained remissions in some of these high risk patients, was intriguing. This is in line with previous studies suggesting that LGL populations can be involved in graft-versus-host reactions,34 can mediate a cytotoxic activity against neoplastic cells,8 or can be associated with solid organ allograft rejection.35,36
Besides their putative anti-tumoral activity, LGL expanded following allo-SCT in our series were also associated with adverse effects against normal hematopoietic progenitors as evidenced by the different episodes of cytopenia encountered by our patients. In such cases, the optimal therapy is unknown. Immunosuppressive therapy using corticosteroids and ATG can be attempted with variable efficacy.
The striking difference between reduced and conventional conditioning regimens is related to the high immunosuppression of the host's immunity based on fludarabine and ATG. ATG results in depletion of lymphocytes and fludarabine, besides its effects on B lymphocytes, demonstrated to inhibit the mixed lymphocyte reaction in vitro. Such reduced and highly immunosuppressive conditioning regimens may lead to a state of immune balance favorable to the emergence of specific T subsets like LGL with some adverse effects, but also a possible anti-tumoral effect. At present, the use of reduced conditioning regimens is rapidly growing in the allogeneic setting, and awareness of this increased rate of LGL expansion following allo-SCT is important because patients with unexplained cytopenias, autoimmune manifestations, or unexpected remissions may be mislabeled.
In conclusion, in this report we suggest that a high rate of LGL expansion can be encountered following allo-SCT using a reduced preparative regimen. The relationship between viral reactivation and high numbers of LGL, suggests that viral stimulation can be the signal for expansion of these cells. This issue is now under investigation by our group, to elucidate the trigger for expansion of LGL after allo-SCT and functional properties of these cells. Investigations whether donor-derived CTL show cross-reactivity against the recipient's tumor cells upon stimulation during viral infections, especially CMV are in progress, with the aim to elicit, both in vitro and in vivo, efficient specific cytotoxic effectors against tumor cells.
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M Mohty was supported by a grant from the ‘Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)’, and from the ‘Fondation de France’ (Paris, France). We thank B Calmels (CTCG, Institut Paoli-Calmettes) for helpful discussions. This work was made possible through access to the tumor cell collection of the Biothèque-Tumorothèque at the Institut Paoli-Calmettes.
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Mohty, M., Faucher, C., Vey, N. et al. Features of large granular lymphocytes (LGL) expansion following allogeneic stem cell transplantation: a long-term analysis. Leukemia 16, 2129–2133 (2002). https://doi.org/10.1038/sj.leu.2402645
- reduced conditioning
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