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© 2001 American Society for Clinical Oncology Identification of Prognostic Factors in 61 Patients With Posttransplantation Lymphoproliferative DisordersFrom the Département d’Hématologie, Laboratoire d’hématologie, Laboratoire d’anatomopathologie, Service d’urologie et de transplantation rénale, and Service de Chirurgie Thoracique, Hôpital Pitié-Salpétrière; Service de Néphrologie and Service d’Hématologie, Hôpital Necker; Service d’Hématologie biologique, Hôpital Avicenne, Bobigny; and Département de biostatistiques et informatique médicale, U444 Inserm, Paris, France. Address reprint requests to Véronique Leblond, MD, Département d’hématologie, Hôpital Pitié-Salpêtrière, 47 boulevard de l’Hôpital, 75013 Paris France; email: veronique.leblond{at}psl.ap-hop-paris.fr
PURPOSE: Prognostic studies of posttransplantation lymphoproliferative disorders (PTLDs) are hindered by the small number of cases at each transplant center. We analyzed prognostic factors and long-term outcome according to clinical manifestations, pathologic features, and treatment and investigated the prognostic value of the non-Hodgkin’s lymphoma International Prognostic Index (IPI) in 61 patients with PTLD. PATIENTS AND METHODS: We studied 61 patients in two institutions who developed PTLD and analyzed factors influencing the complete remission and survival rates.
RESULTS: In univariate analysis, factors predictive of failure to achieve complete remission were performance status (PS) CONCLUSION: PS and the number of involved sites defined three risk groups in our population. The value of these prognostic factors needs to be confirmed in larger cohorts of patients treated in prospective multicenter studies.
POSTTRANSPLANTATION lymphoproliferative disorders (PTLDs) are a rare complication of organ transplantation. In principle, most cases occur within a year after transplantation, are associated with Epstein-Barr virus (EBV) infection, and are of B-cell origin.1 However, PTLDs are very heterogeneous tumors, and the number of cases of late onset is increasing.2 Prevention of organ rejection requires long-term immunosuppression, which places recipients at an increased risk of both infections and neoplastic diseases.3,4 PTLD is thought to be the result of a profound deficiency in cytotoxic T-cells, permitting the outgrowth of EBV-transformed B cells. Some cases of PTLD are not associated with EBV, pointing to other oncogenic pathways.2 PTLD differs markedly from non-Hodgkin’s lymphoma (NHL) in immunocompetent hosts in terms of the clinical course, pathologic findings, and treatment.5,6 PTLD characteristically has a rapid onset, aggressive behavior, and a predilection for extranodal sites and regresses partially or completely after reduction or withdrawal of immunosuppressive therapy. The entire morphologic spectrum of B-cell differentiation, from nonspecific reactive hyperplasia to large-cell lymphoma, can be observed in PTLD, together with a broad spectrum of morphologic and genotypic aspects, ranging from polyclonal polymorphic to monoclonal monomorphic.7-9 Prognostic factors remain to be identified in PTLD, and there is no consensus on treatment. The International Prognostic Index (IPI) for newly diagnosed aggressive lymphoma was recently developed on the basis of data on 3,273 previously untreated immunocompetent patients.10,11 This index is based on five adverse prognostic factors (age > 60 years; performance status > 1; lactate dehydrogenase [LDH] > normal; clinical stage > 2; and extranodal sites > 1) and distinguishes patients at initial diagnosis in terms of the likelihood of response to treatment, progression, and overall survival. An age-adjusted index based on three prognostic factors (performance status [PS], LDH, and clinical stage) has also been developed specifically to predict outcome in patients younger than 60 years of age with aggressive NHL and defines four groups: low-risk patients (0 factor), low-intermediate-risk patients (one factor), high-intermediate-risk patients (two factors), and high-risk patients (three factors). Such an index might be useful to identify patients with PTLD who are likely to have a poor outcome and who could thus be candidates for pilot trials. The aims of this study were to analyze prognostic factors and long-term outcome according to clinical manifestations, pathologic features, and treatment in 61 patients with PTLD and to assess the predictive value of the IPI.
We studied 61 patients who developed lymphoproliferative disorders after kidney (34 patients), heart (19 patients), lung (four patients), or liver (three patients) transplantation between July 1980 and March 1999 in two institutions.
Diagnostic Evaluation
Treatment
Tissue Specimens
EBV Detection Southern blot analysis. EBV DNA was detected by Southern blot analysis with Bam H1-digested DNA extracted from frozen material and a phosphorus-32–labelled probe specific for the Bam H1 W internal repeats of the virus. Positive and negative controls consisted of the EBV-positive Raji cell line and human placental DNA, respectively. Immunohistochemistry. Latent membrane protein 1 expression was detected by immunochemistry with the immunoperoxidase technique and the CS.1-4 monoclonal antibody (Dakopatts, Trappes, France) on paraffin-embedded sections.
Clonality Studies
Statistical Analysis
Population and Time to PTLD Diagnosis and Clinical Manifestations The characteristics of PTLD in the 61 patients are listed in Table 1. Only one disease site was found in 39 patients, whereas 22 patients had multiple sites. The extranodal sites comprised 17 cases of small and/or large bowel involvement, eight cases of pulmonary involvement, and five cases of hepatic involvement. The other extranodal sites were the skin, uterus, jaw, breast, and testis. According to the Ann Arbor classification, there were seven patients with stage I disease, seven with stage II, one with stage III, and 41 with stage IV, excluding the five patients with primary CNS involvement.
Pathologic Findings, Clonality, and EBV Studies Pathologic findings are listed in Table 2. Diffuse proliferation of lymphoid cells was observed in all but one case. In 40 cases, the tumors were classified as monormophic and were composed of uniform, large, noncleaved lymphocytes and immunoblasts with plasmacytic differentiation. Four cases were classified as early lesion (one case), plasmacytoma (one case), Hodgkin’s-like disease (one case), and follicular lymphoma (one case). In the other cases, the tumors were polymorphic and were composed of small lymphocytes, small and large noncleaved cells, and a large proportion of immunoblasts that often showed plasmacytic differentiation. Angiocentric lesions were associated with extensive areas of necrosis. Monoclonality was found in 45 of the 52 tumors tested. Genotypic studies were performed in 33 cases and confirmed monoclonality in 28 cases. The tumors were associated with EBV in 41 of the 56 cases tested. EBV was associated with one T-cell tumor of four tested.
Clinical Outcome The immunosuppressive regimen was modified in 54 cases and prevented disease progression in five. First-line therapy consisted of chemotherapy in 28 cases, and 14 patients entered CR. Twenty-two patients were treated with monoclonal antibodies: 12 received CD21- and CD24-specific antibodies intravenously or intrathecally, with complete remission in eight cases. Three of the seven patients treated with an anti-CD20 monoclonal antibody were cured. Infusion of anti–interleukin-6 monoclonal antibody led to complete remission in one of the three patients thus treated, but this patient relapsed 4 months later. Salvage chemotherapy was administered to 10 patients and was successful in four. Overall, 36 patients entered CR, five after a reduction in immunosuppression, one after surgery, 18 after chemotherapy, and 12 after monoclonal antibody administration. Two patients entered partial remission after chemotherapy. The outcome of the patients who responded is given in Table 3. Treatment failed in 23 patients, who either experienced disease progression or died before treatment evaluation. A total of 35 patients died, 12 in the complete response group and 23 in the failure group. Two patients are alive in partial remission. As shown in Fig 1, the median survival time in the entire group is 24 months, and the median follow-up time among the survivors is 22 months (range, 2 to 105 months).
Prognostic Factors In univariate analysis, factors predictive of failure to achieve complete remission were PS  2 (P = .0001) and nondetection of EBV in the tumor (P = .012). The number of involved sites (one site v > one) was close to statistical significance (P = .054), with a low probability of complete remission in patients with multiple-site disease. The interval between organ transplantation and PTLD (early v late onset), age (< 60 years v 60 years), the transplanted organ, LDH level, the tumor histology, clonality, and treatment modalities did not significantly influence the likelihood of achieving CR. Multivariate analysis identified only PS 2 (P = .0001) as negatively linked to CR. In univariate analysis, factors predictive of shorter survival were PS 2, the number of involved sites (one v > one), primary CNS involvement, T-cell origin, monoclonality, nondetection of EBV in the tumor, and first-line treatment based on chemotherapy. The interval between transplantation and PTLD diagnosis (> 1 year) showed a trend towards statistical significance, with an interval of more than 1 year being associated with poor survival ( Tables 4 and 5). Neither the LDH level (< N v > N) nor the Ann Arbor classification (I to II v III to IV) was associated with better survival. In multivariate analysis excluding the five patients with primary CNS involvement, PS less than two and the number of involved sites (1 v > 1) were both associated with better survival. PS and the number of involved sites together defined three groups of patients: low-risk patients (PS < 2 and < two sites), whose median survival time has not yet been reached; intermediate-risk patients (PS 2 or two or more sites), with a median survival time of 34 months; and high-risk patients (PS 2 and two or more sites), with a median survival time of 1 month (Fig 2). The IPI developed for immunocompetent NHL patients younger than 60 years was less valuable than this specific PTLD index for predicting the response rate: the probability of CR with the specific PTLD index in the three above-defined groups was 86%, 64% and 9%, respectively (P = .004), compared with 100%, 79%, 55% and 31% with the IPI index in low-risk, low-intermediate risk, high-intermediate-risk, and high-risk patients (P = .058). The IPI index also failed to identify patients with better survival ( Fig 3).
PTLD in organ transplant recipients is a clinically and morphologically heterogeneous group of lymphoid proliferation syndromes. The small number of cases occurring in each transplant center and the lack of a reliable classification have hindered studies of the incidence, treatment, and prognosis of PTLD. The present study was aimed at identifying factors predictive of remission and survival in patients with PTLD after organ transplantation and to determine the prognostic value of the IPI in this immunodepressed population. Risk factors for partial or no remission were multiple site disease, PS 2, and nondetection of EBV in the tumor. Multivariate analysis of factors influencing the CR rate identified only a negative link with performance status. Treatment modalities were not predictive of complete remission. The factors influencing survival were the interval between transplantation and PTLD diagnosis, the number of involved sites, primary CNS involvement, PS, T-cell origin, clonality, detection of EBV, and treatment with chemotherapy. Armitage found that the mortality rate in late-onset PTLD was higher than in early-onset PTLD, and that late-onset PTLD was often disseminated.6 Late-onset PTLD, which is mainly monoclonal, points to pathogenic mechanisms other than EBV oncogenicity. Secondary oncogenic events such as bcl-2 or bcl-6 rearrangements, C-myc, N-Ras, and p53 mutations, and LMP1 deletions when EBV is associated with the tumor, could be responsible for true lymphomas and have been shown to be associated with poor survival.9,23,24 The number of disease sites correlates better with tumor burden than does the Ann Arbor stage. Many patients have extranodal disease, explaining the large number of patients in stage IV of the Ann Arbor classification in this series. Nalesnick et al7 showed that a single disease site was associated with a better prognosis than was multiorgan disease. These results are similar to those of Benkerrou et al,25 who, in a large cohort of patients treated with anti–B-cell monoclonal antibodies, found that tumor burden was the only variable that contributed significantly to poor survival. As in immunocompetent patients, PS was a strong prognostic factor, in both univariate and multivariate analysis, for CR and survival, reflecting the patient’s response to the tumor and the patient’s ability to tolerate intensive therapy. As in other series, primary CNS PTLD had a negative influence on survival. Penn and Porat26 reported an 88% mortality rate within the first 6 months after PTLD diagnosis in patients with CNS involvement. A reduction in immunosuppressive regimen does not seem to be effective when PTLD involves the CNS. Furthermore, the CNS is inaccessible to intravenous monoclonal antibodies, and many conventional antitumoral drugs fail to cross the blood-brain barrier. Contrary to NHL in immunocompetent patients, the LDH level (> N) did not seem to modify survival directly in our series, elevated values probably reflecting frequent tumor necrosis more than tumor burden. However, this result conflicts with the report of Horwitz et al27 in which it is stated that elevated LDH was a strong significant factor for freedom from progression in a series of 25 patients. All of our patients with T-cell PTLD died, one in CR and three in treatment failure. The prognosis of T-cell PTLD is bad: the tumor is rarely associated with EBV and is unresponsive to reduced immunosuppression.28,29 Monoclonality has been forwarded as a factor of poor prognosis.30 Polyclonal tumors are more frequent early after the graft and are often associated with a mononucleosis-like syndrome. Pathologic findings are more often plasmacytic hyperplasia with polyclonal EBV or polymorphic PTLD with clonal EBV; no other oncogenetic events are involved in either case.8,9,16 These tumors can respond to a reduction in the immunosuppressive regimen. In this retrospective study, only five of 36 patients in complete remission (14%) entered remission after a reduction in immunosuppressive therapy. This conflicts with the literature, in which 25% of patients who entered CR did so after a simple reduction in immunosuppressive therapy. This discrepancy could be linked to the larger proportion in our series of late-onset PTLD, which is monoclonal and often not associated with EBV. We found that nondetection of EBV in the tumor was associated with a lack of response to treatment and poor survival. The present study confirms our previous report that such tumors are always monoclonal, emerge late after the graft, are disseminated, and carry a poor prognosis, pointing to other pathophysiologic mechanisms.4 It also underlines the importance of screening the tumor for EBV. The type of treatment was not predictive of complete remission, although chemotherapy was associated with poor survival. Chemotherapy used as first-line treatment led to CR in 14 of the 28 patients treated as such. The other 14 patients died, most within the first month, from toxicity or progression. Only nine patients are alive. The other patients died of other causes, except for one patient who died of relapse. Chemotherapy seems to be more sucessful in patients with monomorphic tumors that do not respond to other treatments, such as monoclonal antibodies. Swinnen et al31 described good results after chemotherapy in patients with late-onset PTLD, and Garrett et al32 reported a very good response in patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone.
IPI under 60 years, used for immunocompetent NHL patients, was less valuable in our study in predicting CR and survival than was the specific PTLD index developed here. This confirms the results of Horwitz et al27 in a series of 25 patients, but conflicts with those of Habermann et al,33 who reported that the IPI was a strong prognostic factor in 65 patients with PTLD. In our study, only PS and tumor burden significantly contributed to survival in multivariate analysis, thus defining three groups of patients: those with good prognostic factors (PS < 2 and < two sites), intermediate-risk patients (PS Taken together, these results show that the clinical prognostic factors used for NHL in immunocompetent patients are unsuited to immunosuppressed patients with PTLD. The prognostic factors identified here must be confirmed in larger cohorts of patients treated in prospective multicenter studies with homogeneous treatment strategies.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
