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© 2000 American Society for Clinical Oncology Durable Remission After Aggressive Chemotherapy for Very Late Post–Kidney Transplant Lymphoproliferation: A Report of 16 Cases Observed in a Single CenterFrom the Service de Réanimation et Transplantation; Service d’Anatomopathologie; Service d’Hématologie Adulte, Laboratoire d’Hématologie, Hôpital Necker; Département de Biostatistique et Informatique Médicale, Hôpital Saint-Louis; and Unité d’Epidémiologie des Virus Oncogènes, Institut Pasteur, Paris, France. Address reprint requests to Marie-France Mamzer-Bruneel, MD, Service de Réanimation et Transplantation, Hôpital Necker, 149 rue de Sèvres, 75743 Paris cedex 15, France; email marie-france.mamzer @nck.ap-hop-paris.fr.
PURPOSE: Posttransplant lymphoproliferative diseases (PTLDs) represent a group of potentially lethal lymphoid proliferations that may complicate the course of solid organ transplantation. Although early-onset PTLDs frequently have a favorable outcome, late-onset PTLDs behave more alike aggressive lymphoma. We report a monocentric retrospective study that focused on PTLDs occurring later than 1 year after kidney transplantation (very late–onset PTLDs) to define their incidence, clinical presentation, pathologic features, and outcome. We particularly emphasized the follow-up of patients treated with conventional chemotherapy. PATIENTS AND METHODS: The medical histories of all patients who developed very late–onset PTLD in our institution were reviewed, and diagnostic biopsy materials were retrospectively studied. RESULTS: Very late–onset PTLDs were diagnosed in 16 (1.1%) of 1,421 patients. Mean (± SD) time to tumor onset was 103.93 ± 70.88 months. Most tumors were Epstein-Barr virus–related monomorphic large-cell PTLDs of B phenotype. Ten patients received conventional chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone regimen). Two of them died within 2 months, two achieved partial remission, and six achieved definitive complete remission. Overall median survival time was 13 months and rose to 27 months in the treated group. The main cause of mortality was sepsis. None of the treated patients experienced rejection despite withdrawal of immunosuppressive treatment. CONCLUSION: Despite characteristics of aggressive lymphoma, very late–onset PTLDs after renal transplantation may respond to conventional chemotherapy. However, because a high rate of infectious complications occurred, new therapeutic strategies, such as combinations of anti-CD20 monoclonal antibodies and lower doses of chemotherapy, are warranted.
POSTTRANSPLANT lymphoproliferative diseases (PTLDs) constitute a group of potentially life-threatening complications in solid organ transplantation, occurring in 1% to 2% of kidney transplant recipients.1,2 The absolute number of cases occurring at each transplant center remains small, making it difficult to assess incidence, prognosis, and treatment.3 Moreover, PTLDs represent a clinically and morphologically heterogeneous group of lymphoid proliferations in which the pattern and timing of appearance have changed as the type of immunosuppression has been modified.4,5 Thus, it is possible to define different types of PTLDs with various natural histories and prognoses. It is now well-established that reduction or discontinuation of immunosuppressive drugs are the first options of PTLD treatment. However, using this strategy, only 25% of PTLDs exhibit complete and durable responses.1,6 Thus, it is important to devise interventional therapies. Unfortunately, despite the attempts of many authors, the lack of a reliable unequivocal classification makes the interpretation of published data difficult. Such a classification could be derived from adequate pathologic and clinical analyses. In its absence, many questions remain concerning the best treatment strategy. However, it emerges from literature that early onset PTLDs (< 1 year) frequently have a favorable outcome after withdrawal of immunosuppression or with immune modulation. Therefore, this subset is distinct from very late–onset PTLDs (> 1 year), which seem to behave more like aggressive lymphoma and may require aggressive treatment.7 Likewise, therapeutic approaches should be adapted to the stage of the lymphoma and to the performance status of the patients.2 Conventional chemotherapy was first considered less effective and more toxic in PTLDs than in immunocompetent host lymphomas because the initial mortality rates described in transplanted patients with PTLDs reached 80% after conventional chemotherapy.1 As a consequence of improved medical management of hematologic malignancies, the success of such aggressive treatment is increasing, whereas the toxicity-related mortality rate is decreasing (down to 25%) when used in selected patients with late-onset monoclonal tumors.8 We report a monocentric retrospective study that focused on very late–onset PTLD occurring after kidney transplantation in an attempt to define their incidence, clinical presentation, and pathologic features. We have particularly emphasized the follow-up of patients treated with standard conventional chemotherapy and demonstrated the feasibility and the efficacy of the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen in these cases.
Patients All cases of very late–onset PTLDs were retrieved using our local tumor registry in which all tumors diagnosed in patients who have received a kidney transplant in our institution from January 1959 to January 1999 are prospectively documented. Because virtually all the patients who received a kidney allograft at our center where subsequently observed as outpatients every 3 months, we believe that the observed incidence of PTLD was not underestimated. We focused on very late–onset PTLDs, defined as PTLDs occurring more than 1 year after renal transplantation. Early-onset PTLDs, which have not been systematically registered because of their frequent favorable outcome after reduction in immunosuppressive treatment, were excluded. We retrospectively reviewed, in detail, the medical records of patients in whom very late–onset PTLD was diagnosed by standard histopathologic criteria. Information was collected regarding age, sex, initial nephropathy, and current and previous immunosuppressive treatment, together with clinical presentation, treatment modalities, and outcome. Performance status was retrospectively assessed according to the Eastern Cooperative Oncology Group scale.9 The time between kidney allografting and PTLD onset was defined as the period between the graft and the first signs of PTLD. When PTLD was diagnosed before death, a baseline evaluation had been completed, when possible, by computerized tomographic scans of the head, lung, and abdomen together with endoscopic examination, bone marrow aspiration and/or biopsies, and lumbar puncture for CSF cytology.
Treatment
Outcome and Statistical Method
Pathologic Specimens Immunoperoxidase staining was performed on formalin-fixed sections via the avidin-biotin peroxidase complex method. The panel of antibodies included CD20, CD22, CD3, CD30, immunoglobulins kappa and lambda light chains (Dako, Copenhagen, Denmark) and Ki67 (Immunotech, Marseille, France). Staining for bcl-2 was performed as previously described15 on deparaffinized sections by the alkaline-phosphatase/antialkaline phosphatase procedure (Dako SA, Glostrup. Denmark), using a monoclonal antibody specific for bcl-2 (Dako SA). Sections snap-frozen in liquid nitrogen were available for six patients.
Immunoglobulin Gene Rearrangement Studies
Viral Studies EBV DNA presence and clonality was determined in three patients by southern blot analysis (10 µg of DNA were digested with Bgl II and BamHI/HindIII). The digested products were electrophoresed on agarose gel, transferred to a positively charged nylon membrane, and hybridized overnight with a 32P-labeled 3.2-kb Bgl II restriction fragment joining heavy probe. The presence and clonality of the EBV genome was investigated by hybridization of BamHI-digested DNA to a probe specific for the EBV genomic terminal repeat region. Frozen serum samples taken within 3 months before diagnosis of PTLD were retrospectively tested for antibodies against Kaposi’s sarcoma–associated herpesvirus (KSHV) by an immunofluorescence assay (human herpesvirus 8 immunofluorescence assay test by ABI, Columbia, MD) using Kaposi’s sarcoma line as a source of both lytic and latent KSHV-human herpesvirus 8 antigens at 1:40 serum dilution.17
Incidence From 1959 to the end of 1997, 1,421 patients received 1,629 renal transplantations in our center. During this time, very late–onset PTLDs were diagnosed in 16 human immunodeficiency virus–negative patients (1.1%). Another case of non-Hodgkin’s lymphoma was diagnosed several years after renal transplantation, but this patient was excluded because he had previously developed human immunodeficiency virus infection.
All 16 patients but one (patient no. 3), whose donor was her HLA-identical sister, had received a cadaveric kidney. There were seven males and nine females, and the mean (± SD) age at diagnosis of PTLD was 45.5 ± 9.16 years. Demographic characteristics of the patients are listed in Table 1.
Initial Nephropathy and Previous Immunosuppressive Treatments Diagnoses of initial nephropathy are listed in Table 1. They remained not precisely classified in six patients, but were rather heterogeneous for the others. It is noteworthy that four patients had received immunosuppressive treatment (chlorambucil, two patients; cyclophosphamide, two patients) previous to the graft in an attempt to stop the progression of their initial nephropathy.
Immunosuppressive Regimen Five patients received one course of OKT3 either for prophylactic induction treatment (four patients) or for the treatment of an acute rejection episode occurring 3 months after the graft (one patient). Seven patients received one course of antilymphocyte globulins either for prophylactic induction treatment (six patients) or for the treatment of an acute rejection episode (one patient). A total of nine patients had been treated for acute rejection episodes, receiving high doses of corticosteroids (seven patients), OKT3 (one patient who had received antilymphocyte globulin as prophylactic treatment), or antilymphocyte globulins (one patient who had received OKT3 as prophylactic treatment). The time to tumor onset, defined as the time between kidney allografting and PTLD onset, ranged from 13 to 250 months, with a mean (± SD) of 103.93 ± 70.88 months and a median of 85 months.
Clinical Characteristics
Pathologic Findings and Clonality Histopathologic and molecular biology findings are listed in Table 3. The vast majority of patients (12 of 16) were classified by histopathologic analysis as monomorphic large-cell PTLDs. Only two tumors were polymorphic PTLDs, one was a plasmocytoma-like PTLD and one exhibited the morphologic and immunologic characteristics of an anaplastic large-cell lymphoma of null phenotype (Fig 1). All tumors except the plasmocytoma-like and the anaplastic large-cell lymphoma had a B phenotype, even though CD3-positive cells were found in two cases as an atypical population of medium-size cells always associated with the B-cell population. Bcl-2 protein expression was found in 56% of cases and was rarely strong (one patient). A clonal population was identified by PCR in all six patients tested (patient nos. 1, 4, 6, 7, 10, and 15), but southern blot analysis showed an oligoclonal pattern in one of the four patients tested (patient no. 10).
EBV Findings EBV was present in tumor cells in 11 out of 16 patients, as assessed by either LMP1 positivity using immunohistochemistry (16 of 16 patients), or by RNA or DNA positivity using in situ hybridization (eight of 16 patients), and/or southern blot analysis (four of 16 patients). The EBV genome was detected and was clonal in three of the four patients who were analyzed by southern blot. We failed to detect EBV in five patients, but three were evaluated only by immunohistochemistry because no adequate formalin-fixed or frozen material was available for other studies. Two tumors were EBV negative with at least two methods (patient nos. 11 and 14).
KSHV Serologies
Clinical Outcome
Three patients had exclusive CNS involvement. One of them died of sepsis immediately after surgical tumor resection (patient no. 14). Another patient died within a few days of refractory intracranial pressure after a methotrexate course (patient no. 9). The third patient (no. 16), who had multiple CNS tumors and was treated with high-dose methotrexate together with intrathecal methotrexate infusion and whole-brain radiotherapy followed by high-dose aracytine, achieved partial remission. This patient is still alive 15 months after diagnosis. A systemic involvement was diagnosed in 12 living patients. Two of them died of sepsis soon after surgical tumor resection and before any other treatment (two cases of small bowel involvement responsible for intestinal perforations) (patient nos. 5 and 11). Finally, 10 patients were treated by the CHOP regimen. Nine of them had tumors classified as monomorphic large-cell PTLDs, and the other patient had a plasmocytoma-like PTLD. Two patients (20%) died of sepsis within 2 months (patient nos. 2 and 4). The following three patients (30%) achieved partial remission: patient no. 7 died of sepsis during salvage chemotherapy 20 months after diagnosis; patient no. 1 is currently alive 93 months after diagnosis despite recurrent relapses at other sites (bone, skin, colon, and brain) justifying interferon therapy, local radiotherapy, and repeated surgery; and patient no. 6 achieved complete remission after reinforcement of chemotherapy (high-dose cyclophosphamide) associated with local radiotherapy. This last patient died of sepsis and terminal posthepatitis cirrhosis 27 months after diagnosis while in complete remission. Five patients (50%) achieved primary complete remission, and no relapses were observed in this group of patients. Two of the patients died from unrelated causes. Median survival was 13 months for the whole population but rose to 27 months in the treated group. Currently, five patients are alive, three in complete remission and two in partial remission, with a median follow-up of 37 months (range, 13 to 93 months).
Evolution of Renal Function
PTLDs are well-known as potentially lethal malignant complications of solid organ transplantation. They constitute a clinically and morphologically heterogeneous spectrum of lymphoproliferative disorders that must not be considered as a whole. Unfortunately, the small number of cases occurring at each center and the lack of a reliable, unequivocal classification together with the absence of multi-institutional prospective studies make treatment decisions difficult. This study of 16 cases of PTLD differs from prior retrospective studies. First, the population is rather homogeneous, as all patients had received kidney transplantation in a single center. Second, they were treated in a relatively uniform fashion by chemotherapy. Finally, in this study, we focused only on very late–onset PTLD. This last point is of particular interest as many authors consider that the time between graft and PTLD onset could be the main prognostic factor as well as the most important parameter to discriminate therapeutic options.8,7,18 We chose the interval of 1 year because it is usually accepted as a turning point in the literature and because, despite the observation of a great number of early-onset PTLDs in our center, only one case had been registered in our local tumor registry during the first year after transplantation. All the other tumors disappeared after decreasing the immunosuppressive regimen. Thus, we currently do not even biopsy early infectious mononucleosis-like PTLDs occurring within the first months after transplantation because they generally regress spontaneously or after minimal reduction of immunosuppression. In this report, the vast majority of very late–onset PTLDs were of B-cell origin as 87.5% of the studied tumors exhibited B-cell differentiation markers. Interestingly, we did not find any T-cell origin PTLDs even though the number of such PTLDs, mostly described as late-onset PTLDs, is increasing in the literature,2,5,19,20 A strong association between EBV infection and B-cell PTLD occurring in the setting of solid organ transplantation is now well-documented.21,22 It is generally accepted that immunosuppressive therapy, on the one hand, favors primary (or reactivation of latent) EBV infection and, on the other hand, allows the growth and further transformation of EBV-infected B-cell clones through the impairment of EBV cytotoxic T-cell recognition. The in vivo role of EBV in the genesis of PTLD has only recently been demonstrated by Liebowitz,23 who showed that in EBV-positive PTLD, LMP1 expression was correlated with activation of the nuclear transcription factor NF-kappa B through interactions with intracellular proteins called tumor necrosis factor-receptor-associated factors. In our study, we failed to detect EBV in five PTLDs. In two of these tumors, including the case with null phenotype, EBER detection as well as LMP1 detection were negative. Considering the sensitivity and the specificity of the EBER in situ hybridization technique for diagnostic detection of EBV in latently infected cells,24 these two tumors are likely to be not related to EBV. Unfortunately, in the three other cases, no adequate material was available for in situ hybridization or for southern blot analysis, and thus, their EBV status could not be assessed. Indeed, the absence of detection of LMP1 in tissue sections by immunohistochemistry is clearly not sufficient to determine whether or not these tumors are related to EBV because some tumors may only express Epstein-Barr nuclear antigen 1.25 This finding of EBV-negative PTLD is, however, consistent with recent studies demonstrating an increase of such lymphomas in late occurring PTLDs,7,14,26 In these cases, KSHV serology was negative, which makes it unlikely to have played a role in the development of the PTLD, as recently described.27 In our series of patients, we did not find a strong and consistent correlation between LMP1 protein expression and bcl-2. This finding is in contradiction with data from studies on early PTLD28 that suggested lymphomagenesis of very late–onset PTLD might be caused by a different mechanism. The negativity of EBV and the high level of bcl-2 expression, whatever the expression of LMP1, may have two important clinical implications. First, high levels of bcl-2 could contribute to chemoresistance and to poor outcome in PTLD, as reported in aggressive non-Hodgkin’s lymphoma.15 Secondly, it may explain why, as reported in previous studies, late-onset PTLD usually did not respond to simple reduction (or withdrawal) of immunosuppression. In our series of patients, when very late–onset PTLD was diagnosed before death, the only delay before aggressive treatment was the period needed to determine the extent of the disease. The chemotherapy was started before we could assess the effect of reduction of immunosuppression on tumor regression. We use this strategy because in monoclonal late PTLD, even EBV-positive, reduction of immunosuppression is usually inadequate. Our results in 10 patients treated with the standard CHOP regimen seem interesting and encouraging because early mortality during first-line chemotherapy was only 20% (a result of infectious complications) and because overall mortality during chemotherapy reached only 30%, including one case during salvage chemotherapy for relapse after partial remission. Moreover, all patients surviving after chemotherapy achieved durable partial (10%) or complete (60%) remission, and none of the patients who achieved complete remission have relapsed. These results are comparable with those previously reported in heart transplant recipients8,29 and in liver transplant recipients30,31 and argue in favor of this type of strategy for very late–onset PTLD, whatever the organ transplanted. Larger studies remain necessary to confirm these results as well as to define the best chemotherapy regimen and the value of bcl-2 expression in the outcome of very late–onset PTLD. In our study, we chose the CHOP regimen because it is still considered one of the gold standard treatments for patients with intermediate- or high-grade non-Hodgkin’s lymphoma10 and because this combination, previously successfully used for PTLD,32 has no renal toxicity. In addition to chemotherapy, immunosuppressive drugs were withdrawn to avoid accumulation of toxicity of our prophylactic immunosuppressive treatment with that of chemotherapy. Azathioprine and mycophenolate mofetil, aside from their immunosuppressive effects, are myelosuppressive agents that can induce leukopenia. Moreover, cyclosporine reverts P-glycoprotein–associated multidrug resistance and may thus enhance the myelotoxicity of anticancer agents.33 Therefore, only low doses of corticosteroids were maintained (0.25 mg/kg/d). We did not reintroduce immunosuppressive drugs after chemotherapy because we could not exclude that such drugs might act as direct oncogenic factors34 and because a few cases of relapses have been described after reincreasing immunosuppressive treatment.35 None of the patients developed any acute rejection, and renal function remained stable after a long follow-up. This finding suggests that development of very late–onset PTLD requires a sufficient immunosuppressive status to protect against graft rejection. Alternatively, although Swinnen et al8 have reported severe acute rejection of cardiac transplants with the CHOP regimen, it may be sufficiently immunosuppressive in renal transplant recipients. Even though the best therapeutic strategy for PTLD remains to be defined, very late–onset PTLD, which frequently exhibits characteristics of aggressive lymphoma, nevertheless often responds to conventional chemotherapy. In renal transplant recipients, the CHOP regimen seems suitable because of its lack of renal toxicity. However, larger studies remain necessary to confirm our results. New strategies, such as combination of chimeric anti-CD20 monoclonal antibody and chemotherapy, are now under investigation with the aim of increasing the response rate to lower doses of cytotoxic agents and, thus, decreasing the high rate of infectious complications.
We thank Dr Bosq, Dr Diebold, Prof Reynes, Dr Tulliez, and Prof Zafrani for providing diagnostic biopsy materials. We also thank Nicole de Saint-Sauveur for expert technical assistance and Olivier Boucher for preparing the photomicrographs.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
