Posttransplant Lymphoproliferative Disease: A Series of 23 Cases

Malignancy

Posttransplant Lymphoproliferative Disease: A Series of 23 Cases M.A. Martín-Gómez, M. Peña, M. Cabello, D. Burgos, C. Gutierrez, E. Sola, C. Acedo, A. Bailén, and M. Gonzalez-Molina ABSTRACT Posttransplant lymphoproliferative disease (PTLD) is a rare but clinically important disorder due to its increasing incidence and its impact on renal function and the life of the patient. Between 1979 and 2005, this center performed 1614 kidney transplants, and 23 patients had PTLD. We undertook a retrospective study, analyzing risk factors, presentation, and evolution of the disorder. The most common clinical presentation was fever and adenopathy. All cases except one received calcineurin inhibitors, and nine were treated with monoclonal or polyclonal antibodies. Serology for Epstein Barr virus (EBV) was negative in nine patients at the time of transplant, and in five it became positive on diagnosis of PTLD. The predominant disorder was non-Hodgkin’s lymphoma (NHL), either polymorphous (n ⫽ 11) or monomorphous (n ⫽ 7). The base therapy consisted of reducing or suspending calcineurin inhibitors and the addition of sirolimus and antivirals. Three patients received rituximab, and five chemotherapy. The disease progressed in 36% of the polymorphous NHL, in 67% of the monomorphous, and in 100% of the Hodgkin’s lymphoma, whereas 10 patients had remission. Renal function worsened on diagnosis in eight patients, and the graft was infiltrated in five (confirmed histologically). Five patients lost the graft and 12 died; six due to infection and five due to PTLD. Survival was worse in the patients aged over 55 years. We conclude that in most cases EBV is positive on diagnosis of the PTLD, an age older than 55 years affords a poor prognosis, and lymphocyte infiltration of the graft is common, as is worsening renal function.

P

OSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE (PTLD) is an important clinical entity because of its increasing incidence (1% to 10%, 20-fold greater than that observed in the general population) and its impact on renal function and patient life.1 A major risk factor is the degree of immunosuppression and a negative serology for Epstein Barr virus (EBV).2 Although advances in the diagnosis, classification, and treatment have been made in recent years, the overall outcome of this syndrome remains poor.3 We therefore undertook a retrospective review of patient charts, analyzing patient survival in PTLD (primary endpoint), as well as its risk factors, presentation, and evolution.

PATIENTS AND METHODS Between January 1979 and October 2005, 1614 kidney transplants were performed at Carlos Haya Hospital, Malaga, of whom 23 (1.3%) were later diagnosed with PTLD. In all cases except one, it was the first transplant. The median age at diagnosis was 45 years (range, From the Servicio de Nefrologı´a (M.A.M.-G., M.P., M.C., D.B., C.G., E.S., M.G.-M.), Anatomía Patológica (C.A.), and Hematologı´a (A.B.), Hospital Universitario Carlos Haya, Malaga, Spain. Address reprint requests to Dra. Marı´a Adoración Martı´n Gómez, Hospital Universitario Carlos Haya, Avda. Carlos Haya 82, 29010 Malaga, Spain. E-mail: [email protected]

0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.08.050

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Transplantation Proceedings, 38, 2448 –2450 (2006)

23 CASES OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE 17– 43 years), and seven patients (30%) were older than 55 years. There were 17 (74%) male patients. The underlying disease varied: three renal polycystosis, four hydronephrosis, eight glomerulonephritis, one Alport syndrome, one nephronophthisis, and six not related. The previous time on dialysis ranged from 4 to 157 months (mean 42.55). The patients were homogenous regarding HLA incompatibility (data not shown). The mean follow-up was 31.23 months (range, 1–76 months). The median time from transplantation to development of PTLD was 70.91 months (range, 1–192 months). A bimodal distribution with time after transplantation was observed, with an early peak in the first years after transplantation and a second peak more than 5 years after transplantation. Early PTLD (defined as onset within the first year of transplantation) developed in six patients (26%), and late PTLD developed in 17 (74%). The clinical presentation was varied, with mononucleosislike syndrome (30.4%) and adenopathy (26%) predominating; less frequent were abdominal pain (13%), fever and constitutional syndrome (13%) or splenomegaly (4.3%); in 4.3% it was general malaise. No patient had symptoms related to a mass effect. A similar percentage (39%) of patients had localized (in one organ) and disseminated disease (more than two organs), with no differences in the early or late onset group. Among those with disseminated disease, four patients had involvement of two organs, one in three organs, and two in four organs. The systems most commonly involved, besides the lymph nodes (70.4%), were bone marrow and allograft (both 30.4%), spleen (21.7%), liver (17.4%), lung-pleura (17.4%), and gastrointestinal (8.7%). No patient had central nervous system involvement. Extranodal disease was present in 52%. The pathological diagnosis was reactive polymorphous polyclonal hyperplasia in two patients, nodular sclerosis Hodgkin’s lymphoma in two, polymorphous non-Hodgkin’s lymphoma in 11, monomorphous in seven, and hairy cell leukemia in one. According to Harris et al’s classification,2 10 patients had a low grade of malignancy (polyclonal polymorphous), four an intermediate grade (monoclonal polymorphous), and nine a high grade (monoclonal monomorphous). DHL was significantly increased (⬎500 u/mL) in 26% of the patients, and the B2 microglobulin in 9%, having no association with the disease severity. No significant changes were noted on the blood films, except in the case of hairy cell leukemia. As base immunosuppression, all patients were receiving steroids, 22 (95.6%) calcineurin inhibitors with MMF or azathioprine. No patient was receiving sirolimus at the time of diagnosis. Eleven patients (47.8%) received bolus steroids due to acute rejection. Two patients received monoclonal antibodies (one OKT3 and one basiliximab), five patients received antithymocyte globulin, and two others received OKT3 with thymoglobulin. At the time of diagnosis, five of 10 patients who had not had contact with EBV were positive. Six active EBV (IgM or PCR positive) were detected, four of them primary infections and two reactivations. Overall, serology (IgG, IgM, or PCR) was positive on diagnosis in 57%. No significant differences were found in EBV status between the groups with early and late onset (80 vs 75%, P ⫽ .489). Of the 10 patients who were negative for CMV at the time of transplant, five were positive on diagnosis (two had received prophylaxis). Three active infections were detected. Initial therapy consisted of reduction of the calcineurin inhibitors with no other intervention in two patients (9%). They achieved remission with no relapses during the follow-up time. Five patients needed suspension of the calcineurin inhibitors. Three of them achieved remission, and the other two died due to the disease. In eight patients the calcineurin inhibitors were changed to sirolimus. Three had remission, three progressed, and two are still under

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Fig 1. Kaplan-Meier graph of patient survival after diagnosis of PTLD by age at time of transplantation. treatment. Immunosuppression was suspended in five patients, all of whom lost their graft and four of whom died. Eight (35%) patients received a second intervention, which included chemotherapy in 22%, rituximab in 13%, and surgery with radiotherapy and rituximab in one patient. Of the five patients treated with chemotherapy, two had disease remission and three progression; of the three (13%) patients in whom rituximab was used, two remitted. Acyclovir was given to 16 patients and gancyclovir to six. Ten patients (43.5%) remitted, nine (39%) had progression, and two patients are still being treated. A total of 12 (52.17%) patients died: six due to the disease, five due to infection, and one due to cardiovascular causes. Eleven (48%) patients were alive at the time of the last follow-up. The mean time between diagnosis and death was 8.5 months (range, 1–24) except for the patient who died of cardiovascular causes at 72 months. The group analysis showed significant differences for age and death; the patients younger than 55 years of age surviving longer, with a log-rank of 0.0112 (Fig 1). No differences were found between death and time of disease onset (early, 30% vs late, 50%, P ⫽ .58). A clear trend to a reduced survival was found in the patients who had more than two organs involved (27% vs 60%, P ⫽ .24). The allograft was infiltrated (biopsy) in 21.7% of the patients and transplantectomy was undertaken in four. Although not significant, there was a greater incidence of graft involvement in the early-onset than the late-onset PTLD (50% vs 16%, P ⫽ .186).

DISCUSSION

Posttransplant lymphoproliferative disease is a rare complication of renal transplantation, occurring in 1% to 10% of cases1; 1.3% in our series. A total of 13 patients were EBV-positive at the time of diagnosis, six of whom had active infection. The fact that we found no significant

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differences in EBV carrier status between the early and late onset patients, unlike other studies,4 may be due to the lack of relevant data, as we were unaware of the pretransplant status in seven patients and the status at diagnosis in four patients. As expected, four of the five patients with a negative serology for EBV had disease progression and died. This agrees with most studies in that EBV-negative PTLD patients tend to have a more malignant-appearing histology that behaves more agressively.2 Almost all our patients (95.5%) were receiving calcineurin inhibitors, and half (47.8%) had received monoclonal or polyclonal antibodies. We report two times for disease onset (early/late) for prognostic purposes, as the early form has been associated with benign disease (associated also with EBV infection) and the late form with malignancy (usually EBV negative and with worse response to therapy).4 Three patients had a very early posttransplant onset months 1, 2, 3), attributed, respectively, to administration of OKT3, OKT3 and thymoglobulin, and primary EBV infection. Two of the three died. The clinical presentation was similar to that reported. The frequency of extranodal involvement (52%) coincides with the greater incidence in PTLD than in the nontransplanted population.4 In our series, graft function was altered in almost 52% of the patients and infiltration by the lymphoma was detected in 30%. Although not statistically significant, the early-onset patients had greater graft involvement and infiltration than the late-onset patients (50% vs 16%, P ⫽ .186; and 60% vs 40%, respectively). Other studies have also failed to detect significant differences for kidney transplants, though they have for other organs.4 Our overall mortality (56%) corresponds to that of many other studies (40%–70%)2 with a better prognosis for the early-onset patients (30% mortality vs 50% in the late-onset form), as seen in other series.5 In agreement with other studies,1,2 a significant difference (log-rank ⫽ 0.011) was found in survival between the different age groups at diagnosis, with survival being worse in those aged 55 years or over (Fig 1). No significant differences

were found between age at diagnosis and number of organs involved, disease malignancy, or time of disease onset that would explain the prognostic factor of age. The response to the different treatments is difficult to analyze because the group was pathologically varied. Nevertheless, based on the antiproliferative effect of sirolimus and its inhibition on EBV-infected B cells, of the eight patients treated with it, only three had disease progression. In conclusion, PTLD is an increasingly common disease in renal transplant recipients. The disease has a poor prognosis because of its high mortality and associated graft loss. The frequent need for graft nephrectomy and the increased risk of allograft rejection explain why almost 50% of kidney transplant recipients who survive PTLD eventually lose their allograft within a few months. EBV is one of the most important risk factors for the onset of PTLD and an age at diagnosis above 55 years is prognostic of a poor outcome. The reduction or withdrawal of calcineurin inhibitors is indicated to attempt to cure the disease, and addition of proliferation signal inhibitors, such as sirolimus, may be a therapeutic option for cure and graft survival.6 REFERENCES 1. Caillard S, Dharnidharka V, Agodoa L, et al: Posttransplant lymphoproliferative disorder after renal transplantation in the United States in era of modern immunosuppression. Transplantation 80:1233, 2005 2. Loren AW, Porter DL, Stadtmauer EA, et al: Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant 31:145, 2003 3. Ghobrial IM, Habermann TM, Maurer MJ, et al: Prognostic analysis for survival in adult solis organ transplant recipients with post-transplantation lymphoproliferative disorders. J Clin Oncol 23:7574, 2005 4. Ghobrial IM, Habermann TM, Macon WR, et al: Differences between early and late posttransplant lymphoproliferative disorders in solid organ transplant patients: are they two different diseases? Transplantation 79:244, 2005 5. Faull RJ, Hollett P, McDonald SP: Lymphoproliferative disease after renal transplantation in Australia and New Zealand. Transplantation 80:193, 2005 6. Panwalkar A, Verstovsek S, Giles FJ, et al: Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer 100:657, 2004