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Rituximab therapy is effective for posttransplant lymphoproliferative disorders after solid organ transplantation
Results of a phase II trial
Article first published online: 7 SEP 2005
Copyright © 2005 American Cancer Society
Volume 104, Issue 8, pages 1661–1667, 15 October 2005
How to Cite
Blaes, A. H., Peterson, B. A., Bartlett, N., Dunn, D. L. and Morrison, V. A. (2005), Rituximab therapy is effective for posttransplant lymphoproliferative disorders after solid organ transplantation. Cancer, 104: 1661–1667. doi: 10.1002/cncr.21391
- Issue published online: 3 OCT 2005
- Article first published online: 7 SEP 2005
- Manuscript Accepted: 31 MAY 2005
- Manuscript Revised: 24 MAY 2005
- Manuscript Received: 28 FEB 2005
- posttransplant lymphoproliferative disorders;
- solid organ transplantation;
- extranodal disease
Posttransplant lymphoproliferative disorders (PTLD) remain an uncommon complication of solid organ transplantation with a high mortality rate reported after conventional therapies. Alternative treatments such as rituximab have been explored.
Eleven patients with PTLD, who were CD20 positive, received an intravenous dose of rituximab, 375 mg/m2, weekly × 4 weeks, repeated every 6 months for 2 years in responding patients. The median age of the patients was 56 years (range, 43–68 yrs), and 9 patients were male. The type of solid organ transplantation that these patients received included lung (five patients), kidney (four patients), heart (one patient), and kidney/pancreas (one patient). The median time from transplantation to a PTLD diagnosis was 9 months (range, 1–122 mos). Diagnostic B-cell histology was diffuse large cell lymphoma or polymorphous process. No patient had bone marrow or central nervous system involvement. Primary extranodal disease was noted in 82% of patients. Immunosuppressive therapy was decreased at the time of diagnosis.
Rituximab was well tolerated, with mild infusional blood pressure alterations noted in two patients. The median follow-up period was 10 months (range, 1–32 mos). The overall response rate was 64%, with 6 complete responses (CR), 1 partial response, 2 cases of progressive disease, and 2 deaths. The median duration of CR was 8 months (range, 2–19+ mos). The median time to treatment failure was 10 months (range, 5–25+ mos). The median survival was 14 months (range, < 1–32+ mos). Four patients were alive at the time of last follow-up.
Single-agent rituximab may offer a response and survival advantage in patients with PTLD. Further evaluation of rituximab in these disorders, potentially in combination with other therapies, is warranted. Cancer 2005. © 2005 American Cancer Society.
Posttransplant lymphoproliferative disorders (PTLD) are a serious complication arising in solid organ transplant recipients. The reported incidence varies from 1% to 20%,1–3 depending on factors such as type of immunosuppression, type of organ transplanted, and immune status for Epstein–Barr virus (EBV) infection.4–6 PTLD may be of variable histology, not always fitting International Working Formulation criteria. Most patients develop B-cell (CD20 positive) malignancies, either monoclonal or polyclonal. These malignancies tend to behave more aggressively, and in general, to have poorer outcomes than lymphomas occurring in nonimmunocompromised patients.7 Despite the use of a variety of therapies, including a reduction in immunosuppressive therapy, surgical resection, chemotherapy, and radiation therapy,8–11 mortality rates remain high. As a result of the poor response to conventional therapies in these patients, alternative treatment options such as therapy with monoclonal antibodies (MoAbs) have been tried.
Immunotherapy with MoAbs (anti-CD20, anti-CD21, and anti-CD22) has demonstrated some efficacy, offering a potentially safe and effective treatment.5, 12, 13 Rituximab, a MoAb targeted against CD20, was first approved in 1997 for the treatment of B-cell non-Hodgkin lymphoma (NHL). Although rituximab is widely used in the treatment of NHL, reports concerning the safety and efficacy of rituximab in solid organ transplant recipients with PTLD are to our knowledge limited.14–21 We report our experience with rituximab as therapy in a series of patients with PTLD after solid organ transplantation.
MATERIALS AND METHODS
Between January 1999 and July 2001, 11 patients with newly diagnosed PTLD were identified and evaluated at the University of Minnesota, Washington University School of Medicine (St. Louis, MO), and the Veterans Affairs Medical Center (Minneapolis, MN). All patients had previously undergone solid organ transplantation at one of these sites.
Each of these patients was enrolled on a protocol designed to evaluate the efficacy of rituximab in patients with PTLD. Inclusion criteria included a histologic diagnosis of PTLD of a B-cell immunophenotype (CD20 positive), with histopathologic features consistent with malignant lymphoma, and measurable disease. Patients were age ≥ 18 years, with an expected survival of ≥ 3 months, and a Cancer and Leukemia Group B performance status of 0, 1, or 2. Adequate bone marrow, renal, and hepatic function was required for study entry. Patients with human immunodeficiency virus infection, uncontrolled infection, lymphomatous meningitis, or women who were pregnant were not eligible. Patients may have received previous chemotherapy, but no chemotherapy was permitted in the 4 weeks prior to study entry, and no previous rituximab therapy.
All patients were staged using computed tomography (CT) scans of the chest, abdomen, and pelvis. Central nervous system (CNS) involvement was evaluated by lumbar puncture or a head CT scan. All patients received a bone marrow biopsy.
The primary study endpoints were disease response, duration of disease remission, time to treatment failure, and survival. Secondary endpoints were safety, hematologic toxicity, and infectious complications.
After signed informed consent was obtained from all patients, rituximab (Genentech, Inc., South San Francisco, CA) was administered as a continuous intravenous (i.v.) infusion over 1–4 hours at an initial dose of 375 mg/m2 on Days 1, 8, 15, and 22. In patients with responsive disease, this 4-week cycle of therapy was repeated every 6 months for a maximum of 4 cycles of therapy over 2 years. The pretreatment regimen was comprised of acetaminophen at a dose of 650 mg orally, diphenhydramine at a dose of 50 mg orally or i.v. 30 minutes before rituximab infusion, and antiemetics as needed. Patients were reassessed at 3-month intervals with laboratory evaluations and CT scans. No patient was lost to follow-up.
Chronic immunosuppressive therapy for the solid organ transplantation patients included combinations of prednisone, azathioprine, cyclosporine, mycophenolate, and tacrolimus, which varied by institution and care provider. No patient received OKT3. At the time of PTLD diagnosis, immunosuppressive therapy was reduced in dose or discontinued in all patients at the discretion of the primary managing physician. The concomitant use of acyclovir was also left to the discretion of the primary managing physician.22
A complete response (CR) was defined as no evidence of disease by standard laboratory, radiographic, or histopathologic parameters, which persisted for ≥ 4 weeks. A partial response (PR) was defined as a ≥ 50% decrease in the sum of the products of the perpendicular dimensions of all measurable disease sites, without the appearance of new lesions. Stable disease or no response was defined as a < 50% decrease in the sum of the products of the perpendicular dimensions of all measurable disease sites, and lasting for ≥ 8 weeks. Progressive disease (PD) was defined as a ≥ 25% increase in any lesion, the reappearance of measurable disease, a clear worsening of evaluable disease, or the appearance of any new lesions. Disease remission duration was the interval from the time of documentation of a response to the first evidence of disease recurrence or disease progression. Time to failure was the interval from the initiation of therapy to either progressive disease, disease recurrence, or death from any cause. Survival was defined as the time from PTLD diagnosis to death. Patients who went off study for disease progression or to receive other therapy were considered as treatment failures. All subjects who received at least one dose of medication were assessed for clinical safety, tolerability, and efficacy.
The planned target sample size for the current study was 14 patients. However, the study was closed after the accrual of 11 patients due to the relative success of the treatment regimen in this patient population, and the desire to build on these findings in a subsequent treatment trial. The planned statistical analysis was descriptive only.
The 11 patients enrolled in the current study were diagnosed with PTLD at a median of 9 months after solid organ transplantation (range, 1–122 mos). The patient and transplant characteristics are summarized in Tables 1 and 2. There were four kidney transplant patients, one heart transplant patient, one kidney-pancreas transplant patient, four single-lung transplant patients, and one bilateral lung transplant patient. The median age of the patients was 56 years (range, 43–69 yrs).
|Patient no.||Age at PTLD diagnosis in yrs||Gender||Type of Transplant||Time from Transplant to PTLD diagnosis in (mos)|
|Patient no.||Prednisone||Azathioprine||Immunosuppressive therapy Cyclosporine||MMF||Tacrolimus||Histology||Stage|
|1||+||+||+||—||—||Large cell||IV E|
|7||+||—||+||+||—||High-grade polymorphous||IV E|
At the time of diagnosis, two patients had disease in the transplanted organ. Disease was classified as Ann Arbor Stage I in two patients, Stage II in three patients, Stage III in three patients, and Stage IV in three patients. No patient had CNS or bone marrow involvement. Extranodal disease was found in 9 of 11 patients (82%) in the following sites: lung, stomach, small bowel, skin, liver, and spleen. Creatinine levels ranged from 1.0 to 2.6 mg/dL. Hemoglobin levels ranged from 8.3 to14.4 g/dL. The median lactate dehydrogenase (LDH) level was 518 IU/L (range, 189–1644 IU/L) (normal LDH values, 325–750 IU/L). Titers for EBV or stains by in situ hybridization were positive in six patients, negative in one patient, and not performed in four patients. Three patients received a brief course of acyclovir. Immunosuppressive therapy was reduced in dose or discontinued in all patients at the discretion of the primary managing physician. None of the patients achieved a decrease in tumor size at the time immunosuppression was decreased or discontinued or acyclovir was used. Ten of the 11 patients received rituximab as primary therapy for PTLD. One patient with small bowel involvement underwent jejunal resection and received two cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) before the initiation of rituximab.
Response and outcome data are summarized in Table 3. The median follow-up period was 10 months (range, 1–32 mos). The overall response rate was 64% (55% CR and 9% PR), with 6 CR, 1 PR, 2 cases of PD, and 2 deaths. The 2 deaths occurred in patients who died of disease progression within 1–3 weeks after the intiation of rituximab. Three patients went on to receive other therapies after initial treatment with rituximab. Patient 2, who developed disease progression while receiving initial rituximab, achieved a CR to CHOP chemotherapy (5 cycles), and was disease free at time of death from massive hemorrhage 18 months after diagnosis.10, 23 Patient 8, who achieved only a brief (3 mos) PR to initial rituximab therapy, subsequently received an infusional regimen of 4 cycles of cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE), and remained in a stable PR at the time of last follow-up, 17 months after diagnosis.24 Patient 9, who had a small bowel perforation after 3 doses of rituximab, went on to receive 4 cycles of infusional CHOPE, achieving a PR, and was alive at the time of last follow-up, 15 months after diagnosis. Of the six patients who achieved a CR with rituximab, two occurred after one cycle of rituximab and four occurred after two cycles of rituximab. No patient developed a disease recurrence during the follow-up period. The median duration of a CR was 8 months (range, 2–25+ mos). The time to treatment failure was found to range from 5 to 25+ months (median, 10 mos). The median survival of the patients was 14 months (range, < 1–32+ mos) (Fig. 1). Four patients remained alive at the time of last follow-up.
|Patient no.||Response to rituximab||Disease remission duration in mos||Overall survival in mos||Cause of deathb|
|Initial responsea||Best response|
|1||PRa||CR||25.2+||32.1+||Alive in CR|
|4||PR||CR||18.5+||25.4+||Alive in CR|
|8||PR||PR||14.9||16.8+||Alive in PR after CHOPE|
|9||PD||PD||0||14.4+||Alive in PR after CHOPE|
Rituximab was generally well tolerated with mild blood pressure changes noted in two patients. One patient had brief infusion-related hypotension that resolved with fluid administration, and the other patient developed mild hypertension during infusion that was controlled with medication.
It has been observed that the risk of malignancies in recipients of solid organ transplants is up to 100 times that of the general population when matched by age.8, 25–28 The most common malignancies found are skin or lip carcinomas followed by lymphoproliferative disorders. A number of hypotheses have been proposed to explain this trend in an excess of lymphoproliferative disorders: antigenic stimulation from the allograft, chronic immunosuppression, an oncogenic effect of immunosuppression, as well as an association with EBV infection.29 The lymphoproliferative disorders have been found to have a different histology, to be more clinically aggressive, and, in general, to result in poorer outcomes than “de novo” lymphomas.7 The overall mortality, despite treatment, of PTLD has reportedly varied from 60–81%, with a median survival of 14–19 months.7, 30
Historically, there have been a number of therapeutic approaches to PTLD. A reduction in immunosuppression has been shown to be helpful in select patients.1, 3, 8, 30 Surgical resection and radiotherapy have been implemented and shown to be effective primarily in patients with limited-stage disease.1, 3, 9 In the 1980s, acyclovir therapy was evaluated and shown to have some benefit in individuals with EBV infection.22, 23, 29 Combination chemotherapy regimens including CHOP, COMP (cyclophosphamide, vincristine, methotrexate, leucovorin, and cytosine arabinoside), and proMACE-cytaBOM (cyclophosphamide, doxorubicin, etoposide, cytosine arabinoside, bleomycin, vincristine, methotrexate, and prednisone), and CHOPE have all been used with anecdotal success.1, 3, 10, 24, 31–33 As a result of the limited efficacy noted with chemotherapy as well as the increased morbidity associated with treatment,31–35 alternative therapies have been investigated.
Rituximab is a genetically engineered chimeric murine/human MoAb directed at the CD20 antigen found on normal and malignant B lymphocytes. It initially was approved in 1997 for the treatment of recurrent or refractory low-grade or follicular, CD20-positive, B-cell NHL. B-cell MoAbs such as rituximab have demonstrated increased response rates and a decrease in morbidity in these patients when compared with conventional therapies.5, 13
As a result of the success of rituximab in low-grade NHL, this agent has been utilized in the therapy of small samples of transplant patients with PTLD. Several case reports have been described in which recipients of liver, heart, intestinal, kidney, and lung transplants have achieved a CR with single-agent rituximab (Table 4).14–21 Additional small case series have been reported. In a series reported by Ganne et al.,17 in which eight solid organ transplant recipients with PTLD were treated with rituximab therapy, seven of these eight patients achieved a CR, with one patient requiring two courses of therapy to achieve this response. All 8 patients remained alive at a mean follow-up period of 22.5 months, with 3 patients reported to be in disease remission for > 2.5 years. Preliminary reports of several larger series of patients with PTLD who were treated with rituximab have been reported in abstract form.36–40 The response rates have varied from 37–69% (median, 64%) with a follow-up of 8–32 months. Few side effects of rituximab therapy were reported from these case reports and series.
|Study||No. of patients||Type of organ transplanted||CR response||CR duration|
|Yedibela et al.14||2||Liver||2/2||Not reported|
|Verschuuren et al.15||3||Lung||3/3||2, 6, 16 mos|
|Oertel et al.16||1||Liver||1/1||6 mos|
|Ganne et al.17||8||6 Kidney, 1 kidney/pancreas, 1 liver||7/8||In 3 patients, > 2.5 yrsIn 4 patients, > 10 mos|
|Pham et al.18||1||Kidney||1/1||> 10 mos|
|Berney et al.19||5||Intestinal||5/5||Median 8 mos (range 3–30)|
|Cook et al.20||3||Lung||2/3||6, 8 mos|
|Zilz et al.21||1||Heart||1/1||10 mos|
Preliminary results of the use of rituximab in combination with chemotherapy such as CHOP (R-CHOP) also have been reported in the literature. Shammo et al.34 reported that of 7 patients with PTLD who were treated with chemotherapy (R-CHOP in 6 patients and CHOP in 1 patient), 6 achieved a CR and remained disease free at 18–60 months. In a second report, four patients received R-CHOP and three received single-agent rituximab. The mean overall survival in this group was 18 months, compared with 14 months in the 11 patients who received CHOP chemotherapy.35
In the current study, as well as in preliminary reports of other series, rituximab therapy appears to be a promising treatment for PTLD. We treated 11 patients with PTLD with rituximab, with a 64% overall response rate and a 55% CR rate reported. The median survival period was 14.5 months. Rituximab was well tolerated with few side effects in this very sick population. Based on these data, rituximab appears to be beneficial as first-line therapy for PTLD. Because it has been shown that rituximab adds to the efficacy of chemotherapy in de novo diffuse lymphoma, further studies to investigate the use of chemotherapy in conjunction with rituximab in patients with PTLD are warranted.
- 26Epstein-Barr virus (EBV) associated B cell lymphoproliferative disorders (BLPD) following bone marrow transplantation (BMT) [abstract]. Blood. 1992; 80: 138a., , , et al.
- 30Proposed prognostic model for survival in solid organ transplant recipients with post transplant lymphoproliferative disorders (PTLD) [abstract]. Blood. 2003; 102: 329a., , , et al.
- 32Efficacy of CHOP regimen as first line therapy in posttransplantation lymphoproliferative disorders (PTLD). A retrospective study on 25 cases [abstract]. Blood. 2003; 102: 496., , , et al.
- 33Phase II study of sequential reduction in immunosuppression, interferon alpha-2b, and ProMACE-CytaBOM chemotherapy for post-transplant lymphoproliferative disorder [abstract]. Blood. 2003; 102: 403a., , , et al.
- 34CHOP chemotherapy in combination with Rituxan for the management of post-transplant lymphoproliferative disorder [abstract]. Blood. 2003; 102: 2896., , , et al.
- 35Posttransplant lymphoproliferative disorder: a single centre clinicopathological study of 34 cases complicating solid organ renal transplants [abstract]. Blood. 2003; 102: 310b., , , et al.
- 36Monotherapy with the anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disease. Results of a multicentre phase II study [abstract]. Blood. 2003; 102: 413a., , , et al.
- 37Efficacy and safety of rituximab in B-cell post transplantation lymphoproliferative disorders: final results of a multicenter, open label, phase II trial [abstract]. Blood. 2003; 102: 277a–278a., , , et al.
- 40Rituximab is effective therapy for post-transplant lymphoproliferative disorders not responding to reduction in immunosuppression: a prospective trial in adults and children [abstract]. Proc Annu Meet Am Assoc Cancer Res. 2001; 20: 284a., , , et al.