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Keywords:

  • chemotherapy;
  • EBV < infection;
  • monoclonal antibody;
  • organ transplantation;
  • PTLD < malignancies and long-term compilations;
  • rituximab

Summary

  1. Top of page
  2. Summary
  3. Introduction to PTLD
  4. Conventional PTLD treatment
  5. Rituximab
  6. Rituximab in management of PTLD
  7. Rituximab versus chemotherapy
  8. Conclusion
  9. References

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ and bone marrow transplantations. Rituximab (Rituxan, Mabthera), a chimeric monoclonal antibody to the CD20 antigen on the surface of B-cell lymphocytes, has been used increasingly in the treatment of PTLD. Rituximab was initially approved for the treatment of low-grade non-Hodgkin lymphomas, but multiple case studies, retrospective analyses, and phase II trials demonstrate the benefit of rituximab in PTLD. This paper reviews the current data on rituximab and its promising role in the management of PTLD.


Introduction to PTLD

  1. Top of page
  2. Summary
  3. Introduction to PTLD
  4. Conventional PTLD treatment
  5. Rituximab
  6. Rituximab in management of PTLD
  7. Rituximab versus chemotherapy
  8. Conclusion
  9. References

Post-transplant lymphoproliferative disorder (PTLD) has been broadly defined as a lymphoid proliferation or lymphoma that develops as a consequence of pharmacological immunosuppression following the solid organ or bone marrow transplantation [1]. The histologic subtypes of PTLD range from the early Epstein–Bar virus (EBV)-associated polymorphic lymphoid proliferations to EBV-positive or -negative monomorphic lymphomas of B-cell or less often T-cell origin (Table 1). The majority of cases are EBV-associated, of B-cell origin, and express CD20 antigen [2].

Table 1.  World Health Organization classification of post-transplant lymphoproliferative disease (PTLD) [1].
1. Early lesions
 Reactive plasmacytic hyperplasia
 Infectious mononucleosis-like
2. Polymorphic PTLD
3. Monomorphic PTLD
 B-cell neoplasms
  Diffuse large B-cell lymphoma
  Burkitt/Burkitt-like lymphoma
  Plasma cell myeloma
  Plasmacytoma-like lesions
 T-cell neoplasms
  Peripheral T-cell lymphoma
  Other types
4. Hodgkin-like PTLD

The pathogenesis of EBV-associated PTLD is linked to T-cell dysfunction. The suppressed EBV-specific immune response results in uncontrolled EBV reactivation in adults or primary EBV infection in children [2]. The etiology of EBV-negative PTLD, which is much less common, has not been well defined. It usually occurs later after transplant and has a worse prognosis [3].

The highest risk of developing PTLD is during the first year after transplant [4,5]. In solid organ transplant recipients, the median time of onset of PTLD is about 6 months [5,6]. In bone marrow transplant recipients, the median time of onset is about 2 months and the patients tend to have widespread disease and rapidly progressive course [5,6].

The frequency of PTLD varies depending on the type of transplant and level of immunosuppression. An analysis of 3796 solid organ transplant patients revealed that the highest frequency of PTLD was in lung transplant patients (8.2%) while renal transplant patients had the lowest frequency (1.3%) [5]. Within a group of 2030 patients after renal transplantation, higher level of immunosuppression was associated with an increased risk of developing PTLD [7]. About 30% of pediatric patients after small intestinal transplantation can develop PTLD [8].

Overall, the mortality rate for PTLD is high and has been estimated at about 60% after solid organ transplants and 80% after the bone marrow transplantation [1]. A multivariable model for survival using three adverse factors including poor performance status, monomorphic disease, and graft organ involvement was developed recently [9].

Conventional PTLD treatment

  1. Top of page
  2. Summary
  3. Introduction to PTLD
  4. Conventional PTLD treatment
  5. Rituximab
  6. Rituximab in management of PTLD
  7. Rituximab versus chemotherapy
  8. Conclusion
  9. References

There are no large, prospective, randomized trials that would provide clear guidelines for PTLD treatment. It is challenging to conduct clinical trials in a disease like PTLD because of its heterogeneity and relatively low frequency. Most of the available data on PTLD treatment comes from retrospective analyses. Three basic concepts of PTLD management include enhancement of the immune system, destruction of the lymphoma cells, and the elimination of EBV.

Reduction in immunosuppression

Reduction in immunosuppression (RI) is considered the first line therapy for PTLD [5,10]. The concept is to reconstitute the immune system by reducing the patient's immunosuppressive regimen. The technique is usually tailored to the individual patient based on their organ transplant type. In general, RI would involve deletion of azathioprine or mycophenolate mofetil and minimization of calcineurin inhibitors and steroids. The magnitude of RI is patient-specific and may be limited in those with history of organ rejection or when the graft is indispensable for survival. In kidney transplant patients, when graft rejection is compatible with life, RI can be very aggressive and one can consider complete cessation of immunosuppression.

The time to response for RI is not well defined. In one series, median time to documentation of response was found to be 3.6 weeks [5]. Patients, however, might show signs of clinical improvement within 1–2 weeks. The strategy of RI alone can result in high response rates (RR) ranging from 0% to 89% depending upon the prognostic factors such as elevated lactate dehydrogenase (LDH), multi-organ involvement by PTLD, and organ failure at the time of diagnosis [5]. At the time of PTLD diagnosis, each patient should be assessed for the likelihood of response to RI, the ability to reduce immunosuppressive medications and whether there is time for RI to take effect. Other treatments might need to be used in conjunction with RI if the patient is not a candidate for RI alone.

Chemotherapy

Conventional cytotoxic chemotherapy which has been shown to be curative for many lymphomas in non-PTLD setting can be administered to PTLD patients who fail or are not amenable to RI. In certain aggressive PTLD subtypes (i.e. Burkitt lymphoma-like disease), conventional cytotoxic chemotherapy is used as the first line treatment as less aggressive approaches appear ineffective [11,12].

Various multi-drug regimens such as CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) have been used in PTLD patients [13–19]. In spite of the high RR up to 70%, the associated toxicity is significant and includes treatment-related deaths in about 25% of patients [15,16,20]. The high mortality of the standard chemotherapy regimens in the PTLD population might occur because of various factors including baseline pharmacologic immunosuppression, graft dysfunction, and colonization with resistant or hospital acquired infectious organisms.

Attempts have been made to reduce the toxicity of conventional chemotherapy by decreasing the intensity of chemotherapy doses and by empiric use of colony-stimulating growth factors (G-CSF) to prevent neutropenia [21,22].

Antiviral agents

Targeting EBV by antiviral agents such as ganciclovir or acyclovir has been attempted for prophylaxis and treatment of PTLD [23–25]. In order to prevent development of PTLD, 18 high-risk pediatric patients after liver transplant received 100 days of i.v. ganciclovir at 6–10 mg/kg/day [25]. None developed PTLD as opposed to the 10% PTLD in historical controls [25]. In 198 adult patients who received either ganciclovir or acyclovir during immunosuppressive therapy with antilymphocyte globulin, only 0.5% developed PTLD as opposed to 7% in historical controls [26]. It is difficult to make conclusions based on the limited number of these non-randomized studies as the definition of ‘high-risk’ patients and the dosing are inconsistent.

It is unlikely that antiviral agents would be effective as a monotherapy for treatment of PTLD [27]. The latent EBV-infected B-cells which carry EBV genome and express a limited number of viral proteins are not eliminated by the use of antiviral agents. However, arginine butyrate, which selectively activates the EBV thymidine kinase gene in latently EBV-infected human lymphoid cells and tumor cells, was used in combination with ganciclovir in six patients with PTLD, who were resistant to conventional radiation and/or chemotherapy [28]. The combination produced complete responses (CR) in four of six patients, with a partial response (PR) occurring in the fifth patient [28]. Infusion of patient-derived EBV-specific T-cells is being developed for management of patient with EBV-associated PTLD [29,30].

Other PTLD therapies

Non-specific immune stimulants such as interferon-alpha can enhance immune system in patients with PTLD [13]. However, interferon use has the unfortunate side effect of inducing frequent concurrent allograft rejection and is not widely employed. Other treatment modalities such as external beam radiation and surgery can be used in settings of localized PTLD [5,13].

Monoclonal antibodies

Monoclonal antibodies have an important role in management of hematological malignancies. In PTLD, these agents are attractive because of their low immunosuppressive properties, targeting of lymphocyte and potential activation of the immune system. Successful monoclonal antibody therapy for the treatment of PTLD was first reported with the use of two murine monoclonal antibodies against B-cell antigens (CD21 and CD24) [31,32]. The treatment was tolerated well in all 58 patients enrolled in the multicenter study and 36 (61%) patients achieved CR [32]. With median follow-up of 61 months, the overall survival (OS) was 46% [32]. While the anti-CD21 and anti-CD24 antibodies were not developed commercially, they set the ground work for the monoclonal antibodies in use today.

Rituximab

  1. Top of page
  2. Summary
  3. Introduction to PTLD
  4. Conventional PTLD treatment
  5. Rituximab
  6. Rituximab in management of PTLD
  7. Rituximab versus chemotherapy
  8. Conclusion
  9. References

Structure and mechanims of action

Rituximab is a chimeric anti-CD20 IgG monoclonal antibody consisting of human constant regions linked to murine variable domains [33]. The murine Fab domain of rituximab binds the CD20 antigen, which is a transmembrane protein located on the surface of mature B-cells, but not on hematopoietic stem cells or plasma cells. The CD20 antigen is involved in the regulation of transmembrane calcium conductance and cell-cycle progression during human B-cell activation [34].

Rituximab has three potential mechanisms of action including apoptosis, complement activation, and antibody-dependent cell-mediated cytotoxicity (Fig. 1). In vitro, the binding of rituximab to the CD20 antigen initiates direct signaling leading to apoptosis of the targeted lymphocyte [35,36]. Immune-mediated mechanisms might also play a role. The importance of complement-mediated cytotoxicity was suggested by an experiment with knockout mice lacking the intact complement pathway (C1q–/–). After injection with human CD20-positive tumor cells, the knockout animals failed to respond to rituximab as opposed to the wild-type animals that were cured of the disease [37]. Antibody-dependent cell-mediated cytotoxicity is the third potential mechanism of action. The Fc portion of rituximab binds the Fc receptor of effector cells such as macrophages. As rituximab is also bound to the lymphocyte by the Fab portion, it brings the effector cells to the contact with the lymphocyte. The effector cells are then activated, which result in cellular killing of the lymphoma cells. This theory is supported by data from an animal model with Fc receptor-deficient mouse, in which rituximab had significantly diminished activity [38]. Also, it has been demonstrated that Fcγ receptor polymorphisms affect the affinity for the Fc portion of rituximab and can have an impact on the time to progression in patients with follicular lymphoma who were treated with rituximab [39–41]. New anti-CD20 antibodies are being developed with re-engineered Fc portions to enhance the efficacy of rituximab by increasing the binding affinity to the Fcγ receptor [42].

image

Figure 1. Rituximab: three potential mechanisms of action include apoptosis, complement activation and antibody-dependent cell-mediated cytotoxicity.

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Indications and administration

Rituximab was first approved for the treatment of relapsed low-grade CD20-positive non-Hodgkin lymphomas with reported overall RR up to 50% and CR rates of 5% [43]. However, duration of response in patients with low-grade lymphoma is limited with medium time to progression of 13 months [43]. Since the initial approval, it has been widely used as a single agent or in combination with chemotherapy regimens for the treatment of various CD20-positive hematological malignancies [44–48].

Rituximab also has an expanding role in management of various non-malignant diseases, especially autoimmune conditions including rheumatoid arthritis [49], Sjögren's syndrome [50], systemic lupus erythematosus [51], myasthenia gravis [52,53], autoimmune hemolytic anemia [54,55], and idiopathic thrombocytopenic purpura [56]. In these diseases, it is assumed that B cells play a critical role in the autoimmune process. In transplant patients, several small, non-controlled studies and case reports demonstrated the benefit of rituximab in management of humoral allograft rejection [57–59].

Rituximab is usually administered as a slow i.v. infusion weekly for four doses. As opposed to many chemotherapy agents, it does not require adjustments for lung, kidney, liver, or heart dysfunction. It is recommended to premedicate patients with acetaminophen and antihistamine before each infusion to prevent infusional reactions. If the patient experiences adverse reactions related to rituximab, they usually occur during the first administration. In subsequent infusions, reactions are milder in intensity or do not arise at all [43].

Mild reactions during the infusion (flu-like symptoms, fever, chills, rigors, nausea, headache, and rash) can be treated symptomatically. Rarely, more serious reactions such as angioedema, hypotension, bronchospasm, and hypoxia can occur, usually within 30–120 min of beginning the first infusion. At that time, rituximab should be stopped and supportive care initiated. After resolution of all symptoms, the infusion can be restarted at slower rate.

As of 2004, over 540,000 patients received rituximab world-wide [60]. In a few lymphoma patients, rituximab therapy resulted in major complications including tumor lysis syndrome, infusion-related death, mucocutaneous reactions, delayed neutropenia, and lung injury, but none of these exceeded 0.5% in post-marketing safety data analysis [60]. As rituximab affects both the malignant and non-malignant CD20-positive B cells, there are concerns about infectious complications from the therapy. Despite B-cell depletion for approximately 6 months, immunoglobulin levels remain stable after one cycle of treatment with rituximab in lymphoma patients [45]. Extended use of the drug may result in some decrease of IgM levels [61]. However, patients receiving maintenance rituximab for non-Hodgkin lymphoma were not reported to have an increased infection rate after 2 years of continuous B-cell suppression [47].

There have been case reports of hepatitis B virus (HBV) reactivation resulting in liver failure [62], fatal varicella-zoster infection [63], and pure red cell aplasia because of parvovirus B19 [64] in follicular lymphoma patients treated with rituximab. These events, however, are rare.

Data on safety of rituximab in PTLD patients are limited. Based on the multiple case reports and several phase II trials, patients with PTLD appear to tolerate rituximab as well as de novo lymphoma patients. Of note, reactivation of cytomegalovirus infection resulted in death of a PTLD patient after treatment with rituximab [65]. Those PTLD patients who have an increased risk of HBV infection should be considered for HBV screening test prior rituximab.

Rituximab in management of PTLD

  1. Top of page
  2. Summary
  3. Introduction to PTLD
  4. Conventional PTLD treatment
  5. Rituximab
  6. Rituximab in management of PTLD
  7. Rituximab versus chemotherapy
  8. Conclusion
  9. References

In 1998, Fay et al. reported the first use of rituximab in a pediatric patient with Fanconi disease who developed PTLD 6 months after the matched unrelated donor transplant [66]. The patient developed a tonsillar mass and cervical lymphadenopathy while off immunosuppression. The biopsy was consistent with polymorphic CD20-positive B-cell PTLD. Nearly all B-cell nuclei contained EBV RNA and high levels of EBV DNA were found in peripheral blood. The patient received rituximab in the standard dosing (375 mg/m2 for 4 weekly doses) and experienced tumor regression only 3 days after the first infusion. He achieved CR without relapse at 6 months [66].

Many more case reports and case series of using rituximab in PTLD in various settings appeared in the literature in the next several years [67–86]. The cases include pediatric and adult PTLD patients who underwent solid organ or bone marrow transplantations and achieved excellent results with rituximab. Most of the patients also underwent concurrent RI and some had concurrent antiviral therapy [82]. Many patients experienced clinical improvement within a few days of the first infusion [74,75,77], but in some the benefit was not seen until a few months later [76].

Most patients in the case reports were treated with the standard dose of rituximab at 375 mg/m2 once a week for four consecutive weeks. There were some exceptions to the dosing of rituximab. Five PTLD patients after intestinal transplants were treated by rituximab weekly until CR was achieved (range 3–6 months). Afterwards, the treatment intervals were extended to periods ranging from every other week to every 3 months [87]. With median follow-up of 8 months (range 3–30 months), all of these patients remained in CR and did not have major infections or complications from the ‘rituximab maintenance’ dosing [87].

The majority of the case reports describe the use of rituximab in the early onset PTLD, but it might be effective for patients with late onset PTLD. Dotti et al. presented a case series of five patients who had late onset CD20-positive PTLD (at least 2 years after a solid organ transplant) and were treated with rituximab [71]. Two patients with advanced disease had only PR, but three patients who underwent successful debulking with surgery or radiotherapy prior to rituximab had excellent clinical outcome [71].

Several larger retrospective analyses have been conducted to demonstrate the benefit of rituximab in patients with PTLD [20,87–94]. Milpied et al. reviewed 32 adult PTLD patients, after both solid transplant and bone marrow transplant, who received rituximab [94]. The majority of patients had an early onset (median time of onset 5 months) and an EBV-associated disease. In addition to RI, rituximab was used as the first line treatment in 30 patients and as a salvage treatment in two patients who failed chemotherapy. Most patients received standard 4 weekly doses of rituximab with the median time from diagnosis of PTLD to treatment of 14 days (range 1–110 days). Rituximab treatment was well tolerated and resulted in RR 69% (20 patients achieved CR). There was a better RR for early onset (76%) than late onset (47%) disease. With a median follow-up of 8 months (range 1–16 months), 24 (75%) were alive, with 15 (68%) of the rituximab responders in CR. The 1-year projected survival was 73% [94].

Gonzalez-Barca et al. [93] reviewed data on 108 adult solid organ transplant patients with PTLD including 36 patients who received rituximab. With medium follow-up of 15 months, the OS of patients treated with rituximab was significantly better than for the whole group (76% vs. 21%) [93]. In another retrospective analysis with median follow-up of 41 months, 26 PTLD pediatric patients treated with rituximab were evaluated [88]. The RR was 85% with 18 (69%) patients achieving CR [88]. The four non-responders comprised two EBV-negative cases, Burkitts-like disease, and a fulminant PTLD case at 2 months post-transplant [88]. With the mean follow-up of 41 months, the OS was 73% with one graft loss [88]. An analysis of 33 PTLD patients after allogeneic bone marrow transplant revealed that 26 patients received rituximab [92]. The results were quite striking in favor of rituximab with OS at day 180 for patients treated with rituximab at 46% as opposed to 0% for those who did not receive it. In the group of patients treated with rituximab, the mortality rates of patients with advanced disease were significantly higher (82% vs. 7%) [92].

Phase II trials confirmed the clinical benefit of rituximab in PTLD in prospective manner [88,95–98]. The RR to single agent rituximab in PTLD patients ranged from 44% to 75% with CR rate ranging from 28% to 75%. The duration of CR varied depending on the trial, but there were clearly some patients with prolonged disease-free survival after single agent rituximab. In the largest prospective trial, response assessment by computed tomography was performed at about 3 months after starting the treatment [98]. The major differences in the results of the phase II trials are likely secondary to the heterogeneity of patients enrolled, small sample sizes, and short time of follow-up.

In a multicenter, prospective phase II study, Oertel et al. [97] treated 17 adult patients with standard dose of rituximab for PTLD. The mean follow-up time was 24 months [97]. Overall, 12 (71%) patients responded. Nine patients (53%) achieved CR, with a mean duration of 17.8 months. Two patients relapsed, at intervals three and 5 months after obtaining CR. The mean OS was 37 months with 11 (65%) patients alive at the end of the study. Adverse events were rare and of low grade [97].

In a pediatric population, Webber et al. [88] studied prospectively 14 pediatric patients with refractory disease, defined as those who had relapsed disease, no response to RI, or had concomitant allograft rejection. The patients were given standard dose of rituximab at 375 mg/m2 weekly for 4 weeks with no further treatment for those with CR or for those with no response. Patients with PR received four further doses (weeks 5–8) [88]. The mean follow-up was 18 months. Out of the 12 evaluable patients in the ongoing trial, 75% achieved CR and 10 patients were alive with one graft loss. Two deaths were because of fungal pneumonia and complications from elective surgery in a patient with CR [88].

The largest prospective trial of using rituximab in PTLD was recently published by Choquet et al. [98]. This multicenter, open label, European phase II trial enrolled 46 patients with PTLD after solid organ transplantation who did not improve after RI [98]. The study included both pediatric and adult patients who were treated with standard dose of 375 mg/m2 weekly for 4 weeks. Most of the PTLD cases were of relatively late onset with only 14 (35%) patients with PTLD diagnosis <1 year after their transplantation. At day 80, the RR was 44% including 12 (28%) patients with CR. Normal LDH was a significant predictor for response. At day 360, the responses were maintained in 68% of patients. The OS rate at 1 year was 67%. Rituximab was well tolerated with only two grades three to four adverse events related to the treatment [98].

Single agent rituximab might be effective in prevention of fulminant PTLD. In a group of 49 patients after allogeneic bone marrow transplant, 17 experienced EBV reactivation as detected by positive quantitative polymerase chain reaction (more than or equal to 1000 genome equivalents per milliliter). As reactivation of the virus is thought to correlate with an increased risk of developing PTLD, these patients received ‘pre-emptive’ rituximab [99]. When compared with historical cohort with the same risk profile, this strategy showed a significant reduction in PTLD incidence and eliminated any PTLD-associated mortality [99]. In a study of 56 patients after allogeneic stem cell transplant, monitoring of EBV reactivation and CD8 positive T-cell immune response helped determine when to use rituximab before the immune response was overwhelmed by the viral burden [100].

Apart from its use as a single agent, rituximab has been reported to have chemosensitizing effect on several lymphoma cell lines, possibly by augmenting apoptosis [36,101]. Clinically, patients with CD20-positive non-Hodgkin lymphomas who receive combination treatment of rituximab with cytotoxic chemotherapy have superior outcomes when compared with cytotoxic chemotherapy alone [102]. In PTLD, a pilot trial of rituximab in addition to cyclophosphamide and prednisone was conducted in six patients with history of solid organ transplantation [18]. They received two to six courses of cyclophosphamide (600 mg/m2, on day 1 of each course) and prednisone (1 mg/kg, every 12 h for 10 doses), given every 3 weeks. The first two courses were given in combination with 4–6 weekly doses of rituximab (375 mg/m2). With median follow-up of 12.5 months (range 4–29 months), all patients responded including five patients with CR [18]. The one patient who did not achieve CR had PR, but eventually progressed and died of fulminant disease. There were no infectious complications and all allografts in surviving patients were functional [18]. Preliminary data from an ongoing phase II trial of sequential rituximab followed by CHOP chemotherapy with granulocyte colony-stimulating growth factor (G-CSF) were presented recently [22]. In the 25 evaluable PTLD patients, nine (36%) had severe infections and three (12%) died of treatment-related causes [22].

Rituximab versus chemotherapy

  1. Top of page
  2. Summary
  3. Introduction to PTLD
  4. Conventional PTLD treatment
  5. Rituximab
  6. Rituximab in management of PTLD
  7. Rituximab versus chemotherapy
  8. Conclusion
  9. References

Until recently, patients with PTLD who failed RI were treated with cytotoxic chemotherapy [15,16]. There are no prospective, randomized trials comparing chemotherapy to rituximab for patients who do not respond to RI. However, a recent retrospective study analyzed data on 35 PTLD patients who underwent treatment with rituximab, chemotherapy, or both [20]. The findings confirmed that both single agent rituximab and chemotherapy can be highly effective in patients who failed RI [20]. Both types of therapies resulted in prolonged disease-free survival and cure in a number of PTLD patients. The 22 patients who received rituximab had RR 68% with 13 (59%) patients in CR. Their median OS was 31 months. The 23 patients who received cytotoxic chemotherapy had RR 72% with 13 (57%) patients in CR and the median OS of 42 months. While rituximab was well tolerated, 26% of patients who received chemotherapy died from treatment-related toxicities [20]. An important observation in this study was that patients who failed treatment with rituximab were able to receive salvage chemotherapy later [20]. These results suggest that, when possible, rituximab should be considered first in EBV-related, CD-20-positive cases of PTLD.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction to PTLD
  4. Conventional PTLD treatment
  5. Rituximab
  6. Rituximab in management of PTLD
  7. Rituximab versus chemotherapy
  8. Conclusion
  9. References

Many case reports, retrospective analyses, and several prospective trials have demonstrated that rituximab is effective for CD20-positive PTLD in various settings (Table 2). PTLD patients can achieve long-term CR and potential cure after single agent rituximab treatment. When compared with cytotoxic chemotherapy, rituximab has comparable RR, but significantly reduced toxicity and treatment-associated mortality. Limited data suggest that patients with fulminant, advanced disease, EBV-negative or late-onset tumors are less likely to respond to single agent rituximab [20,71,92,94,98,103]. For these patients, cytotoxic chemotherapy might be necessary early in the treatment course.

Table 2.  Efficacy of rituximab in the treatment of PTLD in various settings.
ReferencePublicationTransplant type (population)nResponse
Elstrom et al. [20]Article/retrospective analysisSolid organ and bone marrow (adults)22Response rate (RR) was 68% and 13 (59%) patients had CR; when compared with patients who received chemotherapy, the RR was similar with less toxicity
Webber et al. [88]Abstract/retrospective analysisSolid organ (pediatrics)26Response rate was 75% and 18 (69%) patients had CR; four non-responders included two Epstein–Bar virus negative cases, one fulminant disease, and one Burkitts-like disease
Ferry et al. [92]Abstract/retrospective analysisBone marrow (pediatric and adult)26Overall survival (OS) at 180 days of 26 patients who received rituximab was 46% (vs. 0% for seven patients who did not received rituximab); patients with less advanced disease and low viral load had better response rate
Milpied et al. [94]Article/retrospective analysisSolid organ and bone marrow (adults)32Response rate was 69% and 20 (63%) patients had complete responses (CR); projected OS was 73% at 1 year; four patients relapsed and three died while in remission
Gonzalez-Barca et al. [93]Abstract/retrospective analysisSolid organ (adult)36The 36 patients who received rituximab had improved OS when compared with the total 108 PTLD patients (76% vs. overall 21% with median follow-up 15 months)
Morrison et al. [95]Abstract/phase II trialSolid organ (adults)8Response rate was 75% with three CRs, three PRs, one progressive disease, and one death
Horwitz et al. [96]Abstract/phase II trialSolid organ (pediatrics and adults)14Response rate was 62% (three with CRs, five with PRs); one patient had stable disease at 1 month; four patients progressed on therapy and went on to receive chemo therapy, resulting in two septic deaths
Webber et al. [88]Abstract/phase II trialSolid organ (pediatric)12Nine (75%) patients had CR, OS was 83% with median follow-up 18 months
Oertel et al. [97]Article/phase II trialSolid organ (adult)17Nine (53%) patients achieved CR, one with PR, one with progressive disease; mean OS 37 months, no severe adverse events
Choquet et al. [98]Article/phase II trialSolid (pediatric and adult)43At day 80, RR was 44% with 12 patients in CR; at day 360, responses were maintained in 68%; the treatment was well tolerated

However, for the majority of EBV-associated CD20-positive PTLD patients, we favor rituximab as the second line of treatment right after RI. Given the significant toxicity, chemotherapy is best reserved for use in patients who are ineligible or fail rituximab. In the future, trials with combination therapies involving rituximab and other immune-based treatments will hopefully improve the clinical outcome of patients with PTLD.

References

  1. Top of page
  2. Summary
  3. Introduction to PTLD
  4. Conventional PTLD treatment
  5. Rituximab
  6. Rituximab in management of PTLD
  7. Rituximab versus chemotherapy
  8. Conclusion
  9. References
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