The pathologic spectrum of PTLD is heterogenous, although the majority of patients are classified as monomorphic subtype. Historically, PTLD was reported to occur at a median of 6 months from SOT (80% within 1 year),28
although recent data suggest this interval is longer.6,18,19,21
Patients with early PTLD more often express EBV, whereas late-onset disease (ie, > 12 months after SOT) is typically EBV negative.8,12,29
Among 80 patients with SOT-related PTLD treated at four centers over a recent 10-year period, we found a median time from SOT to PTLD diagnosis of 48 months, with 61% of diagnoses occurring after 1 year and 15% at 10 years after SOT. EBV-negative disease constituted 42% of patients (for which EBV status was known), which likely reflected the longer time to PTLD diagnosis.8,29
Nelson et al12
showed the incidence of EBV-negative diseases were significantly increased after 1990 versus before 1990 (23% v
2%, respectively; P
< .001), possibly as a result of changing immunosuppressive regimens as well as improved diagnostic techniques. Similar to other published reports, we found a shorter time to PTLD (ie, 11.5 months) among patients with EBV-positive disease.
Therapy of PTLD is not standardized, and treatment strategies often are tailored to specific clinical settings because of the particular SOT graft, risk of rejection, associated comorbidities, and tumor burden/disease presentation. Treatment options include RI, chemotherapy, rituximab, surgery, and radiation, or a combination of these approaches. A long-standing PTLD treatment paradigm has been to initially proceed with RI alone,13
which is associated with complete remission rates of 0% to 50%.5,9,14,30,31
Clinical factors associated with lack of response to RI include late-onset PTLD, elevated LDH, organ dysfunction, and multiorgan involvement.14,30,31
Unfortunately, these are common disease manifestations among patients with PTLD; in addition, responses to RI alone are durable in only 5% to 30% of patients.5,9,14,30
Rituximab has been evaluated as a therapy for PTLD in phase II studies and small case series,10,18,19,21–23,32,33
although it has been used primarily as a salvage therapy utilized after failure of RI (or later). In two, phase II studies of single-agent rituximab for patients who failed RI, the 1- and 2-year PFS were 30%12
respectively. In the latter trial, Gonzalez-Barca et al19
administered a second 4-week course of rituximab for patients without complete remission and found an intent-to-treat complete remission rate of 61%.19
Elstrom et al22
studied patients who received rituximab-based therapy after RI failure. The overall response rate was 68% (complete remission, 59%) for 22 patients treated with single-agent rituximab, and median OS was 31 months; EBV positivity predicted response to rituximab (P
= .014). Scant data are available that use rituximab as first-line therapy. Furthermore, few studies have evaluated the combination of rituximab with chemotherapy as first-line treatment for PTLD.20,34
In this analysis, therapy was at the discretion of the treating physicians, although RI was universally applied. Furthermore, front-line treatment included rituximab-based therapy, in conjunction with RI, for 74% of patients. Patients with bulky disease and high IPI more often received combined chemotherapy and rituximab versus rituximab alone. In addition, RI was decreased to a greater extent for patients who received rituximab and chemotherapy during treatment, in part to prevent infectious complications. However, infectious complications and other toxicities associated were still frequent, especially with chemotherapy, and this was a similar finding to other PTLD reports.14,22,35
Donor organ graft rejection with PTLD treatment has been poorly described. We identified a surprisingly high rate of solid-organ rejection, and the two most common associated factors were late PTLD and use of chemotherapy. Nonetheless, we identified 3-year PFS and OS rates for all patients of 57% and 62%, respectively. Moreover, patients who received first-line rituximab-based therapy had 3-year PFS and OS rates ≥ 70%. In addition, with 40-month median follow-up, only 9% of relapses in our series occurred beyond 1 year. This striking survival plateau has not been noted previously.
Our report confirms several prior observed prognostic factors (eg, presence of CNS disease)5,11,22,36
but also identifies new factors. Prior studies showed that EBV negativity and late PTLDs were associated with inferior survival.8,29,37
Additional factors shown to correlate with outcome include extranodal disease, PS, stage, number of disease sites, and LDH.9,11,21,38,39
On Cox regression multivariate analysis, with treatment removed from the model, we identified CNS involvement, hypoalbuminemia, and BM involvement as the most significant prognostic variables. By using these factors, we formed a survival model that predicted markedly different patient outcomes. An additional simplified model was constructed that included only BM involvement and hypoalbuminemia.
There are several potential explanations of why prognostic factors in PTLD have varied from series to series. First, most PTLD treatment reports have been single-institution studies that examined outcomes over several decades (ie, > 20 to 40 years), during which diagnostic techniques, treatment regimens, and supportive care measures have changed greatly. Second, PTLD series often include heterogenous patient populations. As an example, among the recent series by Knight et al,5
22% of patient diseases included Hodgkin's lymphoma, plasmacytoma, and mucosa-associated lymphoid tissue lymphoma histology, and 32% of patients were pediatric. Studies of pediatric patients with PTLD have reported improved outcomes compared with adult patients.36,40,41
Third, treatment approaches for patients with PTLD have varied, and few have evaluated rituximab as part of first-line management. Interestingly, it appeared that use of early rituximab-based therapy may overcome the adverse prognostic importance of BM involvement and hypoalbuminemia, although this needs to be confirmed in future PTLD studies. Fourth, different characteristics have been included in prognostic analysis. Serum albumin has been shown to be a prognostic factor associated in hematologic malignancies42–44
; however, hypoalbuminemia has not been examined previously as a prognostic factor in PTLD.
In summary, we found among a large multicenter cohort of patients with PTLD, that the use of rituximab-based therapy in conjunction with RI was associated with significantly improved survival compared with prior reports. This may be related to the use of rituximab-based therapy as first-line therapy (rather than as rescue therapy after failure of RI) in addition to improved supportive care measures. The vast majority of relapses were confined to the first year after PTLD diagnosis, and durable remissions were observed thereafter. Multivariate analysis identified variables predictive of outcome, and a simplified survival model that was based on two clinical factors was constructed; risk-stratified OS rates ranged from 89% to 11%. Furthermore, this is the first paper to identify low albumin as a strong adverse prognostic factor in PTLD. Clinical and tissue-based studies with prospective evaluation of rituximab-based therapy and prognostic factor analyses through multicenter and multinational collaborations are warranted.