Key Points
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In a retrospective study, patients with B-cell PTLD treated with DM-R-EPOCH experienced a median overall survival of 6.4 years.
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Adverse events seen with R-EPOCH appear similar to those with R-CHOP but with lower treatment-related mortality.
Visual Abstract
Abstract
Posttransplant lymphoproliferative disorders (PTLD) are rare complications of solid organ transplantation, which carry significant morbidity and mortality. Phase 2 trials that use sequential rituximab (R) followed by R, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) have become an acceptable approach for B-cell PTLD, although it carries a high risk of treatment-related mortality (up to 11%). Many aspects of B-cell PTLD biology and patient characteristics parallel AIDS-related lymphomas in which dose-modified R, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DM-R-EPOCH) has been demonstrated to be highly efficacious and safe. In this single-institution retrospective study of (N = 101) adult transplant recipients with B-cell PTLD, 65 received DM-R-EPOCH, 8 received R-CHOP, and 17 received R monotherapy. Median progression-free and overall survival was 4.4 years and 6.4 years, respectively, for DM-R-EPOCH and 1 year and 1.1 years, respectively, for R-CHOP. Rates of neutropenia and infection were 70% and 77%, respectively, for DM-R-EPOCH, and 88% each for R-CHOP. Treatment-related mortality for patients treated with DM-R-EPOCH and R-CHOP was 4.7% and 25%, respectively. The median number of cycles of DM-R-EPOCH was 6, and between 73% and 89% of patients received a relative dose intensity of ≥80% for cyclophosphamide, etoposide, and doxorubicin. The relative dose intensity of vincristine was <80% in 56% of patients because of frequent omission for gastrointestinal involvement of PTLD. Collectively, these data suggest that DM-R-EPOCH does not lead to excessive toxicity in patients with B-cell PTLD and support the need for further prospective clinical studies.
Introduction
Posttransplant lymphoproliferative disorders (PTLDs) constitute a group of lymphoid and/or plasmacytic proliferations that arise because of immunosuppression after hematopoietic stem cell transplantation or solid organ transplant (SOT). PTLD is a rare complication of SOT, occurring in ∼2.6% of cases, the frequency varying by transplant type, with reported 5-year incidence reaching as high as 18% in patients with multivisceral transplants.1 Because of the increasing number of SOTs being performed, the incidence of PTLDs is expected to increase.2,3 Moreover, despite PTLD first being described >50 years ago, it remains a significant source of morbidity and mortality in transplant recipients.1,4
Several histopathologic subtypes of PTLD exist with varying outcomes, making PTLD a heterogenous condition. Patients with nondestructive PTLDs are often treated with reduction in immunosuppression alone.5 According to the most recent World Health Organization guidelines, destructive lesions are usually categorized as polymorphic lymphoproliferative disorder or posttransplant lymphoma (previously known as monomorphic PTLD).6 B-cell posttransplant lymphomas are most common and histologically mirror variants of lymphoma in immunocompetent hosts, such as diffuse large B-cell lymphoma (DLBCL). Destructive PTLDs often require treatment beyond reducing immunosuppression alone.5,7,8
Currently, prospective evidence to guide treatment for B-cell PTLD is limited to a few phase 2 trials, which have used rituximab (R) with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).9, 10, 11 These studies support a sequential and risk-stratified approach in which, after an initial course of R, patients are assessed by computed tomography (CT) scan and stratified to receive either further R or R-CHOP if their initial response is suboptimal. However, treatment of high-risk PTLD using R-CHOP has been unsatisfactory, with a 2-year overall survival (OS) of 59%, grade ≥3 adverse event rate of 50%, and treatment related mortality (TRM) of 8% to 11%.9,11 More recently, adding ibrutinib to either R or R-CHOP in a similar risk stratified approach failed to improve the response rate or OS.12 Hence, investigation for more effective and less toxic treatments is warranted.
In many ways, transplant recipients are similar to patients with advanced HIV/AIDS: they are immunocompromised with impaired T-cell function, receive medications that risk drug-drug interactions, often have serious comorbidities, and are at increased risk of developing cancer via impaired immune surveillance and higher oncogenic infection rates.13 Furthermore, AIDS-related DLBCL share some biologic similarities to PTLD, and R-CHOP similarly underperforms with a TRM of 14%.14 Given this, R with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) was explored by the AIDS malignancy consortium for treating AIDS-related DLBCL and demonstrated a 73% complete response (CR) rate, 2-year OS of 70%, and TRM of 9.8%.15 As such, dose-modified R-EPOCH (DM-R-EPOCH) in place of R-CHOP per the AIDS malignancy consortium may benefit patients with B-cell PTLD.
At Columbia University Irving Medical Center (CUIMC), it has become common practice to treat B-cell PTLD with DM-R-EPOCH after the findings in AIDS-related DLBCL. We report a single-center retrospective study evaluating the efficacy and safety of commonly used treatment strategies for PTLD including single-agent R, R-CHOP, and DM-R-EPOCH.
Methods
We conducted an institutional review board–approved, single-center retrospective analysis of patients diagnosed with PTLD after SOT at CUIMC. All patients aged ≥18 years who were diagnosed between January 2008 and January 2021 were included. Patients were identified by International Classification of Diseases codes and the records manually reviewed. PTLD diagnosis and subtype was confirmed by expert hematopathologists at CUIMC according to World Health Organization guidelines contemporary to the time of diagnosis.16 In addition, tumor immunophenotypic characteristics were reviewed, including results of Epstein-Barr encoding region (EBER) in situ hybridization, and CD30 and CD138 status. Patient demographics including age, sex, and race, as well as transplant characteristics including date and type of transplant, incidence of posttransplant Epstein-Barr virus (EBV) viremia and peak EBV titer measured in international unit per milliliter in either plasma or whole blood, and immunosuppressant regimen were identified using Structured Query Language (SQL) queries of the electronic medical record and manually reviewed as needed. PTLD treatment was recorded as either single-agent R, R-CHOP, R-EPOCH, or “other,” as well as the number of treatment cycles and doses received. Chemoimmunotherapy regimens were given without a preceding phase of R monotherapy. Treatment response was according to Lugano classification17 based on either positron emission tomography/CT or CT imaging and reviewed manually. Dates of disease progression and death were manually reviewed.
Data on neutropenia, thrombocytopenia, packed red blood cell and platelet transfusion, infection, renal injury, liver injury, diarrhea, tumor lysis syndrome (TLS), reduction in left ventricular ejection fraction (LVEF), and allograft rejection were collected for assessment of treatment toxicity. Patient charts were reviewed manually to determine whether an adverse event was attributable to treatment. As part of this assessment, the event must have occurred within 6 months of their last cycle of frontline therapy. To emphasize the clinical relevance of our findings, toxicity was determined with specific definitions. Neutropenia and renal and hepatic injury were graded per Common Terminology Criteria for Adverse Events, version 5.0. Infectious complications and thrombocytopenia were graded similarly but only grade ≥3 and grade ≥4 events were included, respectively. Diarrhea was defined as the need for antidiarrheal agents or hospitalization in the absence of an otherwise clear infectious culprit. TLS was defined by laboratory criteria, treatment specific to this complication, or documentation by treating physician in the electronic medical record. Reduction in LVEF was qualified by having at least a 10% reduction in this parameter by echocardiogram compared with pretreatment baseline, or the onset of new congestive heart failure. Allograft rejection was determined by review of pathologic sampling of allograft tissue; the frequency of allograft tissue sampling was variable and ranged from routinely performed (eg, as in heart transplant recipients) to only as indicated by clinical suspicion. TRM was determined individually by manual chart review.
Relative dose intensity (RDI) for R-EPOCH was calculated by determining the percentage of intended dose received assuming that 100% of the intended dose would be defined as 200 mg/m2 of etoposide, 1.6 mg/m2 of vincristine, 375 mg/m2 of cyclophosphamide, and 40 mg/m2 of doxorubicin per treatment cycle. The RDI was determined based on the number of treatment cycles a patient received rather than standardizing calculations to an expected number of delivered-treatment cycles. For example, if a patient received 2 cycles of R-EPOCH, with each cycle consisting of 200 mg/m2 of etoposide, 0.8 mg/m2 of vincristine, 375 mg/m2 of cyclophosphamide, and 10 mg/m2 of doxorubicin, then the RDI of etoposide, vincristine, cyclophosphamide, and doxorubicin would be (400/400) × 100% = 100%, (1.6/3.2) × 100% = 50%, (750/750) × 100% = 100%, and (20/80) × 100% = 25%, respectively.
Statistical analysis
Among patients treated with R-EPOCH, R-CHOP, and R monotherapy, comparison between baseline demographics and disease- and treatment-specific data were conducted with analysis of variance or Fischer exact testing, as appropriate. In patients treated with R-EPOCH, these same variables were assessed using univariate Cox proportional hazards regression and subsequently multivariate Cox proportional hazards regression, with hazard ratios (HR) along with their 95% confidence intervals (CIs) reported. Progression-free survival (PFS) was calculated from the treatment start date to the date of disease relapse/progression, with patients being censored at last follow-up or death without relapse. OS was calculated from the treatment start date to the date of death or last follow-up. In patients treated with R-EPOCH, PFS and OS analyses were also performed, stratified by EBER and CD30 and CD138 status. Both PFS and OS were estimated using the Kaplan-Meier method, with median PFS/OS (mPFS/mOS) reported along with their 95% CIs.
Results
Between 2008 and 2021, 149 patients were identified; 48 patients were excluded because they did not have pathologically confirmed PTLD (n = 23), had T-cell or classic Hodgkin lymphoma PTLD (n = 14), were aged <18 years at the time of diagnosis (n = 6), had surgical resection of disease as their only treatment (n = 4), or had insufficient records for complete review of analyzed covariates (n = 1; Figure 1).
Figure 1.
Distribution of frontline treatment strategies for PTLDs delineated by treatment strategy. Treatment regimens for B-cell PTLD included R-EPOCH, R-CHOP, R monotherapy, reduction of immunosuppression alone, or “other.” The “other” regimens included brentuximab vedotin with R (n = 2); CODOX-M (cyclophosphamide/cytarabine, vincristine, doxorubicin, and methotrexate) n = 2; dexamethasone alone (n = 1); COPDAC (cyclophosphamide, vincristine, prednisone, and dacarbazine) n = 1; high-dose methotrexate (n = 1); temozolomide, etoposide, liposomal doxorubicin, dexamethasone, ibrutinib, and R (TEDDI-R; n = 1); R-CE (R, cyclophosphamide, and etoposide) n = 1.
Baseline characteristics
A total of 101 patients were identified with a B-cell PTLD; 65 patients were treated with R-EPOCH (64.4%), 8 with R-CHOP (7.9%), 17 with R (16.8%), and 11 (10.9%) with alternative regimens (Table 1). The median age at diagnosis was 59 (18-82), 60 (18-73), and 59 (18-82) years for those treated with R-EPOCH, R-CHOP, and R monotherapy, respectively (P = .26). Males comprised 58.5% of the patients treated with R-EPOCH, 62.5% of those treated with R-CHOP, and 58.8% of those treated with R (P = 1.0). For patients treated with R-EPOCH and those treated with R-CHOP, kidney transplant was the most common SOT performed (n = 26 [40%] and n = 4 [50%], respectively), whereas in patients treated with R, lung transplant was most common (n = 7 [41.2%]); however, this difference was not significant (P = .15).
Table 1.
Baseline patient and disease characteristics
| Characteristic | R-EPOCH (n = 65) | R-CHOP (n = 8) | R (n = 17) | P value | Other (n = 11) |
|---|---|---|---|---|---|
| Median age at PTLD diagnosis, y (range) | 59 (18-82) | 60 (18-73) | 59 (18-82) | .26317 | 59 (19-82) |
| Sex, n (%) | 1.00000 | ||||
| Male | 38 (58.5) | 5 (62.5) | 10 (58.8) | 7 (63.6) | |
| Female | 27 (41.5) | 3 (37.5) | 7 (41.2) | 4 (36.4) | |
| Organ transplanted, n (%) | .15208 | ||||
| Heart | 5 (7.7) | 0 (0) | 2 (11.8) | 3 (27.3) | |
| Liver | 14 (21.5) | 0 (0) | 1 (5.9) | 3 (27.3) | |
| Kidney | 26 (40.0) | 4 (50.0) | 5 (29.4) | 4 (36.4) | |
| Lung | 18 (27.7) | 2 (25.0) | 7 (41.2) | 1 (9.1) | |
| Multiple | 2 (3.1) | 2 (25.0) | 2 (11.8) | 0 (0) | |
| EBV viremia after SOT, n (%) | 40 (61.2) | 5 (62.5) | 11 (64.7) | 1.00 000 | 9 (81.8) |
| Median peak EBV titer (range) | 922 (0-1 300 00) | 1022 (<200-1 300 000) | 922 (0-154 738) | .00 680 | 944 (<200-4252) |
| LDH ≥ ULN at time of diagnosis, n (%) | 43 (66.2) | 5 (62.5) | 13 (76.5) | .74 997 | 5 (45.5) |
| Median time from transplant to PTLD, mo (range) | 83 (1-288) | 25 (5-115) | 31 (2-207) | .24512 | 110 (5-266) |
| PTLD histology, n (%) | .00 005 | ||||
| Monomorphic DLBCL | 48 (73.8) | 7 (87.5) | 3 (17.6) | 6 (54.5) | |
| Monomorphic Burkitt | 4 (6.2) | 0 (0) | 0 (0) | 2 (18.2) | |
| Monomorphic plasmablastic | 3 (4.6) | 0 (0) | 0 (0) | 0 (0) | |
| Monomorphic mantle cell | 0 (0) | 0 (0) | 1 (5.9) | 0 (0) | |
| Monomorphic marginal zone | 0 (0) | 0 (0) | 1 (5.9) | 0 (0) | |
| Polymorphic | 10 (15.4) | 1 (12.5) | 12 (70.6) | 3 (27.3) | |
| PTLD histology markers, n (%); missing data, n (%) | |||||
| EBER | 25 (38.5); 1 (1.5) | 4 (50); 0 (0) | 14 (82.4); 1 (5.9) | .00 141 | 6 (54.5); 1 (9.1) |
| CD30 | 15 (23.1); 27 (41.5) | 3 (37.5); 4 (50) | 9 (52.9); 8 (47.1) | .00 099 | 4 (36.4); 3 (27.3) |
| CD138 | 10 (15.4); 43 (66.2) | 0 (0); 7 (87.5) | 5 (29.4); 10 (58.8) | .38 985 | 2 (18.2); 8 (72.7) |
| Median no. of IS drugs at diagnosis (range) | 2 (1-4) | 2 (2-3) | 2 (1-3) | .68 847 | 2 (1-3) |
| Reduction of IS, n (%) | 62 (95.4) | 7 (87.5) | 17 (100.0) | .44 442 | 10 (90.9) |
| Median time to treatment start, d (range) | 16 (0-78) | 27 (3-218) | 13 (0-87) | .02 902 | --- |
| Median no. of treatment cycles (range) | 6 (1-6) | 4.5 (2-6) | 6 (1-16) | .00 164 | --- |
| Started treatment electively as outpatient, n (%) | 36 (55) | 5 (62.5) | 8 (47%) | .7787 | --- |
| Patients receiving CNS prophylaxis, n (%) | 5 (7.69) | 0 (0.0) | 1 (5.56) | .44 155 | --- |
| Patients who received radiation therapy, n (%) | 1 (1.54) | 2 (25) | 3 (17.64) | .00 606 | --- |
CNS, central nervous system; IS, immunosuppression; LDH, lactate dehydrogenase; ULN, upper limit of normal.
The median time from transplant to diagnosis was similar in those treated with R-CHOP and R, being 25 (5-115) and 31 (2-207) months, respectively, and in those treated with R-EPOCH it was 83 (1-288) months, however, this difference was not significant (P = .25). Histologically, most patients who received R-EPOCH (73.8%) or R-CHOP (87.5%) had monomorphic DLBCL whereas those treated with R monotherapy had mostly polymorphic PTLD (70.6%; P < .001). Although the rate of EBV viremia after SOT was nearly identical between the 3 treatment groups, the peak EBV level was significantly different (P. =.01). It was similarly noted that the frequency of EBER in situ hybridization positivity was significantly different between these groups and positive in 38.5%, 50.0%, and 82.4% of those treated with R-EPOCH, R-CHOP, and R, respectively (P = .001). When CD30 staining was performed, it was positive in 15 of 38 (39.4%) patients treated with R-EPOCH, 3 of 4 (75.0%) patients treated with R-CHOP, and 9 of 9 (100%) patients treated with R (P = .001). CD138 staining was infrequently performed, but when done, it was positive in 10 of 22 (45.5%), 0 of 1 (0%), and 5 of 7 (71.4%) patients treated with R-EPOCH, R-CHOP, and R, respectively (P = .39).
The median number of immunosuppressive agents used pre-PTLD diagnosis was 2 in each group (P = .69), and immunosuppression was reduced in nearly all patients. The median time from diagnosis to treatment was 16, 27, and 13 days, respectively, among those treated with R-EPOCH, R-CHOP, and R (P = .03). Treatment was initiated electively on an outpatient basis in 55%, 62.5%, and 47% of patients treated with R-EPOCH, R-CHOP, and R (P=.78), respectively, whereas the remainder required treatment initiation as inpatients in either malignant hematology units or intensive care units.
Outcomes
The mPFS for patients treated with R-EPOCH was 53 months (95% CI, 44 to not reached [NR]), 12 months (95% CI, 4 to NR) with R-CHOP, and 19 months (95% CI, 4 to NR) with R monotherapy (Figure 2A-C). In those treated with R-EPOCH, neither EBER nor CD30 and CD138 status significantly affected PFS (Figure 3A-C). Overall, 14 patients who received R-EPOCH experienced disease progression. Of 14 patients, 7 experienced a CR on end-of-treatment positron emission tomography scan. In those who progressed, the median time from last dose of R-EPOCH to progression was 2 months (range, 0-73). The median number of R-EPOCH cycles was 5 (range, 2-6) in those who experienced progression compared with 6 in the total group who received R-EPOCH.
Figure 2.
Survival based on treatment regimen. (A-C) Kaplan-Meier curves for PFS in patients treated with R-EPOCH (A), R-CHOP (B), and R monotherapy (C). (D-F) Kaplan-Meier curves for OS in patients treated with R-EPOCH (D), R-CHOP (E), and R monotherapy (F).
Figure 3.
Suvival based on disease characteristics. (A-C) Kaplan-Meier curves for PFS in patients treated with R-EPOCH stratified by EBER (A), CD30 status (B), and CD138 status (C). (D-F) Kaplan-Meier curves for OS in patients treated with R-EPOCH stratified by histologic subset including EBER (D), CD30 status (E), and CD138 status (F).
The mOS for patients treated with R-EPOCH was 77 months (95% CI, 50 to NR), 13.5 months (95% CI, 8 to NR) with R-CHOP, and 28 months (95% CI, 5 to NR) with R (Figure 2D-F). Neither EBER nor CD30 and CD138 status significantly affected OS in R-EPOCH treated patients (Figure 3D-F).
In univariate analysis of patients treated with R-EPOCH, heart transplantation (HR, 3.35; 95% CI, 1.02-10.98; P = .046), lung transplantation (HR, 3.08; 95% CI, 1.35-7.04; P = .01), monomorphic plasmablastic morphology (HR, 6.37; 95% CI, 1.80-22.59; P = .004), and the number of immunosuppressive drugs at the time of diagnosis (HR, 1.20; 95% CI, 1.12-3.56; P = .02) had a significantly negative impact on PFS whereas the number of treatment cycles received (HR, 0.76; 95% CI, 0.64-0.92; P=.004) positively affected PFS. In contrast, only lung transplantation (HR, 3.92; 95% CI, 1.51-10.17; P = .005) and the number of immunosuppressive drugs at the time of diagnosis (HR, 2.38; 95% CI, 1.23-4.58; P=.01) significantly negatively affected OS whereas the number of treatment cycles received (HR, 0.76; 95% CI, 0.62-0.94; P = .01) had a significantly positive association (Table 2).
Table 2.
Univariate analysis for patients treated with R-EPOCH with respect to PFS and OS
| Characteristic | PFS |
OS |
||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | |
| Age at diagnosis | 1.002 | 0.978-1.026 | .878 | 1.024 | 0.995-1.054 | .109 |
| Male | 0.635 | 0.321-1.256 | .192 | 0.478 | 0.217-1.055 | .068 |
| Transplant type | ||||||
| Kidney | ----- | ----- | ----- | ----- | ----- | ----- |
| Heart | 3.351 | 1.023-10.979 | .046 | 3.258 | 0.811-13.086 | .096 |
| Liver | 0.729 | 0.242-2.200 | .575 | 0.893 | 0.249-3.197 | .861 |
| Lung | 3.078 | 1.346-7.035 | .008 | 3.922 | 1.512-10.173 | .005 |
| MVT | 2.291 | 0.485-10.823 | .295 | 1.515 | 0.170-13.475 | .710 |
| EBV viremia after SOT | 1.145 | 0.571-2.293 | .702 | 0.879 | 0.414-1.866 | .737 |
| Peak EBV titer | 1.000 | 1.000-1.000 | .482 | 1.000 | 1.000-1.000 | .604 |
| LDH ≥ ULN at time of diagnosis | 0.999 | 0.496-2.010 | .997 | 0.977 | 0.454-2.105 | .953 |
| Time from transplant to PTLD | 0.997 | 0.995-1.004 | .888 | 0.999 | 0.993-1.004 | .610 |
| PTLD histology | ||||||
| Monomorphic DLBCL | ----- | ----- | ----- | ----- | ----- | ----- |
| Monomorphic Burkitt | 1.708 | 0.391-7.445 | .476 | 2.103 | 0.473-9.357 | .329 |
| Monomorphic plasmablastic | 6.374 | 1.798-22.594 | .004 | 3.556 | 0.788-16.045 | .099 |
| Polymorphic | 2.014 | 0.858-4.727 | .108 | 2.148 | 0.845-5.461 | .108 |
| PTLD histology markers | ||||||
| EBER | 1.057 | 0.536-2.085 | .872 | 1.167 | 0.557-2.445 | .683 |
| CD30 | 1.314 | 0.591-2.293 | .503 | 1.245 | 0.543-2.877 | .560 |
| CD138 | 0.543 | 0.204-1.443 | .220 | 0.762 | 0.239-2.428 | .646 |
| No. of IS drugs at diagnosis | 1.998 | 1.122-3.559 | .019 | 2.376 | 1.234-4.578 | .010 |
| Time to treatment start | 1.007 | 0.984-1.029 | .570 | 1.008 | 0.984-1.034 | .511 |
| No. of treatment cycles | 0.763 | 0.635-0.917 | .004 | 0.764 | 0.620-0.943 | .012 |
| Started treatment electively outpatient | 1.224 | 0.626-2.393 | .555 | 1.248 | 0.587-2.654 | .564 |
| CNS prophylaxis | 1.889 | 0.563-6.336 | .303 | 1.037 | 0.245-4.384 | .961 |
MVT, multivisceral transplant.
Of the significant variables found in univariate analysis, multivariate analysis of PFS in patients treated with R-EPOCH showed only heart transplantation (HR, 6.78; 95% CI, 1.83-25.18; P = .004) and the number of immunosuppressive drugs at the time of diagnosis (HR, 2.14; 95% CI, 1.05-4.36; P = .036) had a significantly negative impact whereas the number of treatment cycles (HR, 0.73; 95% CI, 0.56-0.94; P = .016) had a significantly positive impact. In multivariate analysis of OS, heart transplantation (HR, 5.42; 95% CI, 1.28-23.01; P = .0.022) and the number of immunosuppressive drugs at the time of diagnosis (HR, 2.49; 95% CI, 1.17-5.28; P = .018) persisted as significantly negative detriments whereas the number of treatment cycles received (HR, 0.73; 95% CI, 0.57-0.95; P = .017) remained a significantly positive finding (Table 3).
Table 3.
Multivariate analysis for patients treated with R-EPOCH with respect to PFS and OS
| Characteristic | PFS |
OS |
||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | |
| Transplant type | ||||||
| Kidney | ----- | ----- | ----- | ----- | ----- | ----- |
| Heart | 6.780 | 1.826-25.180 | .004 | 5.418 | 1.276-23.010 | .022 |
| Liver | 0.941 | 0.298-2.974 | >.9 | 1.012 | 0.278-3.686 | >.9 |
| Lung | 1.578 | 0.611-4.070 | .3 | 2.222 | 0.802-6.153 | .12 |
| MVT | 0.668 | 0.088-5.090 | .7 | 0.625 | 0.058-6.733 | .7 |
| PTLD histology | ||||||
| Monomorphic DLBCL | ----- | ----- | ----- | ----- | ----- | ----- |
| Monomorphic Burkitt | 2.357 | 0.500-11.110 | .3 | ----- | ----- | ----- |
| Monomorphic plasmablastic | 1.313 | 0.290-5.947 | .7 | ----- | ----- | ----- |
| Polymorphic | 1.500 | 0.526-4.276 | .4 | ----- | ----- | ----- |
| No. of IS drugs at diagnosis | 2.138 | 1.049-4.357 | .036 | 2.489 | 1.173-5.279 | .018 |
| No. of treatment cycles | 0.727 | 0.560-0.943 | .016 | 0.732 | 0.566-0.946 | .017 |
R-EPOCH dosing
The RDI of the chemotherapies that constitute R-EPOCH are reported in Table 4. At least 80% of the intended dose of cyclophosphamide, etoposide, and doxorubicin was delivered in 84.2%, 73.0%, and 88.9% of patients, respectively, with 66.7% receiving a RDI of >100% for cyclophosphamide. Vincristine was a notable exception for which 55.6% of patients received an RDI of <80%. This is reflective of vincristine omission in those with luminal gastrointestinal involvement or the onset of debilitating neuropathy.
Table 4.
RDI of R-EPOCH constituent chemotherapies
| RDI, n (%) | Cyclophosphamide | Etoposide | Vincristine | Doxorubicin |
|---|---|---|---|---|
| <80 | 10 (15.9) | 17 (27.0) | 35 (55.6) | 7 (11.1) |
| 80-100 | 11 (17.5) | 44 (69.8) | 26 (41.3) | 48 (76.2) |
| >100 | 42 (66.7) | 2 (3.2) | 2 (3.2) | 8 (12.7) |
Compared with those who received an RDI of ≤100% of cyclophosphamide, those who received an RDI of >100% of cyclophosphamide experienced a significantly improved PFS (HR, 2.28; 95% CI, 1.14-4.55; P = .018) and OS (HR, 2.52; 95% CI, 1.16-5.45; P = .016; Figure 4). Those who received a cyclophosphamide RDI of >100% do not appear to have experienced an excess of toxicity (Table 5).
Figure 4.
Survival based on relative dose intensity. (A) PFS (measured in months) in patients treated with R-EPOCH who received either a cyclophosphamide RDI of ≤100% (orange; “yes”) or >100% (green; “no”). (B) OS (measured in months) in patients treated with R-EPOCH who received either a cyclophosphamide RDI of ≤100% (orange; “yes”) or >100% (green; “no”).
Table 5.
Adverse event data by cyclophosphamide RDI in R-EPOCH
| Adverse events | Cyclophosphamide RDI of ≤100% (n = 20), n (%) | Cyclophosphamide RDI of >100% (n = 42), n (%) |
|---|---|---|
| Neutropenia∗ | 14 (70.0) | 30 (71.4) |
| Grade 3-4∗ | 17 (85.0) | 23 (54.8) |
| Received pRBC transfusion | 16 (80.0) | 24 (57.1) |
| Grade 4 thrombocytopenia∗ | 4 (20.0) | 10 (23.8) |
| Received platelet transfusion | 3 (15.0) | 7 (16.7) |
| Infection∗‡ | 17 (85.0) | 31 (73.8) |
| Renal injury | ||
| Any grade∗ | 11 (55.0) | 18 (42.9) |
| Grade 3-4∗ | 2 (10.0) | 1 (2.4) |
| Liver injury | ||
| Any grade∗ | 4 (20.0) | 11 (26.2) |
| Grade 3-4∗ | 2 (10.0) | 4 (9.5) |
| Diarrhea†‡ | 4 (20.0) | 11 (26.2) |
| TLS‡ | 5 (25.0) | 3 (7.1) |
| Reduction in LVEF‡ | 1 (5.0) | 1 (2.4) |
| Allograft rejection‡ | 2 (10.0) | 1 (2.4) |
pRBC, packed red blood cell.
Grade determined by Common Terminology Criteria for Adverse Events, version 5.0, criteria.
Defined as requiring antidiarrheal medications for symptomatic control.
No grade 4 events.
Toxicity
Data on toxicity was available for review in all except 1 patient treated with R-EPOCH. Among those treated with R-EPOCH, R-CHOP, and R, hematologic toxicity and infection were the most common types of adverse event experienced (Table 6). Rates of neutropenia were 70.3%, 87.5%, and 41.2% for those treated with R-EPOCH, R-CHOP, and R, respectively. For each treatment group, most neutropenic events were grade 3/4 in severity, comprising 82.6%, 85.7%, and 71.4% of cases in patients treated with R-EPOCH, R-CHOP, and R, respectively. Packed red blood cell transfusion rates were similar between patients treated with R-EPOCH and R-CHOP, although numerically lower in the former at 62.5% compared with 75%. Grade 4 thrombocytopenia occurred in 21.9%, 12.5%, and 5.9% of those treated with R-EPOCH, R-CHOP, and R, respectively. Grade ≥3 infections were seen in 76.6%, 87.5%, and 58.8% of patients treated with R-EPOCH, R-CHOP, and R.
Table 6.
Treatment-related adverse events
| Adverse events | R-EPOCH (n = 64), n (%) | R-CHOP (n = 8), n (%) | R (n = 17), n (%) |
|---|---|---|---|
| Neutropenia∗ | 45 (70.3) | 7 (87.5) | 7 (41.2) |
| Grade 3-4∗ | 37 (82.2) | 6 (85.7) | 5 (71.4) |
| Received pRBC transfusion | 40 (62.5) | 6 (75.0) | 6 (35.3) |
| Grade 4 thrombocytopenia∗ | 14 (21.9) | 1 (12.5) | 1 (5.9) |
| Received platelet transfusion | 11 (17.2) | 3 (37.5) | 0 (0.0) |
| Infection∗‡ | 49 (76.6) | 7 (87.5) | 10 (58.8) |
| Renal injury | |||
| Any grade∗ | 29 (45.3) | 2 (25.0) | 7 (41.2) |
| Grade 3-4∗ | 3 (4.7) | 1 (12.5) | 2 (11.8) |
| Liver injury | |||
| Any grade∗ | 15 (23.4) | 2 (25.0) | 1 (5.9) |
| Grade 3-4∗ | 6 (9.4) | 0 (0.0) | 0 (0.0) |
| Diarrhea†‡ | 13 (20.3) | 3 (37.5) | 4 (23.5) |
| TLS‡ | 8 (12.5) | 1 (12.5) | 1 (5.9) |
| Reduction in LVEF‡ | 2 (3.1) | 0 (0.0) | 0 (0.0) |
| Allograft rejection‡ | 3 (4.7) | 0 (0.0) | 0 (0.0) |
Grade determined by Common Terminology Criteria for Adverse Events, version 5.0, criteria.
Defined as requiring anti-diarrheal medications for symptomatic control.
No grade 4 events.
In patients treated with R-EPOCH, renal and liver injury occurred in 45.3% and 23.4%, respectively. Grade ≥3 renal injury was uncommon, occurring in 4.7% whereas grade ≥3 liver injury occurred in 9.4%. In those treated with R-CHOP, renal and liver injury were both seen in 25.0% of patients, with 12.5% experiencing grade ≥3 renal injury and no patient experiencing grade ≥3 liver injury. For both groups, TLS was seen in 12.5% of patients. LVEF reduction and allograft rejection were rare events, occurring in only 3.1% and 4.7%, respectively, of patients treated with R-EPOCH, with each occurrence being histologically graded as mild. No patients treated with R-CHOP experienced either of these adverse events.
TRM
Of 65 patients who received R-EPOCH, 10 died either during treatment or within 6 months of receiving their last dose of therapy. Of these 10 patients, 9 had records sufficient to determine whether the likely cause of death was treatment related. In total, 3 of 64 (4.7%) patients were determined to have experienced TRM related to R-EPOCH. The 3 patients who died were aged 63, 69, and 70 years. The underlying disease in these patients was monomorphic DLBCL (n = 1), and monomorphic plasmablastic (n = 1) and polymorphic (n = 1) PTLD. All 3 deaths were related to infection in the setting of chemotherapy-induced neutropenia after either 1 cycle (n = 2) or 6 cycles (n = 1) of therapy. Causes of death were secondary to Pseudomonas aeruginosa bacteremia from pneumonia, pneumonia without an identifiable microorganism, and septic shock of unknown source, respectively.
Of 8 patients who received R-CHOP, 4 patients died while either on treatment or within 6 months of their last dose of therapy. Two of these deaths were determined likely attributable to treatment-related effect, corresponding to a TRM of 2 of 8 (25.0%). Of these 2 patients who died, their ages were 64 and 65 years. Both had monomorphic DLBCL PTLD; 1 death was attributed to polymicrobial bacteremia and ultimately Enterococcus meningitis in the setting of neutropenia and the presence of an enterocutaneous fistula after 2 cycles of R-CHOP. The other death was secondary to upper airway hemorrhage in the setting of severe chemotherapy-induced thrombocytopenia in a patient requiring tracheostomy for pneumonia. The remaining 2 deaths not attributable to treatment effect were related to disease progression.
Of 17 patients who received R, 11 patients died within recorded follow-up. Of these 11 deaths, 7 occurred within a 6-month window of completing R; however, no death was considered related to R (TRM, 0%). Of 7 deaths, 4 were related to disease progression.
Discussion
Among 101 patients diagnosed with B-cell PTLD at CUIMC between 2008 and 2021, most were treated with R-EPOCH and experienced a mOS of 6.4 years without associated excess toxicity. Although the small sample sizes of patients treated with alternative regimens precluded direct statistical comparison, this finding compared favorably with other treatment strategies, both at CUIMC and those published previously. The demographics and distribution of SOT type was similar to that published at other institutions.8,18 The CUIMC population had a relatively low proportion of EBV-associated tumors. Whereas the incidence of EBV-associated PTLD has been estimated as high as 80% in the United States,19,20 only ∼60% of patients in our study developed EBV viremia after SOT and in the group of patients treated with R-EPOCH, only 25% of tumors were EBER positive. Furthermore, the time from transplant to diagnosis was longest in the R-EPOCH group. These findings coincide with the rising prevalence of EBV-negative PTLD, particularly in those with longer intervals between transplant and PTLD diagnosis. Although the pathobiological differences between EBV positive and negative PTLDs are distinct,21 there has been no evidence that this portends to difference in outcomes.9,22, 23, 24 In keeping with this, there was no significant association with EBER and PFS or OS in univariate analysis for patients treated with R-EPOCH.
Although R has changed the landscape of PTLD treatment, its efficacy as a single agent is associated with brief durations of response.25 Studies have demonstrated R monotherapy to have a CR rate between 28% and 52%, and reported event-free survival rates of <50% with a median 2-year follow-up.26, 27, 28, 29 In this study, R monotherapy was used infrequently, selected in only 16.8% of patients with B-cell PTLD with 7 of 17 patients being lung transplant recipients. Although the retrospective nature of this study precludes understanding this bias, it is likely because of the frailty and comorbidity of lung transplant recipients. R demonstrated a mPFS of 19 months and mOS of 28 months. Of note, 70.6% of patients who received R monotherapy had polymorphic PTLD, which is sometimes considered to have a favorable prognosis.8,30 Despite this, 64.7% of patients who received R died within our follow-up period. Although R was well tolerated, 57.1% of patients who died within 6 months of treatment did so from disease progression. This finding may also be confounded by measures such as performance status (PS) or competing comorbidities that influenced both treatment selection and outcome.
Currently, the strongest data for the treatment of PTLD has come from prospective phase 2 clinical trials, which have supported the use of a sequential and risk-stratified approach using R-CHOP for those deemed at high risk.10,11 However, these trials included only patients with an Eastern Cooperative Oncology Group PS of ≤2 and, despite this, showed limited survival in high-risk subgroups. In real-world practice, the proportion of patients with an Eastern Cooperative Oncology Group PS of 3 to 4 after SOT has been reported at ∼25%.31,32 Although the cohort of patients who received R-CHOP in the PTLD-1 RSST trial were reported to have experienced a mOS of 7.1 years,10 retrospective studies of R-CHOP in PTLD reflective of real-world practice have not replicated such results, with reported mOS of 2 to 5 years. 33, 34, 35, 36 Moreover, in the high-risk and very high-risk groups of the PTLD-2 trial who were treated with R-CHOP with/without R with oxaliplatin, cytarabine, and dexamethasone, the 2-year OS was 59% in the former and the mOS was only 7.4 months in the latter.10 Although R-CHOP was infrequently chosen as initial therapy in the CUIMC cohort, comprising only 7.9% (n = 8), outcomes were poor, with a mOS of only 13.5 months. Moreover, although rates of major toxicity including frequency of hematologic adverse events and infections were similar to those in patients treated with R-EPOCH, the TRM of R-CHOP was high at 25.0%, with the remainder of deaths attributable to disease progression.
Most patients with B-cell PTLD treated at our institution received R-EPOCH as frontline therapy, comprising 64.4% (n = 65) of patients. This analysis found a mPFS of 4.4 years and mOS of 6.4 years with this treatment, which compares favorably with the mOS of 6.6 years described in the PTLD-1 ST and RSST trials without limitations in PS. Although PS could not be accurately obtained in this retrospective study, 45% of patients required urgent initiation of therapy inpatient, likely indicating a PS of ≥2. We found no significant interaction of EBER or CD30 and CD138 status with PFS or OS. Of the analyzed covariates, only the number of immunosuppression drugs at the time of diagnosis and heart transplantation negatively predicated for OS, an observation that has been noted in prior studies.37 A significantly positive survival impact was seen with the number of R-EPOCH treatment cycles received. Interpreting this latter finding would be best evaluated prospectively in a study in which both PS and dose intensity can be contextualized. Regarding toxicity, hematologic and infectious complications were the most frequently observed and were similar with what was observed in our patients treated with R-CHOP but with a numerically better incidence of neutropenia and infection in those treated with R-EPOCH. Importantly, the rate of allograft rejection in patients treated with R-EPOCH was low at 4.7% (n = 3) and TRM of 4.7%, whereas the TRM with R-CHOP in the PTLD-1 trial was 11%.9
In terms of dose delivery, we found that maintaining an RDI of ≥80% throughout R-EPOCH treatment was achieved in most for each component chemotherapy including 66.7% of patients receiving an RDI of >100% for cyclophosphamide. The exception to this was vincristine for which 55.6% of patients received an RDI of < 80%. Compared with those who received an RDI of ≤100%, those who received an RDI of >100% of cyclophosphamide may have experienced clinical benefit with a significantly improved PFS (mPFS, 19 months vs 71 months) and OS (mOS, 61 months vs 111 months). However, this may be biased by PS, which was unrecorded, as those fit enough to tolerate cyclophosphamide dose escalation may have had a better prognosis from the onset.
There are several limitations to this study. For one, the retrospective nature made collecting data on certain variables such as PS and disease stage unfeasible. Understanding how these measures affect both treatment choice and outcome would be an important step in contextualizing their utility and efficacy. Although PS was not directly captured, it is worth noting that there was no difference among the treatment groups in the proportion of patients who were able to start treatment electively on an outpatient basis. In addition, the relatively small number of patients treated with R-CHOP and R precluded meaningful statistical comparison between our groups of interest. Furthermore, there was variability in R-EPOCH dosing and dose escalation as it was administered per provider discretion, thus making conclusions about optimal dose level challenging.
In summary, treatment with R-EPOCH in the CUIMC cohort demonstrates efficacy for B-cell PTLD without excess toxicity compared with other commonly used chemoimmunotherapy regimens, and survival outcomes that compare favorably with historical controls. Given this, the data support prospective investigation of R-EPOCH for the treatment of SOT recipients with PTLD particularly in place of R-CHOP in a risk-stratified approach to preserve the possibility of chemotherapy-free treatment for low-risk patients. It is hopeful that with evolving treatment strategies for PTLD, including cellular therapy options, outcomes may be improved for patients with this disease.
Conflict-of-interest disclosure: H.-J.C. reports honoraria from ADC Therapeutics. A.H.L. reports consultant role with, and membership on the board of directors or advisory committees of AbbVie, AstraZeneca, BeiGene, Synthekine, and Loxo-Lilly. B.P. reports consultant role with Takeda, Seattle Genetics, Celgene, Verastem, and Astex; and reports research funding from ONO Pharma USA and SciTech. J.E.A. reports honoraria from ADC Therapeutics and AstraZeneca. The remaining authors declare no competing financial interests.
Acknowledgments
J.E.A. acknowledges The Stewart Family Fund and The Esther and Oded Aboobi Lymphoma Research Fund.
Authorship
Contribution: B.C. designed the research, collected data, analyzed and interpreted data, and wrote the manuscript; M.F. designed the research, and collected and interpreted data; S.J. collected data; H.-J.C. designed the research, analyzed and interpreted data, and wrote the manuscript; E.O., P.G., and A.S. collected data and critically reviewed the manuscript; B.M. performed research and collected data; Y.C. performed statistical analysis, analyzed and interpreted data, and wrote the manuscript; G.B. performed research and wrote the manuscript; A.H.L. and B.P. designed the research and critically reviewed the manuscript; and J.E.A. designed the research, analyzed and interpreted data, and wrote the manuscript.
Footnotes
Data are available on request from the corresponding author, Jennifer E. Amengual (jea2149@columbia.edu).
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