Non-DLBCL monomorphic and Hodgkin lymphoma PTLD: clinical insights and treatment strategies Open Access

Posttransplant lymphoproliferative disorder (PTLD) comprises a heterogeneous group of lymphoid and plasmacytic proliferations that develop after solid organ transplantation (SOT) or hematopoietic stem cell transplantation (SCT).^1-3 PTLD incidence varies across transplant centers and is influenced by follow-up duration, transplanted organ type, and immunosuppressive regimens.^2,4,5 A well-established risk factor is Epstein-Barr virus (EBV) recipient-donor serological status mismatch.⁶ In hematopoietic SCT, additional PTLD risk factors include selective donor T-cell depletion and use of unrelated or HLA-mismatched donors and umbilical cord blood.^2,4 PTLD incidence follows a bimodal distribution. Early-onset PTLD typically occurs within 6 to 12 months after transplant and is usually EBV-positive, whereas late-onset PTLD arises after 1 year of transplant, with an increase in monomorphic non–diffuse large B-cell lymphoma (non-DLBCL) histologies.^1-3 

The World Health Organization (WHO) fourth edition classified PTLD as a distinct entity and organized immunodeficiency-related lymphoproliferative disorders according to clinical setting. In contrast, the WHO fifth edition introduced the broader category of immunodeficiency and dysregulation–associated lymphoproliferative disorders to reflect the overlapping morphology and pathogenesis across these contexts (Table 1).

Monomorphic PTLD accounts for 60% to 80% of all PTLD cases and include lymphoid and plasmacytic proliferations that meet WHO criteria for defined B-cell, plasma cell, or T-cell/natural killer (NK) cell neoplasms seen in immunocompetent individuals. The most common subtype is DLBCL-PTLD, representing 70% to 80% of monomorphic cases. Its management is guided by treatment strategies adapted from phase 2 studies, typically involving reduction in immunosuppression (RIS) and a risk-stratified sequential immunochemotherapy (RSST) approach.^1-3,7,8 In contrast, non-DLBCL monomorphic PTLDs such as Burkitt lymphoma (BL), PTLDs of T/NK-cell origin (T/NK-cell), and plasmacytic variants are less common, clinically heterogeneous, and lack prospective data to guide management. Treatment approaches for these subtypes are primarily based on case series, retrospective reports, and regimens used in immunocompetent patients.^9-20 Although not classified as monomorphic PTLD, classic Hodgkin lymphoma PTLD (cHL-PTLD) represents another distinct and clinically relevant PTLD type.^21,22 This review synthesizes current evidence on the epidemiology, clinical features, treatment strategies, and outcomes of these less common PTLD types, offering a practical framework for their management (Tables 2 and 3; Figures 1 and 2).

Burkitt lymphoma-PTLD (BL-PTLD) accounts for <1% of all PTLD cases.¹⁸ An analysis of 203 557 SOT recipients from the US Transplant Cancer Match Study (1987-2009) reported a BL-PTLD incidence of 10.8 per 100 000 person-years, which is 23 times higher than that in the general population.²³ BL-PTLD typically manifests late after transplantation, with the largest retrospective study of 55 patients reporting a median time to diagnosis of 5.4 years after transplant.¹⁸ BL-PTLD is commonly associated with EBV, with the 2 largest case series reporting histologic EBV-encoded small RNA positivity in 69% and 49% of patients.^9,18 This is higher than sporadic and HIV-associated cases but lower than pediatric BL-PTLD, for which EBV detection has been reported in up to 90% of cases.^{4,9,18,20,23,24} Despite its frequent association with EBV, BL-PTLD typically arises from germinal center B cells, whereas EBV⁺ DLBCL-PTLD more commonly shows a non–germinal center phenotype.²⁵ Most cases harbor MYC translocations; however, a report by Ferreiro et al noted cases that lacked MYC translocation.²⁶ 

Due to the rarity of BL-PTLD, identifying risk factors for its development can be challenging. However, in the analysis of 203 557 SOT recipients from the US Transplant Cancer Match Study, younger recipients (aged <18 years) and those receiving liver or heart transplants had a higher incidence of BL-PTLD than adult and kidney transplant recipients. Additionally, male recipients, those who were EBV-seronegative at baseline, and individuals treated with azathioprine and corticosteroids were at increased risk.²³ 

Two major retrospective studies have provided valuable insights into the clinical features, treatment approaches, and outcomes of BL-PTLD in adults.^9,18 Walczak et al reviewed 55 BL-PTLD cases from multiple registries.¹⁸ Similarly, a multicenter study by Bobillo et al analyzed 20 cases of BL-PTLD across 10 transplant centers.⁹ In both studies, kidney was the most transplanted organ, with a median age at diagnosis of ∼40 years. Both studies reported a predominance of high-risk and aggressive features, including advanced Ann Arbor stage IV (84% of the Walczak et al cohort and 80% in the Bobillo et al cohort), elevated lactate dehydrogenase levels (84% vs 95%), and extranodal disease (89% vs 73%). The gastrointestinal tract was the most frequently involved organ in both studies.

Both Walczak et al and Bobillo et al described multiple treatment approaches for patients with BL-PTLD, with most undergoing RIS in conjunction with either an RSST-based approach (initial rituximab monotherapy followed by chemotherapy upon inadequate response) or upfront combination chemoimmunotherapy. Notably, no patient in either study was treated with RIS alone. In the study by Walczak et al, most patients received frontline chemotherapy, with or without immunotherapy, whereas an RSST-based approach was implemented in 25% of patients.¹⁸ Chemotherapy regimens used across both studies included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and BL protocol–based regimens.^9,18 A key treatment-related finding was that survival outcomes did not differ significantly between patients treated with an RSST-based approach and those who received upfront chemoimmunotherapy. However, the consistent need for chemotherapy was evident, as rituximab monotherapy within an RSST-based strategy proved inadequate.^9,18 In the study by Walczak et al, only 1 of 14 patients achieved a complete response (CR) with rituximab alone, whereas in the cohort reported by Bobillo et al, none of the 3 patients treated with rituximab monotherapy achieved CR, all requiring subsequent chemotherapy.^9,18 

A sequential approach may improve tolerability in patients who are unfit for chemotherapy, although evidence is limited. In the study by Zimmermann et al, 5 patients received rituximab induction course followed by 4 cycles of R-CHOP (rituximab-CHOP) and all achieved CR, with no treatment-related mortality and superior overall survival (OS) than 2 patients who received upfront combination chemoimmunotherapy.²⁰ Findings from the study by Zimmermann et al, along with those from Walczak and Bobillo et al, suggest that R-CHOP may yield CRs and survival outcomes comparable with those of BL regimens, which have been associated with higher treatment-related mortality.^9,18,20 Walczak et al reported a median OS of 7.1 years and a median progression-free survival (PFS) of 4.9 years, whereas Bobillo et al observed a median OS of 139 months and a median PFS of 16 months. Notably, both studies identified bone marrow involvement as an adverse prognostic factor. Achieving CR with first-line therapy predicted better outcomes in the Walczak et al study. EBV status did not affect survival in either study.^9,18 

These treatment-related observations in BL-PTLD highlight the necessity of chemotherapy for achieving meaningful responses and suggest that, although evidence is limited, a sequential approach may be appropriate in select patients. R-CHOP may provide a favorable balance of efficacy and tolerability compared with more intensive BL protocol regimens.²⁷ A proposed treatment approach for BL-PTLD is illustrated in Figure 1.

Although salvage chemotherapy is generally associated with poor outcomes in patients with BL-PTLD who fail standard frontline regimens, limited studies and case reports suggest potential benefit from novel therapies. However, due to the rarity of BL-PTLD, enrollment in clinical trials has been limited, and most available data come from isolated cases or small numbers of patients included in broader studies. In a phase 2 study by Haque et al evaluating allogeneic EBV-specific cytotoxic T lymphocytes (EBV-CTLs) in EBV-positive PTLD, 1 adult patient with BL-PTLD who had failed conventional therapy achieved a CR sustained through 6 months after infusion.²⁸ Additionally, a case report described a pediatric patient with chemoimmunotherapy-refractory BL-PTLD who achieved a durable CR after autologous anti-CD19 chimeric antigen receptor T-cell therapy, maintained at 16 months of follow-up. Therefore, enrollment of patients with BL-PTLD in clinical trials of novel therapies is strongly encouraged, particularly for those unfit for frontline chemoimmunotherapy or with relapsed/refractory disease.²⁹ 

Central nervous system (CNS) involvement is frequent in BL. In the 2 largest retrospective studies of BL-PTLD, CNS involvement at diagnosis was reported in 13% and 7% of cases, respectively.^9,18 In the study by Walczak et al, 7 patients with CNS involvement were treated with intrathecal methotrexate (MTX; n = 3), IV MTX (n = 2), both (n = 1), or whole-brain radiation therapy (WBRT; n = 1). A CR was achieved in 5 patients (71%).¹⁸ Zimmermann et al found that the addition of rituximab to CHOP reduced the risk of secondary CNS disease in patients with BL-PTLD.²⁰ Bobillo et al reported that CNS prophylaxis was administered in 16 of 20 patients with BL-PTLD, using intrathecal or IV MTX, and only 2 patients experienced CNS relapse, suggesting a possible benefit from prophylaxis.⁹ Although the CNS prophylaxis modality is contingent on the frontline regimen and patient related factors, we recommend incorporating CNS prophylaxis into the treatment of BL-PTLD (Figure 1).

PTLD of T/NK-cell origin (T/NK-cell PTLD) comprises a heterogeneous group of lymphoproliferations that fulfill the morphologic and phenotypic diagnostic criteria for T/NK-cell lymphomas or leukemias. Accordingly, no polymorphic T-cell PTLD entities are recognized separately. Although definitive evidence of clonality is essential for diagnosing T/NK-cell PTLDs, clonality alone is insufficient for diagnosis, because patients undergoing iatrogenic immunosuppression may exhibit limited T-cell repertoires.¹⁶ 

The reported incidence of T/NK-cell PTLD varies across studies, ranging from 2% to 15% of all PTLDs in Western countries, with higher rates reported in South Asia.^16,30,31 These generally present as late-onset PTLD. Although kidney transplant recipients account for most reported cases, the highest organ-specific incidence occurs in cardiac transplant recipients.^12,16,32 

Approximately one-third of T/NK-cell PTLDs are associated with EBV, although this proportion varies across different subtypes.^10,12,16 The pathogenesis of EBV-positive and EBV-negative T/NK-cell PTLD remains poorly understood. In EBV-positive T-cell PTLD, it has been hypothesized that EBV may infect a subset of T cells, potentially through CD21 or other unidentified receptors, or that EBV-infected B-cells may provoke a dysregulated T-cell response due to iatrogenic impairment of T-cell regulatory function.^12,33,34 In contrast, EBV-negative T-cell PTLD may involve other viral triggers or represent de novo T-cell lymphomas arising coincidentally in transplant recipients, with biological behavior similar to their counterparts in immunocompetent individuals.^12,35 This latter hypothesis is supported by a gene expression profiling study demonstrating that T/NK-cell PTLDs share molecular signatures with their non-PTLD counterparts.³⁶ 

The 2 largest compilations of T/NK-cell PTLD cases include a literature review of 130 cases by Swerdlow et al and a meta-analysis of 156 cases by Herreman et al.^12,16 These studies highlighted the broad spectrum of T/NK-cell lymphoma and leukemia subtypes in transplant recipients of all age groups, with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) being the most common, followed by hepatosplenic T-cell lymphoma (HSTCL). Systemic and primary cutaneous anaplastic large cell lymphoma (ALCL) were also frequently reported.^12,16 A male predominance was noted in both studies, along with frequent extranodal involvement (>90%) and common infiltration of the bone marrow, peripheral blood, and spleen. CNS involvement was identified in ∼5% of cases.^12,16 

T/NK-cell PTLDs are generally treated with chemoimmunotherapy regimens similar to those used for their counterparts in immunocompetent patients. These typically do not respond to RIS alone, although RIS may be attempted in more indolent subtypes such as intestinal indolent T-cell lymphoproliferative disorder and large granular lymphocytic leukemia. Limited case reports showed that brentuximab vedotin monotherapy may offer clinical benefit in patients with CD30⁺ T-cell PTLD who are unfit for standard frontline chemoimmunotherapy.^37,38 There is currently no direct evidence supporting the use of consolidation with high-dose chemotherapy (HDCT) and autologous SCT (ASCT) in this setting, because the approach is largely extrapolated from data in immunocompetent patients. If this strategy is considered, treatment-related mortality must be carefully weighed, making appropriate patient selection critical. A proposed treatment approach for T/NK-cell PTLDs is summarized in Figure 2.

T/NK-cell PTLD carries the poorest prognosis among all PTLDs. Subtypes such as PTCL-NOS and HSTCL are associated with particularly poor outcomes, whereas entities such as T-cell large granular lymphocytic leukemia appear to retain the relatively favorable prognosis seen in immunocompetent individuals. Retrospective reports suggest that EBV association and disease confined to the gastrointestinal tract may be associated with improved outcomes.^12,16 In the study by Swerdlow et al, the median OS was only 6 months.¹⁶ T-cell large granular lymphocytic leukemia and extranodal NK/T-cell lymphoma had the best outcomes (median OS not reached). Outcomes were poorest in HSTCL, PTCL-NOS, and ALCL, with median OS of 5, 3, and 2.5 months, respectively. Although treatment details were limited, 60 patients received chemotherapy, 20 had unknown therapy, 2 received skin-directed therapy for mycosis fungoides, and 4 received radiation. Forty-four patients received neither chemotherapy nor radiation; this group included those managed with RIS alone or surgery. RIS alone was effective in 2 patients (1 ALCL, 1 PTCL-NOS), whereas surgical resection was adequate in 1 case of enteropathy-type T-cell lymphoma.¹⁶ In the meta-analysis by Herreman et al, primary cutaneous ALCL and systemic ALCL had the most favorable outcomes, with median OS of 17 and 11 months, respectively, although still shorter than typically observed in immunocompetent patients. HSTCL had the worst prognosis (median OS of 5 months), followed by PTCL-NOS, with a median OS of 2 months for EBV-negative cases and 7.5 months for EBV-positive cases.¹² 

Plasmacytic PTLD can manifest along a pathological spectrum, ranging from plasmablastic lymphoma to plasmacytoma-like and plasma cell myeloma–like PTLD. National registries and transplant databases estimate that plasmacytic PTLD accounts for ∼0.2% to 4% of all PTLD cases.^21,39,40 In a large study of 202 600 transplant recipients using linked data from 15 state/regional cancer registries and the US SOT registry, the risk of developing plasmacytic neoplasms was 1.8-fold higher than in the general population. Incidence increased with age; however, due to the rarity of plasmacytic neoplasms in the general population at younger ages, standardized incidence ratios were highest in younger transplant recipients. The study also found that risk was greatest among recipients who were EBV seronegative at the time of transplant.⁴¹ Plasmacytic PTLDs typically have a delayed onset after transplant, show less variation in incidence by type of transplanted organ, and often lack CD20 expression, rendering rituximab ineffective in most cases.^15,17,41 

Plasmacytoma-like PTLD has the most favorable prognosis among plasmacytic PTLDs and typically behaves similar to extramedullary plasmacytoma in immunocompetent individuals. A key distinction, however, is its frequent association with EBV, identified in up to half of cases, unlike plasmacytomas in immunocompetent individuals, in which EBV association is rare.^15,17,41 Although plasmacytoma-like PTLD can involve various organs and lymph nodes, osseous and bone marrow involvement is uncommon. This contrasts with plasmacytomas in immunocompetent individuals, in whom these sites are more frequently affected. Involvement of the transplanted organ appears to be uncommon.^15,17,41 Engels et al demonstrated that the incidence of plasmacytoma-like PTLD increases with longer posttransplant follow-up. In their analysis of 38 cases, risk factors included EBV seronegativity at the time of transplant and the use of monoclonal antibodies for induction, whereas the use of mycophenolate mofetil was associated with decreased risk.⁴¹ 

RIS, with or without radiation, is often effective in eradicating plasmacytoma-like PTLDs. In a case series by Trappe et al, which included 8 cases of plasmacytoma-like PTLD (4 localized and 4 disseminated disease), EBV was positive by in situ hybridization in tissue sections of 3 patients. Of 6 patients, 2 responded to RIS, with RIS alone being effective in 1 localized and 1 disseminated case. The other 3 patients with localized disease were treated with surgery or radiation. Among the 3 patients with disseminated disease who failed RIS, plasma cell–directed systemic therapy was initiated, and 1 patient ultimately died of disease progression.¹⁷ In the case series by Richendollar et al, 3 of 4 patients achieved CR with RIS alone; 1 patient eventually relapsed and died of PTLD. Interestingly, another patient who did not respond to RIS achieved CR after systemic therapy plus EBV-CTLs.¹⁵ 

Plasma cell myeloma-PTLD (PCM-PTLD) is rare, and limited data are available regarding its clinical characteristics and outcomes. Ofori et al described 11 cases of PCM-PTLD identified through a single institutional pathology database.¹⁴ All cases were EBV negative, and osseous involvement was uncommon, occurring in only 1 patient. The immunophenotype and cytogenetic abnormalities closely resembled those seen in multiple myeloma (MM) among immunocompetent individuals. Of 11 patients, 10 received proteasome inhibitor–based therapy, with treatment responses and a 5-year OS rate of 54.5%, comparable with outcomes in the general MM population. However, patients with plasmablastic features had poorer survival outcomes.¹⁴ Safadi et al identified 7 cases of PCM-PTLD occurring after kidney transplantation between 2001 and 2012. Notably, 4 patients had a history of monoclonal gammopathy of undetermined significance before transplantation. Despite a higher incidence of renal involvement in PCM-PTLD, the study found that both patient survival and graft survival were similar to those observed in the general MM population.⁴² 

Most of the current knowledge on plasmablastic lymphoma (PBL) comes from studies in patients with HIV and in older individuals without known immunodeficiency. In transplant recipients, PBL features neoplastic B cells with immunoblastic morphology, plasma cell immunophenotype, and absent mature B-cell antigens. The most comprehensive data on PBL-PTLD come from 2 studies: a prospective case series of 8 patients reported to the German PTLD registry between 2006 and 2012 (accounting for 4% of all registry cases), and a retrospective case series of 11 patients reported by Leeman-Neill et al.^13,19 In both reports, PBL-PTLD was predominantly late-onset, most frequently occurring in heart or kidney transplant recipients. In the study by Zimmermann et al, 7 of 8 patients developed PBL-PTLD >10 years after transplant. Patients were predominantly male and presented with extranodal disease, irrespective of disease stage. EBV association was reported in 63% and 55% of cases in the Zimmermann and Leeman-Neill cohorts, respectively, whereas MYC rearrangements were identified in 33% and 45% of cases, respectively. The prognostic significance of EBV negativity and MYC rearrangements varied across studies.^13,19 

PBL-PTLD is typically managed in line with HIV-associated PBL, using chemotherapy in combination with RIS, as RIS alone is usually ineffective.^19,43 Local therapy was reported to be insufficient even in patients with early stage localized disease.¹⁹ Leeman-Neill et al reported survival durations ranging from 0 to 15.9 years. Regimens across studies included CHOP and more intensive options such as DA-EPOCH (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin).^13,19 Given the lack of prospective data showing improved survival with intensified regimens in PBL, the use of more aggressive approaches beyond CHOP chemotherapy such as HDCT and ASCT should be approached with caution. The addition of plasma cell–directed agents has also been explored in PBL and is currently under investigation in clinical trials.^13,43,44 Given that these agents (daratumumab and bortezomib) are generally well tolerated and already available in clinical practice, their incorporation into therapy for younger, fit patients with PBL-PTLD may be reasonable, although data remain limited.

Our proposed treatment approach varies depending on where the disease falls along the spectrum of plasmacytic PTLD (Figure 2).

Primary CNS PTLD (PCNS-PTLD) is predominantly of monomorphic B-cell histology resembling DLBCL and is most commonly reported after kidney transplantation.^10,11,45,46 Combined primary and secondary CNS-PTLD account for 5% to 15% of all PTLDs, with PCNS-PTLD being more common.^10,45 Differentiating between primary and secondary CNS-PTLD is clinically important, not only because management strategies may differ, but also due to differences in prognosis. In a retrospective study of 136 patients from a transplant registry, PCNS-PTLD was associated with a more favorable prognosis than secondary CNS-PTLD.⁴⁵ Most cases present as late-onset PTLD, despite histologic EBV positivity in >90% of cases.^10,11,46 

In addition to EBV status, certain radiographic features may help distinguish PCNS-PTLD from primary CNS lymphoma (PCNSL) in immunocompetent individuals.^10,47,48 PCNS-PTLD is also less likely to abut the cerebral spinal fluid (CSF) or involve the leptomeninges or ocular structures, all of which are more common in PCNSL. When PCNS-PTLD is suspected radiographically, a biopsy is essential for definitive diagnosis if anatomically feasible, as CSF analysis usually reveals nonspecific abnormalities but occasionally can have positive cytology. Although a detectable EBV viral load in the CSF may strongly suggest PCNS-PTLD, it is neither diagnostic nor consistently elevated. The same limitation applies to EBV viral load in the peripheral blood. In the study by Evens et al, only 30% of PCNS-PTLD cases had a detectable EBV DNA in the peripheral blood.^10,45 

Although PCNS-PTLD is generally considered a poor prognostic factor within the broader PTLD spectrum, outcomes are heterogeneous.^39,49 In the study by Evens et al, which included 84 patients with PCNS-PTLD (76% monomorphic DLBCL-like histology), the median OS was 17 months, with a 3-year OS of 53%.¹⁰ In contrast, Guney et al reported a median OS of 122 months and a 5-year OS of 67.5% among 24 patients with CNS-PTLD, 21 of whom had PCNS involvement.¹¹ Cavaliere et al identified 34 cases of PCNS-PTLD, mostly monomorphic B-cell histology, from institutions participating in the International Primary CNS Lymphoma Collaborative Group, reporting a median OS of 47 months.⁴⁶ Across retrospective studies, several prognostic factors have been identified including lack of response to first-line therapy, older age, elevated lactate dehydrogenase, and a Ki-67 labeling index of ≥80.^10,11,46 

Treatment strategies varied across reports but commonly included systemic chemotherapy (eg, MTX, cytarabine), rituximab, radiation, and surgical resection.^10,11,46 RIS alone is usually insufficient and potentially risky due to the delayed onset of clinical response in the context of life-threatening CNS involvement. In the study by Evens et al, 6 patients received RIS alone; 5 had progression, whereas 1 initially responded but later relapsed.¹⁰ Rituximab monotherapy is rarely sufficient in PCNS-PTLD, particularly in late-onset disease.^7,10 Evens et al observed CR in 3 of 5 patients with PCNS-PTLD after treatment with rituximab, all of whom had early-onset disease; none of the late-onset cases responded.¹⁰ 

As in PCNSL, high-dose MTX (HDMTX)-based regimens are recommended as first-line therapy for PCNS-PTLD, usually initiated with rituximab and steroids. Evens et al reported overall response rate (ORR) and CR rate of 63% and 45%, respectively, after frontline HDMTX in patients with PCNS-PTLD.¹⁰ The more favorable survival outcomes observed in the study by Guney et al may reflect more consistent use of HDMTX and rituximab compared with the Evens et al cohort.^10,11 Importantly, kidney transplantation alone should not be considered a contraindication to receiving HDMTX. In the study by Evens et al, a trend toward improved PFS was observed in patients treated with high-dose cytarabine (HDAC) and/or rituximab.¹⁰ However, this finding should be interpreted with caution, because several patients treated according to the MSKCC protocol (HDMTX followed by HDAC) experienced disease progression during HDMTX and did not proceed to HDAC. These patients were classified as not having received HDAC, potentially biasing the analysis. Although these data suggest that HDAC may have a role in PCNS-PTLD, HDMTX remains a key component of PCNS-PTLD treatment, particularly because many patients are unfit for aggressive chemotherapy. First-line WBRT is generally avoided due risk of neurotoxicity but may be considered in patients unfit for systemic therapy. Evens et al showed that incorporating WBRT into initial therapy, with or without systemic agents, did not lead to improved ORRs or CR rates.¹⁰ 

In PCNSL outside the PTLD setting, patients who respond to MTX often undergo consolidation with HDCT and ASCT or continue MTX maintenance if unfit for ASCT.^50,51 However, the applicability of this approach in PCNS-PTLD remains uncertain. Very few patients with PCNS-PTLD reported in the literature have undergone HDCT and ASCT, likely due to poorer performance status compared with those with PCNSL.^10,52 Therefore, consolidation with HDCT and ASCT should be approached with caution and considered only in patients with excellent performance status. A proposed treatment approach for PCNS-PTLD is illustrated in Figure 1.

Although Bruton tyrosine kinase inhibitors are now utilized in the treatment of PCNSL, their applicability in PCNS-PTLD remains uncertain due to the lack of MYD88 alterations in most EBV-positive cases despite a predominantly non–germinal center phenotype.¹¹ 

Adoptive cell therapy using EBV-CTLs has shown promising activity in relapsed/refractory EBV-positive B-cell PTLD,⁵³ including cases with CNS involvement.⁵⁴ Tabelecleucel, an off-the-shelf, allogeneic EBV-CTL product, is the most extensively studied to date. In 18 patients with EBV-positive CNS-PTLD across 4 open-label studies, tabelecleucel demonstrated an ORR of 78% and a 2-year OS of 55%, with a favorable safety profile.⁵⁴ EBV-CTLs may be practice-changing for patients with PCNS-PTLD refractory to conventional therapies and could potentially be incorporated into the frontline setting for patients unfit for systemic therapy (ClinicalTrials.gov identifier: NCT04554914) or if future studies demonstrate superiority over current standard approaches.

HL-PTLD is a rare subtype of PTLD, accounting for ∼3% to 8% of cases. For diagnosis, HL-PTLD must meet the stringent criteria established for cHL in immunocompetent individuals.^21,22,39 Rosenberg et al analyzed 192 HL-PTLD cases from the Scientific Registry of Transplant Recipients and compared them with 13 847 patients with HL from the surveillance, epidemiology, and end results (SEER) database (HL-SEER) using exact matching and multivariable models.²² The median time from transplant to HL-PTLD diagnosis was 88 months. Patients with HL-PTLD were older with more extranodal disease than HL-SEER controls. Reed-Sternberg cells were EBV positive in 74% of cases. Small case reports and series have raised concerns about the tolerability of chemotherapy regimens in patients with HL-PTLD. Caillard et al analyzed 66 159 kidney transplant recipients from the US Renal Data System, identifying 60 cases of HL-PTLD. They found that none of the patients died from lymphoma, but 30% died from infections.²¹ However, Rosenberg et al concluded that receipt of any chemotherapy reduced risk of mortality in HL-PTLD, whereas no chemotherapy and nonstandard HL regimens resulted in higher mortality rates than HL-specific regimens.²² Five-year OS was significantly lower in HL-PTLD vs HL-SEER (57% vs 80%, P < .001), with similar trends in disease-specific survival. Older age and high creatinine predicted worse OS.²² 

A proposed treatment approach for HL-PTLD is summarized in Figure 1. In early-stage disease, RIS may be attempted alone, with escalation to standard HL chemotherapy and radiation protocols if the response is inadequate.⁵⁵ For advanced-stage HL-PTLD, doxorubicin, bleomycin, vinblastine, with dacarbazine remains a viable option, given the heightened infection risk associated with brentuximab vedotin + doxorubicin, vinblastine, and dacarbazine; if the latter is used, comprehensive infectious prophylaxis is essential.⁵⁶ Although nivolumab + doxorubicin, vinblastine, and dacarbazine is increasingly used in newly diagnosed advanced-stage HL,⁵⁷ it is generally avoided in transplant recipients due to risk of graft rejection.^58,59 

In patients unfit for standard frontline chemoimmunotherapy, single-agent brentuximab vedotin may be a reasonable option, as demonstrated in a case report of HL-PTLD.⁶⁰ Additionally, the combination of brentuximab vedotin and bendamustine may offer a more tolerable alternative to standard regimens in patients who are unfit, based on promising outcomes seen in immunocompetent patients with cHL.⁶¹ Participating in clinical trials exploring novel therapies for HL-PTLD is encouraged. In a phase 2 study by Haque et al, 5 patients with pretreated HL-PTLD received allogeneic EBV-CTLs; all responded (4 CRs, 1 partial response), with sustained remissions reported at 6 months.²⁸ 

Monomorphic non-DLBCL PTLDs comprise a spectrum of uncommon but clinically significant entities that typically present later after transplantation, with variable biology and prognosis. Management usually requires more than RIS, with treatment strategies tailored to histology and patient fitness. Emerging therapies, such as EBV-CTLs and chimeric antigen receptor T cells, have shown promise in related lymphoid malignancies; however, their use has been minimally explored in monomorphic non-DLBCL PTLD. Collaborative efforts and prospective studies are essential to inform evidence-based management and improve outcomes for patients with these rare forms of PTLD.

Contribution: All authors wrote the manuscript, provided expert input, and approved the final version of the manuscript.

Conflict-of-interest disclosure: T.M.H. served on a data monitoring committee for Eli Lilly. The remaining authors declare no competing financial interests.

Correspondence: Suheil Albert Atallah-Yunes, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; email: albert.atallahmd@gmail.com.