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Abstract

Posttransplant lymphoproliferative disorder (PTLD) is a rare lymphoid and/or plasmocytic proliferation that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to identify the pathologic features and clinical outcomes of T-cell PTLD, an extremely rare subtype of PTLD, after allo-HSCT. In this study, six allo-HSCT recipients with T-cell PTLD from five transplant centers in China were enrolled. All the T-cell PTLD were donor-derived, and three patients were with monomorphic and three with polymorphic types, respectively. All patients received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy. Five patients achieved complete response (CR), and one experienced progressive disease (PD). The median time from HSCT to onset was 4 (range: 0.6-72) months, analyzed in combination with the other 16 patients with T-cell PTLD identified from previous reports. About 56.3% of the T-cell samples (9/16) were positive for in situ hybridization with an Epstein–Barr virus (EBV)-encoded small nuclear early region (EBER ISH). CHOP-based chemotherapy might be the optimal strategy for patients who showed no response to empiric therapy with a CR rate of 87.5%. In conclusion, our study observed that T-cell PTLD has distinct clinical manifestations and morphological features, which characterized by less relation to EBV, later occurrence, and poorer prognosis when compared with B-cell PTLD.

Keywords

T-PTLD allo-HSCT EBV poor prognosis

Introduction

Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), with an incidence ranging from 3% to 9%^1,2. For the patients with inappropriate therapy, the mortality could be as high as 52.7% within 3 years³. Most PTLDs after allo-HSCT are originated from donor-derived B-cell, associating with Epstein–Barr virus (EBV) reactivation^4,5. In the last two decades, risk-stratified therapeutic strategies⁵, particularly CD20 antibody, have greatly improved the survival of B-cell PTLD patients³. About 61.8% to 69.4% patients achieved complete remission (CR) after rituximab-based therapy^3,6.

T-cell PTLD is extremely rare after allo-HSCT. Kuno et al.⁴ reported that T-cell PTLD occurred in 0.39% of allo-HSCT recipients and was more likely to be EBV-negative and recipient-origin. The treatment of T-cell PTLD was different from B-cell PTLD. Because of its scarcity, knowledge about pathogenesis, risk factors and prognosis rely predominantly on case reports and small series, and its characteristics and therapeutic protocols were still unclear. In this case series study, we enrolled six cases of T-cell PTLD and aimed to identify their clinical characteristics and outcomes. In addition, we systemic reviewed 16 cases reported in previous studies.

Materials and Methods

Patient Selection

This multicenter, retrospective study was designed by the First Affiliated Hospital of Soochow University, Wuhan Tongji Hospital, the First Affiliated Hospital, Zhejiang University School of Medicine, Shanghai General Hospital, and Shanghai Ruijin Hospital. Allo-HSCT recipients who transplanted between January 2017 and September 2023 were retrospectively screened, and the eligibility criteria were as followed: (1) aged ≥ 16 years; (2) diagnosed with T-cell PTLD. The patients without complete medical information were excluded. The last follow-up was December 31, 2023. The study was approved by the Institutional Review Board of each participated hospital and was conducted in accordance with the Declaration of Helsinki.

Morphological and Molecular Analysis

All biopsy materials were diagnosed by hematopathologists according to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissue published in 2017⁷. Immunohistochemical (IHC) analysis was performed with monoclonal antibodies on formalin-fixed, paraffin-embedded (FFPE) tissues. In situ hybridization (ISH) with an EBV-encoded small nuclear early region (EBER)-1 probe was performed to detect possible EBV infection. EBV-DNA loads in peripheral blood were measured by quantitative polymerase chain reaction (qPCR).

A donor-recipient chimerism study of tumor tissue was performed by quantitative PCR with fluorochrome-labeled primers for polymorphic microsatellite markers containing short tandem repeat (STR) sequences or Y chromosome-based fluorescence in situ hybridization (FISH) analysis. FISH analysis of PTLD tissues was performed in cases after sex-mismatched allo-HSCT. To exclude the contamination of residual recipient-derived non-hematolymphoid cells, the FFPE tissues for the chimerism analyses were prepared after confirming that the tumor cells were numerically dominated by hematoxylin and eosin or IHC staining. For polymorphic PTLD, T-cell PTLD was diagnosed when T-cells account for the dominant clone of neoplastic cells.

Transplant Regimen

The preconditioning regimen included cytarabine, busulfan, cyclophosphamide, semustine, and anti-thymocyte globulin (ATG)^8,9. The protocols for acute graft versus host disease (GvHD) and infection prophylaxis were reported previously¹⁰.

Definitions

Any regimens that include (1) ≥9.6 mg/kg intravenous busulfan, (2) ≥140 mg/m² of melphalan were considered as myeloablative conditioning (MAC). EBV viremia was defined as any levels of EBV DNA detected in plasma by PCR, and the threshold for preemptive therapy was ≥1000 IU/mL.

Clinical staging of T-cell PTLD was evaluated according to the Lugano Modification of Ann Arbor Staging System, and the Lugano response criteria were introduced for response assessments¹¹.

Data Collection

Investigators in each hospital utilized the institutional electronic medical records of clinical databases in each hospital. The collected data included information on patients’ demographics and diagnosis of the underlying disease, pathology, and immunohistochemistry of involved tissue. All the data were independently reviewed by two hematologists and one pathologist with rich experience.

Published Articles

We searched for all available articles in the PubMed database using the search terms “(T-cell) AND ([lymphoproliferative disorder] OR (PTLD)) AND (case report) AND (HSCT)” between 1990 to 2023, and reviewed case reports of T-cell PTLD after allogeneic HSCT.

Results

Clinical Features of Our Patients

Six patients with T-cell PTLD were identified, and their characteristics were shown in Table 1. The median age at allo-HSCT was 22 years old (range: 16–58). T-PTLD were diagnosed within 6 months post-HSCT, and the median interval from allo-HSCT to occurrence of symptoms was 53 (range: 20–114) days. All patients received MAC with ATG as aGvHD prophylaxis. Five patients received haplo-identical related donor (HID) HSCT, and experienced EBV viremia before PTLD with a median peak EBV-DNA load of 10.3 × 10⁴ (range: 1.4–153 × 10⁴) IU/ml. Case 4 was diagnosed with EBV-negative PTLD, as both the donor and recipient were negative for pre-transplant EBV serostatus¹². Case 2 experienced EBV reactivation concurrent with aGvHD. All patients presented fever and lymphadenopathy when PTLD was diagnosed.

Table 1.

Patients’ Characteristics.

Case number	1	2	3	4	5	6
Age(y)/sex	55/F	21/M	19/M	58/M	23/F	16/M
Diagnosis	AML	AML	T-ALL	CMML	B-ALL	T-LBL
Donor	MUD	HID	HID	HID	HID	HID
HLA match	10/10	5/10	6/10	NA	5/10	9/10
Conditioning intensity	MAC	MAC	MAC	MAC	MAC	MAC
GvHD prophylaxis	CsA + MMF + MTX	CsA + MMF + MTX	CsA + MMF + MTX	CsA + MMF + MTX	CsA + MMF + MTX	CsA + MMF + MTX
ATG	Y	Y	Y	Y	Y	Y
aGvHD	N	Y	N	N	N	N
EBV viremia	Y	Y	Y	N	Y	Y
Preemptive therapy	Rituximab (4 doses)	Rituximab (1 dose)	None	None	Rituximab (3 doses)	Rituximab (1 dose)
EBV viremia after preemptive therapy	Positive	Positive	Positive	/	Negative	Positive
Onset posttransplant (day)	114	58	61	20	48	31
Initial presentation	Fever, snuffle, sore tonsil	Fever, cervical LAP, sore throat	Neck pain, scalp pain	Fever, cervical and axillary LAP	Fever, snuffle, rhinorrhea, neck lumps	Fever
Involved sites	Nasopharynx, oropharynx, tonsil, esophagus, stomach, ileum, colon, rectum, liver, spleen, lung; cervical and retroperitoneal LN	Oropharynx, cervical LN	Nasopharynx, cervical LN	Cervical and axillary LN	Subcutaneous lesions, nasopharynx, liver, spleen; cervical, axillary, mediastinal and retroperitoneal LN	Nasopharynx
Pathology	Polymorphic	Monomorphic/PTCL-NOS	Polymorphic	Monomorphic/PTCL-NOS	Polymorphic	Monomorphic/PTCL-NOS
CD3	Positive	Positive	Positive	Positive	Positive	Positive
CD5	Negative	Negative	Negative	Positive	Negative	Positive
CD7	Positive	Positive	Positive	NA	NA	Negative
CD20	Negative	Negative	Negative	Focal positive	Sporadic positive	Negative
CD30	Negative	Positive	Positive	Focal positive	NA	Negative
EBER ISH	Positive	Positive	Negative	Negative	Positive	Positive
Ki-67 (%)	60	70	80	60	40	30
Origin	Donor	Donor	Donor	Donor	Donor	Donor
Onset-diagnosis (day)	20	4	36	10	29	20
Stage	IVB	IIB	IIA	IIB	IVB	IIB
Therapy	CHOPE	CHOP*1 + DLI	CHOP*2	CHOPE + chidamide	CHOP	CHOPE
Response to therapy	CR	PD	CR	CR	CR	CR
Outcome	Alive	Death	Death	Death	Alive	Alive
Cause of death	/	PTLD	Infection	Infection	/	/
Onset-death or last F/U (day)	47	88	116	260	1804	1775

Abbreviations: PTLD, posttransplant lymphoproliferative disorder; HSCT, hematopoietic stem cell transplantation; F, female; M, male; AML, acute myeloid leukemia; T-ALL, t-cell acute lymphoblastic leukemia; CMML, chronic myelomonocytic leukemia; B-ALL, b-cell acute lymphoblastic leukemia; MUD, matched unrelated donor; HID, haplo-identical donor; HLA, human leukocyte antigen; MAC, myeloablative conditioning; GvHD, graft versus host disease; PTCy, post transplantation cyclophosphamide; MTX, methotrexate; MMF, mycophenolate mofetil; CsA, cyclosporine; ATG, anti-thymocyte globulin; Y, yes; N, no; aGvHD, acute graft versus host disease; EBV, Epstein–Barr virus; LAP, lymphadenopathy; LN, lymph node; PTCL-NOS, Peripheral T-Cell Lymphoma, Not Otherwise Specified; CD, cluster of differentiation; NA, not available; ISH, in situ hybridization; EBER, Epstein–Barr early RNA; CR, complete remission; PD, progressive disease; CHOPE, cyclophosphamide, doxorubicin, vincristine, prednisone and etoposide; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; DLI, donor lymphocyte infusion; F/U, follow-up.

Pathological Findings of T-PTLD Patients

Three patients were diagnosed as monomorphic PTLD (PTCL-NOS, Peripheral T-Cell Lymphoma, not otherwise specified), and the other three were polymorphic diseases (Table 1). Donor-derived PTLD was verified in all six patients. IHC staining showed that four of the six patients had positive EBER ISH. The median Ki67 index was 60% (range: 30%–80%). T-cell PTLD neoplastic cells were positive for CD7 (3/6) and CD30 (3/6), and the majority tested negative for CD5 (4/6) and CD20 (4/6).

Representative IHC results of Case 1 (Polymorphic PTLD) are shown in Fig. 1. The neoplastic cells were positive for CD2, CD3, CD7, CD8, and CD43 (Fig. 1A–E), partially positive for CD79a, Granzyme B, and TIA-1 (Fig. 1F–H), and negative for CD5, CD20, and CD30. Scattered lymphocytes were positive for EREB (Fig. 1I). The Ki-67 of these cells was approximately 60% (Fig. 1J).

Figure 1.

Representative histology and immunohistochemical analysis of T-cell PTLD (Case 1). Polymorphic PTLD, positive for CD2 (A), CD3 (B), CD7 (C), CD8 (D), and CD43 (E), partial positive for CD79a (F), Granzyme B (G), and TIA-1 (H) scattered positive for EBER ISH (I), Ki-67 (J) expression of neoplastic cells.

Treatment and Clinical Outcomes

Four patients received rituximab at 375 mg/m² for pre-emptive therapy with a median of 2 (range: 1–4) doses for EBV viremia, and one patient turned negative for EBV DNA. It took a median of 20 (range: 4–36) days to diagnose T-cell PTLD from the detection of EBV viremia. Once T-cell PTLD was diagnosed with pathology, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy was initiated in all patients. Five patients achieved CR. In patients achieving CR, two died of infection and the other three were still in CR with follow-up. One patient experienced progressive disease (PD) and died of PTLD.

Clinicopathological Features of T-Cell PTLD After Allo-HSCT

We identified 16 patients with T-cell PTLD after allo-HSCT in literature review (Table 2)^4,13–21. Among these 16 patients and 6 patients of our case series, the median age at transplantation was 32.5 (range: 2-67) years, and 36.4% patients (8/22) were 50 years or older at transplant. The primary diseases included myeloid malignancy (n = 8), lymphoid malignancy (n = 12), and aplastic anemia (n = 2). About 57.1% (n = 12) patients received HLA-matched allo-HSCT. Around 54.5% (n = 12) of patients received ATG as GvHD prophylaxis. About 68.2% (n = 15) of patients experienced aGvHD before PTLD. The median interval to PTLD was 4 (range: 0.6-72) months, and 72.7% (n = 16) occurred during the first year after allo-HSCT. About 50.0% of patients (n = 11) experienced EBV viremia before T-cell PTLD was diagnosed.

Table 2.

Literature Review of T-Cell PTLD Patients After Allo-HSCT.

Patient number	Age (year)/sex	Primary disease	Donor type	Condition intensity	GvHD prophylaxis	ATG	GvHD	EBV viremia	PTLD onset-transplantation (month)	Initial presentation	Involved sites	Cell origin	Ki-67	Immunostaining	EBER	Therapy	Response to therapy	Outcome	Cause of death	Follow-up time after onset (month)	Reference
1	14/M	AML	MSD	MAC	MTX	-	+	-	43	Posterior cervical lymphadenopathy.	Skin, chest wall, testis, BM	Recipient	NA	Positive for CD1, CD2, CD3, CD4, CD7	NA	Allo-HSCT	not evaluable due to TRM	Death	VOD	28	Zutter et al.¹³
2	9/M	ALL	MSD	MAC	MTX	-	+	-	21	Pleural effusion, and a right atrial mass infiltrated the myocardium	Pleural effusion	NA	NA	Positive for UCHL-1 CD3, CD4, CD5, CD7	NA	Chemotherapy, Rituximab	PD	Death	PTLD	6
3	2/F	ALL	MMUD	MAC	MTX	+	+	-	2	Fever, emesis, abdominal pain, and hepatomegaly	Liver	Donor	NA	Positive for CD2, CD7 and CD8	NA	Withdrawing treatment	/	Death	PTLD	0.4
4	13/M	SAA	MSD	RIC	CsA	-	-	+	19	Bilateral lymphadenopathy of the cervical, axillary and inguinal areas, high fever (.39°C), facial swelling and a foreign body sensation during swallowing	bilateral cervical and mediastinal lymph node	Recipient	NA	Positive for UCHL-1	negative	None	/	Alive	/	20	Wang et al.¹⁴
5	39/M	CML	MUD	MAC	NA	+	+	NA	6	Lymphocytosis	PB and BM	Donor	NA	Positive for CD3 and CD8	negative	None	/	Death	BO	4	Au et al.¹⁵
6	47/M	CLL	MSD	NA	NA	-	+	-	5	NA	BM	Donor	NA	NA	NA	NA	/	Alive	/	6	Chang et al.¹⁶
7	57/M	WM	MSD	NA	NA	-	+	-	4	NA	BM	Donor	NA	NA	NA	NA	/	Alive	/	18	Chang et al.¹⁶
8	56/M	MCL	MSD	RIC	TAC	-	+	NA	72	NA	Skin	Donor	NA	Positive for CD3, CD4, CD5, CD7	negative	None	/	Alive	/	12	Santos-Briz et al.¹⁷
9	44/F	CIMF	MSD	NA	NA	-	+	-	5	NA	Liver	Recipient	NA	Positive for LCA, CD3, CD7 and CD8	negative	Chemotherapy, allo-HSCT	PD	Death	PTLD	2	Nishida et al.¹⁸
10	26/F	T-ALL	MUD	NA	CsA/MTX/MMF	+	+	NA	5	Pharyngeal foreign body sensation and pharyngeal discomfort	nasopharyngeal posterior wall	NA	focal exceeding 50%	Vast majority of atypical lymphocytes were positive for CD45RO, CD3, CD20. Scattered lymphocytes were positive for CD5, CD38, CD99, CD138, TIA-1	positive for majority atypical lymphocytes	Cyclosporine tapering	CR	Alive	/	38	Gu et al.¹⁹
11	15/M	CML	MSD	NA	CsA/MMF	-	+	-	72	Knee pain	left distal femur	NA	40%	Positive staining for both CD3 and CD43, weak positive staining for myeloperoxidase and CD15, and strong positive staining for CD99 and LCA.	NA	CHOP	CR	Death	PTLD	17	Han et al.²⁰
12	22/F	SAA	MUD	NA	TAC/MTX	+	-	+	2	Recurrent fevers and progressive lymphadenopathy in the left posterior cervical and supraclavicular fossa regions	supraclavicular lymph node	NA	NA	The large lymphocytes were positive for CD79a, while the middle-sized lymphocytes were positive for CD3	positive	Rituximab + CHOP	not evaluable due to death for MOF	Death	MOF	3	Tanaka et al.²¹
13	58/M	AML	MMUD	RIC	TAC/MTX	-	+	+	4	NA	Intestine	Recipient	NA	Positive for CD3 and CD4	negative	CHOP, CHASE	CR	Death	PTLD	7	Kuno et al.⁴
14	67/M	AITL	MMUD	RIC	TAC/MTX/ATG	+	+	+	3	NA	Liver, BM	Recipient	NA	Positive for CD30	positive	Brentuximab vedotin, GCD	CR	Death	PTLD	3
15	56/F	AITL	MMUD	RIC	TAC/MTX	-	+	+	1	NA	BM	Recipient	NA	Positive for CD3, CD8	positive	None	/	Death	PTLD	0.4
16	59/M	AML	CB	RIC	TAC	+	+	+	42	NA	Skin, Intestine, Pharynx, BM	NA	NA	Positive for CD3	positive	Rituximab	PD	Death	PTLD	78

Abbreviations: AITL, angioimmunoblastic T-cell lymphoma; ALL, acute lymphoblastic leukemia; Allo-HCT, allogeneic hematopoietic cell transplantation; BM, bone marrow; BO, bronchiolitis obliterans; CIMF, chronic idiopathic myelofibrosis; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; LBL, lymphoblastic lymphoma; LGL, large granular lymphocyte; LPD, lymphoproliferative disease; MCL, mantle cell lymphoma; MMUD, mismatched unrelated donor; MOF, Multiple organ failure; MRD, matched related donor; UCHL-1, Ubiquitin carboxyl-terminal hydrolase isozyme L1; PB, peripheral blood stem cell; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; RIC, reduced-intensity conditioning; SAA, severe aplastic anemia; TRM, transplantation related mortality; VOD, veno-occlusive disease; WM, Waldenstrom macroglobulinemia; TAC, tacrolimus; CB, cord blood; GCD, gemcitabine, carboplatin, and dexamethasone; CHASE, cyclophosphamide, cytarabine, etoposide, and dexamethasone; TIA, T-cell intracellular antigen-1; LCA, leukocyte common antigen.

The most common symptom was fever, followed by pain or lump caused by lymphadenopathy. The lymph node was frequently involved, leading to the various clinical characteristics. The immunotypes of T-cell PTLD were heterogeneous. Of 16 patients with EBER ISH results, 56.3% of the tissues (9/16) were positive for EBER. Chimerism analysis showed that 64.7% of the cases (11/17) were donor-derived.

Sixteen of 22 T-cell PTLD patients received interventions, including chemotherapy (n = 13), allo-HSCT (n = 2) and one patient only with reduction of immunosuppressive agents. Of 15 patients in this study who had therapy information and response evaluation, 53.3% of the patients (8/15) received CHOP-based chemotherapy. 87.5% of these patients (7/8) achieved CR, and the CR rate of other therapies was 29% (2/7). About 40.1% of patients (9/22) died of PTLD. Kaplan–Meier analysis showed that the median OS of the 22 patients was 7 months.

Comparison of T-Cell PTLD and B-Cell PTLD

We further compared the features of T-cell and B-cell PTLD after allo-HSCT. The characteristics are summarized in Table 3. Few studies reported the incidence of T-cell PTLD after allo-HSCT, although T-cell PTLD accounted for approximately 5%–15% of all PTLD after solid organ transplantation (SOT)^22,23. Several studies have provided dissociating patterns between EBV-positive and EBV-negative PTLD^24–26. The relatively low positive rate of EBER ISH for T-cell PTLD compared with B-cell PTLD (53.3% vs. 60-80%^4,5) is consistent with previous study²³ suggesting that the pathogenesis of T-cell PTLD may be different from B-cell PTLD. T-cell PTLD developed later than B-cell PTLD after allo-HSCT (median: 5 months vs. 2-3 months²⁷). Besides, the treatment of T-cell PTLD was more limited, and the OS of patients with T-cell PTLD was inferior to that of patients with B-cell PTLD (median OS: 6.5 months vs. 6.6 years)²⁸, because B-cell PTLD would benefit from rituximab-based therapy²⁸.

Table 3.

Comparison of T-Cell PTLD and B-Cell PTLD in Allo-HSCT Patient.

	T-cell PTLD	B-cell PTLD
Positive rate of EBER ISH^a	53.30%	60%–80%
Onset time (Median)^a	4 months	2–3 months
Treatment	IST plus specific chemotherapy	Rituximab-therapy plus chemotherapy
OS (Median)^a	7 months	6.6 years

Abbreviation: PTLD: posttransplant lymphoproliferative disorder; EBER ISH, in situ hybridization with an EBV-encoded small nuclear early region; IST: immunosuppressive therapy; OS: overall survival.

These data of T-cell PTLD were calculated from 22 patients in this study. Other data were summarized from systematic review of previous literatures.

Discussion

In this retrospective analysis, we presented the clinical features and outcomes of six patients with T-cell PTLD after allo-HSCT, and systemic reviewed 16 T-cell PTLD patients in the literatures. We found that T-cell PTLD had a later onset, weaker association with EBV, and a poorer response to chemotherapy compared with B-cell PTLD.

The impact of the intensity of conditioning regimen on the development of PTLD remains controversial. Previous studies revealed that reduced-intensity conditioning (RIC) with ATG as aGvHD prophylaxis increased the probability of EBV reactivation after allo-HSCT²⁹, and RIC conditioning increased the risk of EBV-PTLD³⁰. On the contrary, Xuan et al.³¹ observed that intensified conditioning was one of the risk factors for EBV viremia and PTLD. However, T-cell PTLD is rarely reported. Tiede et al.²³ confirmed that allo-HSCT was associated with early-onset T-cell PTLD. The primary independent favorable prognostic factors included younger patients, T-cell PTLD of the large granular lymphocytic leukemia subtype, a combination of radiotherapy/radio chemotherapy and reduced immunosuppression²³. In addition, patients receiving HID HSCT with ATG as GvHD prophylaxis were predisposing to higher incidence of EBV viremia (83.3% vs. 46%) and earlier onset of T-cell PTLD (median: 2 months vs. 5 months) in our series, compared with the other 16 T-cell PTLD patients.

EBV mainly infects B lymphocytes and has the capacity for transforming B-cells and driving the pathophysiology of B-cell PTLD^32,33. As previously reported, less T-PTLD were EBV-related than that of B-cell PTLD³⁴. The association between T-cell PTLD and EBV was weaker as a lower rate of EBER positivity in IHC was detected in this study. Nevertheless, Chuhjo et al.³⁵ found that EBV could infect T- and B-cells simultaneously, inducing clonal proliferation of both types of lymphocytes in profound immunocompromised patients. Some researchers believed that a cofounding, T-cell proliferation and transformation-promoting role of adjacent EBV-positive B-cells. In a recent work by Wang et al.³⁶, EBV infected the full spectrum of the hematopoietic system including both lymphoid and myeloid lineages, so as hematopoietic stem cells (HSCs) in the chronic active EBV patients.

Besides, the majority of PTLDs after allo-HSCT were donor-derived, while those following SOT always recipient derived^37,38. This research also supported this conclusion as all our T-cell PTLD patients and most of the reviewed cases were donor originated. The cell of origin after transplantation may influence the treatment choice. Immunosuppression tapering (IST) was first considered for low-risk PTLD patients with acceptable physical conditions. IST allows recovery of the host’s immune system, promoting EBV-specific T-lymphocytes to proliferate and control the disease³⁹. More aggressive treatment, including chemotherapy, radiotherapy, surgery, rituximab, and cellular immunotherapy, such as donor lymphocyte infusion, would be considered when patients showed no response to IST¹⁹.

As the low incidence and dismal outcomes of T-cell PTLD, a key question is how to diagnose and intervene without delay. In our series, failure to empiric rituximab therapy (n = 4) led to pathological examination to confirm the PTLD subtype; therefore, these patients took a longer time to final diagnosis (59.5 [range: 31–114] days vs. 34 [20–48] days) leading to a lower response to CHOP-based therapy (3/4) compared with the other two patients who performed biopsy when symptoms onset. We recommended that patients with probable PTLD should perform biopsy promptly, and for patients who did not respond to IST and/or rituximab-based therapy, the diagnosis of T-cell PTLD should be considered. CHOP-based chemotherapy may be the preferred option, given it provided higher CR rate (87.5% vs. 29.0%) for T-PTLD compared to the other therapies.

This study has some limitations, including its retrospective designed, small sample size and heterogeneity of the patients. As the incidence of T-PTLD is rather low, the systemic review and the present case series would provide new insights into future studies for T-cell PTLD.

In summary, T-cell PTLD displays distinct characteristics compared with B-cell PTLD, which characterized by less connections to EBV, later occurrence, and poorer prognosis. Research is necessary to investigate the risk factors, how to diagnosis timely and more effective treatment for T-cell PTLD.

Footnotes

Author Contributions

X.H. and Y.C. designed the study. C.J. and J.H. wrote the manuscript. C.J., J.H., J.S., T.Y., Y.Z., M.H. H.Y., J.S., L.W., F.C., Y.C. and X.H. were involved in collecting, analyzing, or interpreting research data and writing the manuscript. C.J. and J.H. analyzed research data.

Ethical Approval

Institutional databases were retrospectively reviewed to extract demographic, clinical and genetic data. All procedures complied with the tenets of the Helsinki Declaration, and approved by Institutional Review Boards of participating centers. The requirement for written informed consent was waived, owing to the non-interventional and retrospective nature of the study.

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (grant no. 82170206) and Shanghai Municipal Health Commission Project of Disciplines of Excellence (grant no. 20234Z0002).

ORCID iDs

Jingtao Huang

Jimin Shi

Liping Wan

References

Fujimoto

Hiramoto

Yamasaki

Inamoto

Uchida

Maeda

Mori

Kanda

Kondo

Shiratori

Miyakoshi

, et al. Risk factors and predictive scoring system for post-transplant lymphoproliferative disorder after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019;25(7):1441–49.

Kinzel

Dowhan

Kalra

Williamson

Dabas

Jamani

Chaudhry

Shafey

Jimenez-Zepeda

Duggan

Daly

, et al. Risk factors for the incidence of and the mortality due to post-transplant lymphoproliferative disorder after hematopoietic cell transplantation. Transplant Cell Ther. 2022;28(1):53.e1–e10.

Styczynski

Gil

Tridello

Ljungman

Donnelly

van der Velden

Omar

Martino

Halkes

Faraci

Theunissen

, et al. Response to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis. 2013;57(6):794–802.

Kuno

Ito

Maeshima

Taniguchi

Tanaka

Inamoto

Kurosawa

Kim

Fukuda

. T-cell posttransplant lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Int J Hematol. 2020;112(2):193–99.

Amengual

Pro

. How I treat posttransplant lymphoproliferative disorder. Blood. 2023;142(17):1426–37.

Chen

Sun

Zhang

Liu

Cheng

Huang

Wang

. Dynamic monitoring of plasma Epstein-Barr Virus DNA load can predict the occurrence of lymphoproliferative disorders after haploidentical hematopoietic stem cell transplantation. Zhonghua Xue Ye Xue Za Zhi. 2023;44(4):284–88.

Baram

Asaulenko

Spiridonov

Krivolapov

. WHO classification of tumors of hematopoietic and lymphoid tissues, 2022 (5th edition): lymphoid tumors. Arkhiv Patologii. 2023;85(4):24–31.

Wang

Liu

Q-F

Lin

Yang

Y-J

X-D

Huang

X-J

. Optimizing antithymocyte globulin dosing in haploidentical hematopoietic cell transplantation: long-term follow-up of a multicenter, randomized controlled trial. Sci Bull. 2021;66(24):2498–505.

Wang

Liu

Q-F

L-P

Liu

K-Y

Zhang

X-H

Fan

Z-P

D-P

Huang

X-J

. Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood. 2015;125(25):3956–62.

10.

Shen

M-Z

Hong

S-D

Lou

Chen

R-Z

Zhang

X-H

L-P

Wang

Yan

C-H

Chen

Y-H

Han

, et al. A comprehensive model to predict severe acute graft-versus-host disease in acute leukemia patients after haploidentical hematopoietic stem cell transplantation. Exp Hematol Oncol. 2022;11(1):25.

11.

2023 NCCN clinical practice guidelines in oncology (NCCN Guidelines®) B-cell lymphomas version 6.2023—October 10, 2023. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf.

12.

H-R

Yang

T-T

Zhao

Y-M

Tan

Y-M

Gao

Q-Q

Huang

Shi

J-M

. Successful treatment of early onset Epstein-Barr virus-negative T-cell lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation with histone deacetylase inhibitor chidamide. Chin Med J. 2021;134(22):2756–58.

13.

Zutter

Durnam

Hackman

Loughran

Jr Kidd

Ashley

Petersdorf

Martin

Thomas

. Secondary T-cell lymphoproliferation after marrow transplantation. Am J Clin Pathol. 1990;94(6):714–21.

14.

Wang

Jou

Chiang

Lin

. T cell lymphoproliferative disorder following bone marrow transplantation for severe aplastic anemia. Bone Marrow Transplant. 2000;26(8):893–97.

15.

Lam

Lie

Pang

Kwong

. T-cell large granular lymphocyte leukemia of donor origin after allogeneic bone marrow transplantation. Am J Clin Pathol. 2003;120(4):626–30.

16.

Chang

Kamel-Reid

Hussain

Lipton

Messner

. T-cell large granular lymphocytic leukemia of donor origin occurring after allogeneic bone marrow transplantation for B-cell lymphoproliferative disorders. Am J Clin Pathol. 2005;123(2):196–99.

17.

Santos-Briz

Romo

Antúnez

Román

Alcoceba

Garcia

Vazquez

González

Unamuno

. Primary cutaneous T-cell lymphoproliferative disorder of donor origin after allogeneic haematopoietic stem-cell transplantation. Clin Exp Dermatol. 2009;34(8):e778–81.

18.

Nishida

Yamamoto

Ohta

Karasawa

Kato

Uchida

Wake

Taniguchi

. T-cell post-transplant lymphoproliferative disorder in a patient with chronic idiopathic myelofibrosis following allogeneic PBSC transplantation. Bone Marrow Transplant. 2010;45(8):1372–74.

19.

Cai

Yuan

Huang

Jing

Zhu

Zhao

Wang

Han

, et al. Successful treatment of polymorphic post-transplant lymphoproliferative disorder after allo-HSCT with reduction of immunosuppression. Int J Clin Exp Med. 2014;7(7):1904–909.

20.

Han

Sun

Chen

Wang

Liu

Chen

. Primary distal femur T-cell lymphoma after allogeneic haematopoietic stem cell transplantation for chronic myeloid leukaemia: a rare case report and literature review. J Int Med Res. 2014;42(2):598–605.

21.

Tanaka

Takizawa

Miyakoshi

Kozakai

Fuse

Shibasaki

Moriyama

Ohshima

Toba

Furukawa

Sone

, et al. Manifestations of fulminant CD8 T-cell post-transplant lymphoproliferative disorder following the administration of rituximab for lymphadenopathy with a high level of Epstein-Barr Virus (EBV) replication after allogeneic hematopoietic stem cell transplantation. Intern Med. 2014;53(18):2115–19.

22.

Swerdlow

. T-cell and NK-cell posttransplantation lymphoproliferative disorders. Am J Clin Pathol. 2007;127(6):887–95.

23.

Tiede

Maecker-Kolhoff

Klein

Kreipe

Hussein

. Risk factors and prognosis in T-cell posttransplantation lymphoproliferative diseases: reevaluation of 163 cases. Transplantation. 2013;95(3):479–88.

24.

Nakid-Cordero

Choquet

Gauthier

Balegroune

Tarantino

Morel

Arzouk

Burrel

Rousseau

Charlotte

Larsen

, et al. Distinct immunopathological mechanisms of EBV-positive and EBV-negative posttransplant lymphoproliferative disorders. Am J Transplant. 2021;21(8):2846–63.

25.

Morscio

Dierickx

Ferreiro

Herreman

Van Loo

Bittoun

Verhoef

Matthys

Cools

Wlodarska

De Wolf-Peeters

, et al. Gene expression profiling reveals clear differences between EBV-positive and EBV-negative posttransplant lymphoproliferative disorders. Am J Transplant. 2013;13(5):1305–16.

26.

Naik

Riches

Hari

Kim

Chen

Bachier

Shaughnessy

Hill

Ljungman

Battiwalla

Chhabra

, et al. Survival outcomes of allogeneic hematopoietic cell transplants with EBV-positive or EBV-negative post-transplant lymphoproliferative disorder: a CIBMTR study. Transpl Infect Dis. 2019;21(5):e13145.

27.

Landgren

Gilbert

Rizzo

Socié

Banks

Sobocinski

Horowitz

Jaffe

Kingma

Travis

Flowers

, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. 2009;113(20):4992–5001.

28.

Trappe

Dierickx

Zimmermann

Morschhauser

Mollee

Zaucha

Dreyling

Dührsen

Reinke

Verhoef

Subklewe

, et al. Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or R-CHOP consolidation in an international, prospective, multicenter phase II trial. J Clin Oncol. 2017;35(5):536–43.

29.

Peric

Cahu

Chevallier

Brissot

Malard

Guillaume

Delaunay

Ayari

Dubruille

Le Gouill

Mahe

, et al. Features of Epstein-Barr Virus (EBV) reactivation after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation. Leukemia. 2011;25(6):932–38.

30.

Lindsay

Othman

Heldman

Slavin

. Epstein-Barr virus posttransplant lymphoproliferative disorder: update on management and outcomes. Curr Opin Infect Dis. 2021;34(6):635–45.

31.

Xuan

Huang

Fan

Zhou

Zhang

Liu

Sun

Liu

. Effects of intensified conditioning on Epstein-Barr virus and cytomegalovirus infections in allogeneic hematopoietic stem cell transplantation for hematological malignancies. J Hematol Oncol. 2012;5:46.

32.

Dharnidharka

Webster

Martinez

Preiksaitis

Leblond

Choquet

. Post-transplant lymphoproliferative disorders. Nat Rev Dis Primers. 2016;2:15088.

33.

Young

. EBV-driven B-cell lymphoproliferative disorders: from biology, classification and differential diagnosis to clinical management. Exp Mol Med. 2015;47(1):e132.

34.

Herreman

Dierickx

Morscio

Camps

Bittoun

Verhoef

De Wolf-Peeters

Sagaert

Tousseyn

. Clinicopathological characteristics of posttransplant lymphoproliferative disorders of T-cell origin: single-center series of nine cases and meta-analysis of 147 reported cases. Leuk Lymphoma. 2013;54(10):2190–99.

35.

Chuhjo

Yachie

Kanegane

Kimura

Shiobara

Nakao

. Epstein-Barr virus (EBV)-associated post-transplantation lymphoproliferative disorder simultaneously affecting both B and T cells after allogeneic bone marrow transplantation. Am J Hematol. 2003;72(4):255–58.

36.

Wang

Wei

Yan

Zhang

Gong

Suolitiken

Song

Chen

, et al. Chronic active Epstein-Barr Virus disease originates from infected hematopoietic stem cells. Blood. 2024;143:32–41.

37.

Kinch

Cavelier

Bengtsson

Baecklund

Enblad

Backlin

Thunberg

Sundström

Pauksens

. Donor or recipient origin of posttransplant lymphoproliferative disorders following solid organ transplantation. Am J Transplant. 2014;14(12):2838–45.

38.

Olagne

Caillard

Gaub

Chenard

Moulin

. Post-transplant lymphoproliferative disorders: determination of donor/recipient origin in a large cohort of kidney recipients. Am J Transplant. 2011;11(6):1260–69.

39.

Al Hamed

Bazarbachi

Mohty

. Epstein-Barr virus-related post-transplant lymphoproliferative disease (EBV-PTLD) in the setting of allogeneic stem cell transplantation: a comprehensive review from pathogenesis to forthcoming treatment modalities. Bone Marrow Transplant. 2020;55(1):25–39.

T-Cell Posttransplant Lymphoproliferative Disorders After Allogeneic Hematopoietic Stem Cell Transplantation: Case Series and Systemic Review

Abstract

Keywords

Introduction

Materials and Methods

Patient Selection

Morphological and Molecular Analysis

Transplant Regimen

Definitions

Data Collection

Published Articles

Results

Clinical Features of Our Patients

Pathological Findings of T-PTLD Patients

Treatment and Clinical Outcomes

Clinicopathological Features of T-Cell PTLD After Allo-HSCT

Comparison of T-Cell PTLD and B-Cell PTLD

Discussion

Footnotes

Author Contributions

Ethical Approval

Statement of Human and Animal Rights

Statement of Informed Consent

Data Availability Statement

Declaration of Conflicting Interests

Funding

ORCID iDs

References