Rituximab-based treatments followed by adoptive cellular immunotherapy for biopsy-proven EBV-associated post-transplant lymphoproliferative disease in recipients of allogeneic hematopoietic stem cell transplantation

Figures & data

Table 1. Characteristics of patients receiving rituximab-monotherapy or rituximab+chemotherapy

	R-COP/R-CHOP		Rituximab monotherapy
	n	%	n	%	p
	38		46
Age median (range)	21.5 (14–46)		25 (9–49)
Sex male	23	61	31	67	0.513
Stage I/II	29	76	38	83	0.475
Nodal only	21	55	32	70	0.176
≧2 extranodal sites	3	8	2	4	0.494
Histology	0		8
Early lesion	0		21
Polymorphic monomorphic	38		17
HLA-matched^*	6	16	11	24	0.356
Donor related^#	27	71	38	83	0.208
PBSCT^!	12	32	10	22	0.307
RI	21	55	19	41	0.202
DLI for inducing CR and relapse-prophylaxis	7	18	12	26	0.403
CTL for inducing CR and relapse-prophylaxis	4	11	4	9	0.776
DLI for only relapse-prophylaxis	17	45	26	57	0.282
CTL for only relapse-prophylaxis	6	16	1	2	0.025

* Patients receiving HLA-matched grafts.

^# Patients transplanted from related donors.

^! Patients receiving only PBSCT, relative to the patients receiving PBSCT+BMT.

RI, reduction of immunosuppression; R, rituximab; R-COP, rituximab (375 mg/m², day 0) + cyclophosphamide (600 mg/m², day 1) + vincristine (2 mg, day 1) + prednisolone (60 mg, day 1–5); R-CHOP, R-COP + epirubicin (75 mg/m², day 1); PBSCT, peripheral blood stem cell transplantation; BMT, bone marrow stem cell transplantation; DLI, Granulocyte colony-stimulating factor-mobilized donor lymphocyte infusion; EBV-CTL, Epstein-Barr virus-specific cytotoxic T lymphocytes.

Table 2. Characteristics of patients receiving DLI or EBV-CTL for inducing CR

	CTL		DLI
	n	%	n	%	p
	8		19
Age median(range)	23(14–41)		19(13–45)
Sex male	6	75	12	63	0.551
Stage I/II	7	88	14	74	0.430
Nodal only	6	75	9	47	0.187
≧2 extranodal sites	0		2	11	0.340
Histology	0	0	1	5	0.508
Early lesion	2	25	5	26	0.943
Polymorphic monomorphic	6	75	13	68	0.732
HLA-matched^*	1	13	2	11	0.882
Donor related^#	7	88	16	84	0.826
PBSCT^!	1	13	3	16	0.826
RI	2	25	6	32	0.732
R-CHOP/COP	4	50	7	37	0.525

* Patients receiving HLA-matched grafts.

^# Patients transplanted from related donors.

^! Patients receiving only PBSCT, relative to the other patients receiving PBSCT+BMT.

RI, reduction of immunosuppression; R, rituximab; R-COP, rituximab (375 mg/m², day 0) + cyclophosphamide (600 mg/m², day 1) + vincristine (2 mg, day 1) + prednisolone (60 mg, day 1-5); R-CHOP, R-COP + epirubicin (75 mg/m², day 1); PBSCT, peripheral blood stem cell transplantation; BMT, bone marrow stem cell transplantation; DLI, Granulocyte colony-stimulating factor-mobilized donor lymphocyte infusion; EBV-CTL, Epstein-Barr virus-specific cytotoxic T lymphocytes.

Figure 1. Study profile. DLI, Granulocyte colony-stimulating factor-mobilized donor lymphocyte infusion; EBV-CTL, Epstein-Barr virus-specific cytotoxic T lymphocytes; PD, progression of disease; CR, complete remission; MODS, multiple-organ disfunction syndrome; PFS, progression-free survival; OS, overall survival. *: included two CR patients not receiving DLI or EBV-CTL.

Figure 2. Lymphocyte percentages in circulation and EBV-specific cytotoxic lymphocyte activity of patients who received DLI and EBV-CTL infusion. No significant difference was observed between patients received DLI and EBV-CTL in lymphocytes (CD3⁺ T cells, p = 0.552; CD16⁺CD56⁺ NK cells, p = 0.549; CD19⁺ B cells, p = 0.704). (A), (B) and (C): The percentages of CD3⁺ T cells, and CD16⁺CD56⁺ NK cells before cellular immunotherapies were not different from those before rituximab-based treatment (p = 0.471 and p = 0.603, respectively), while the CD19⁺ B cells before the cell infusions were less than those before the rituximab-based treatments (p < 0 .001). The percentages of CD3⁺ T cells, CD16⁺CD56⁺ NK cells, CD19⁺ B cells were increased in the 1st month after cellular immunotherapies than those before cell infusions (p = 0.001, p = 0.01, p < 0 .001, respectively), higher in the 3rd month than those in the 1st month after DLI or EBV-CTL (p < 0 .001, p = 0.009, p < 0 .001, respectively), and reached their maximal in the 3rd, 6th, 6th month, respectively. The CD4⁺ T cell to CD8⁺ T cell ratio increased since the 3rd month (p < 0.001), no differences among the 6th, 9th and 12th month. (D) In the spot assay, the IFNγ spot numbers before the cell infusion were not different from those before rituximab-based treatments (p = 0.296), while more in the 1st month than those before cell infusion (p < 0 .001), more in the 3rd month than those in the 1st month after cellular immunotherapies (p < 0 .001) and more in the 6th month than those in the 3rd month (p < 0 .001), no differences among the 6th, 9th and 12th month after cellular immunotherapies. The EBV-CTL activity in EBV-CTL treatment group was higher than that in the DLI group (p = 0.001). Notes: Arrows denote the time of rituximab-based treatments.

Figure 3. Lymphocyte subsets in a relapsed PTLD patient.

Figure 4. Response duration, time to progression, progression-free survival and overall survival.