Improving Cytomegalovirus-Specific T Cell Reconstitution after Haploidentical Stem Cell Transplantation

Table 1

CMV-specific immune recovery after haploidentical stem cell transplantation.

Group/Reference	Number	Disease	Graft manipulation	Conditioning	NRM or TRM	CMV infection	Immune reconstitution (IR)	Comments
TCD haplo-SCT
Perugia; [2]	17	End-stage chemoresistant leukemia	Extensively TCD	TBI + ATG + Cy + Thio	40% NRM; mainly CMV and Aspergillus infection	NR	NR
Perugia; [11]	43	Acute leukemia	Extensively TCD	TBI + ATG + Flu + Thio	The infection-related mortality rate 25–35%	NR	CD4+ >0.1 × 10^9/L at day 60 and >0.3 × 10^9/L at day 180
Lilleri et al.; [12]	48	Malignant or nonmalignant hematological diseases	T cell-depleted peripheral blood CD34+ progenitor cells	ATG + TBI or chemotherapy	9% in R+ or 8% in R− (1-year)	4% in R− and 83% in R+	61% recipients reconstituting CMV-CTL within the first 3 months	Young patients
Chen et al.; [13]	22	Refractory hematological malignancies	Mobilized peripheral blood stem cells depleted of CD3+ cells	Flu + Thio + Mel + OKT3	NR	1/22 patients developed CMV infection	The median number of CD4+ and CD8+ T cells was about 0.2×10^9/L and above 0.1×10^9/L at 3 months	Pediatric recipients
Federmann et al.; [14]	28	Hematological malignancies	CD3/CD19-depleted grafts	Flu or (Clo) + Thio + Mel + OKT-3	NR	Eight of 28 patients had cytomegalovirus reactivation	A median of 205 CD3+ cells/𝜇L, 70 CD3+ CD4+ cells/𝜇L, and 66 CD3+ CD8+ cells/𝜇L on day 100
Pérez-Martínez et al.; [16]	30	Acute leukemia	CD3/CD19-depleted	Flu + Bu + Thio + mP	23% NRM (7/30)	Two of 30 patients have died because of CMV pneumonia	A median of 167±64/𝜇L CD4+ cells versus 364±174/𝜇L CD8+ cells on day 30, 155±47/𝜇L versus 410±119/𝜇L on day 60, and 217±72/𝜇L versus 537±192/𝜇L on day 90.	Children
Unmanipulated haplo-SCT
Peking University; [21]	50	Hematological diseases	G-CSF-primed bone marrow and unmanipulated PBSCs	Ara-C + Bu + Cy + simustine + ATG	19.5±6.0% NRM (2-year)	The cumulative incidence of CMV antigenemia in the early posttransplant phase was 49.9±7.2%	CD4+ T cells at 152.91 (13.29–579.63)/𝜇L on day 90, 163.28 (23.29–875.60)/𝜇L on day 180, and 277.49 (16.91–579.48)/𝜇L on day 365; CD8+ T cells at 672.79 (48.23–2,556.01) on day 90, 918.42 (115.00–4,047.91)/𝜇L on day 180, and 884.16 (175.84–2,441.58)/𝜇L on day 365
Peking University; [22]	42	Malignant hematological disorders	G-CSF-primed bone marrow and unmanipulated PBSCs	Ara-C + Bu + Cy + simustine + ATG	24% NRM (10/42)	The cumulative incidence of CMV reactivation was 87.67% (75.70–95.48%); 5 of them had CMV disease (day 22–50).	The CD8+ T cell count equaled that of controls at day 60, and the median number of CMV-CTL cells was comparable to that of controls from day 30 to day 360
Kurokawa et al.; [24]	66	Hematologic malignancies	Unmanipulated PBSCs and/or bone marrow	ATG + BU + Mel with TBI or Flu	11% NRM (7/66)	CMV antigenemia occurred in 45 of 57 evaluable patients	CD3+ >1600/𝜇L at day 180 and CD8+ >1200/𝜇L at day 180. The lowest numbers of CD3+, CD4+, and CD8+ T cells were seen at 1 month after transplantation but all continued to rise until 6 months after transplantation.
Lee et al.; [25]	83	Acute leukemia and myelodysplastic syndrome	Unmanipulated PBSCs	BU + Flu + ATG	18% (95% CI, 12%–29%) TRM	Fifty-eight of 72 evaluated patients (81%) had CMV pp65 antigenemia.	CD8+ lymphocyte counts exceeded pretransplantation levels at 2 months, and >90% of patients maintained counts >200/𝜇L at 3 months after transplantation. 12 months after transplantation, 24 of 27 patients (89%) had CD4+ lymphocyte counts more than 200/𝜇L.
Kanda et al.; [26]	12	Hematologic malignancies	Unmanipulated PBSCs	Alemtuzumab + TBI or Flu based	17% NRM (2/12)	Ten of the 12 patients experienced CMV reactivation, and CMV disease was observed in three patients	CD3+/CD4+ and CD3+/CD8+ T cells were strongly suppressed within 2 months after haploidentical peripheral blood SCT but recovered on day 90. CMV-CTLs were detected on day 90 at 0.03–0.25% of CD8+ T cells
Rizzieri et al.; [27]	49	Hematologic malignancies or marrow failure	Unmanipulated PBSCs	Flu + Cy + Alemtuzumab	31% NRM (15/49)	Twenty-five percent of patients experienced a severe infection, whereas 86% experienced reactivated CMV	The median number of CD4+ and CD8+ T cells was about 100/𝜇L and 400/𝜇L at 3 months for transplant recipients without GVHD.

TCD: T cell-depleted; PBSC: peripheral blood stem cell; NRM: nonrelapse mortality; TRM: treatment-related mortality; CMV: cytomegalovirus; R−: CMV-negative recipients; R+: CMV-positive recipients; CMV-CTL: cytomegalovirus-specific T cells; NR: not reported; TBI: total body irradiation; ATG: antithymocyte globulin; Cy: cyclophosphamide; Thio: thiotepa; Flu: fludarabine; Mel: melphalan; Clo: clofarabine; Bu: busulfan; mP: methylprednisolone; Ara-C: cytosine arabinoside.