Table 1.
Summary of patients’ characteristics and γδ T-cell clinical outcomes (qualitative).
| aGVHD | Relapse | Viral infections | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study | N | Male, n (%) | Patient age, median (range), y | Donors | Source | Diagnosis (n) | Cond. | GVHD prophylaxis | Follow-up, median (range) | γδ Phenotype | Grade, d | n (%) | Outcome | n (%) | Outcome | n (%) | Outcome |
| Norton et al (1992)30 | 10 | NR | 29 | NR | BM | AML (6), ALL (2), CML (1), NHL (1) | NR | NR | 120 d (20-480) | Anti-TCRVδ1 IHC | NR | 7 (70) | No association between γδ T-cell number and aGVHD | NR | NR | NR | NR |
| Diamond et al (1995)41 | 130 | NR | 33 (15-56) | MUD, SIB | BM | ALL (24), AML (30), CML (47), myeloma (6), MDS (5), AA (4), lymphoma (4), others (10) | NR | CSA, MTX, prednisone | NR | Anti-TCRγδ IHC | 1-3, 100 d | 50 (38) | Lymphocytic infiltrates from GIT, liver, and skin are memory αβ T cells | NR | NR | NR | NR |
| Hirokawa et al (2000)46 | 23 | NR | 32 (16-49) | MUD | PB (3) + BM (20) | ALL (3), AML (4), MDS (2), CML (2) | MAC | CSA, MTX | 1.5 y | Total γδ, Vδ-chain CDR3 spectratype | 1-3, 100 d | 5 (22) | No association between γδ T-cell number and aGVHD | NR | NR | NR | No association between γδ T-cell number and CMV reactivation |
| Galimberti et al (2006)47 | 20 | 13 (65) | 51 (35-66) | SIB | PB (20) | MM (20) | NMA | CSA, MTX | 35 mo (17-128) | Vδ-chain CDR3 spectratype, anti-TCRVδ2 IF | >2, 100 d | 8 (40) | Appearance of a new T-cell prominent clone after aGVHD onset | 6 (30) | Appearance of a new T-cell prominent clone after achieved MRD-negativity | 5 (25) | No new T-cell clones associated with CMV reactivation |
| Fujishima et al (2007)48 | 44 | 22 (50) | 30 (16-58) | MUD | PB (7) + BM (35) + CB (2) | AML (15), ALL/LBL (16), CML (8), MDS (3), AA (1), atypical CML (1) | MAC | CSA, MTX | 10 y | Total γδ, Vδ1, Vδ2, Vδ3, and Vδ1 CDR3 spectratype | >2, 100 d | 16 (36) | No association between Vδ1 TCR clonality and aGVHD | 14 (32) | No association between Vδ1 TCR clonality and relapse | 24 (54) | No association between Vδ1 TCR clonality and CMV reactivation. EBV is associated with Vδ1 skewed distribution |
| Koh et al (2007)49 | 20 | NR | NR | NR | NR | NR | NR | NR | 100 d | CD3+ TCRVδ2+ | lcGvHD and ecGvHD | 14 (70) | Reduced γδ T-cell count and frequency in cGVHD group | NR | NR | NR | NR |
| Barron et al (2009)50 | 38 | 19 (50) | 48 (20-72) | MUD (10), related (23), mismatched (5) | PB (35) + BM (2) + CB (1) | AML (15), MM (5), CML (5), ALL (4), lymphoma (4), CLL (2), MDS (2), PNH (1) | MAC, RIC, NMA | NR | 360 d | Total γδ (CD69+, IFNγ+ ELISPOT) | NR | NR | NR | NR | NR | 21 (55) | No difference on CMV-specific response mediated by γδ T cells (CD69+IFN-γ+) assessed by ELISPOT |
| Knight et al (2010)51 | 40 | 23 (57) | 37 (7-63) | SIB (23), MUD (15), mismatched (2) | BM (17) + PB (23) | ALL (7), AML (10), CML (3), MM (4), AA (4), NHL (6), HL (1), MDS (3), FasL deficiency (1), β-thalassemia (1) | MAC, RIC | NR | 24 mo | Total γδ, Vδ1, Vδ2, Vδ3 | NR | NR | NR | NR | NR | 6 (15) | Associated with Vδ2 population expansion between 3 and 12 mo after HSCT. Higher absolute numbers of Vδ2- population in CMV+/+ patient-donor pairs |
| Watanabe et al (2011)52 | 30 | 15 (50) | ≃44.15 (19-64) | Related, MUD | BM + PB + UCB | ALL (16), AML (9), MDS (4), AA (1) | MAC (21), RIC (9) | CSA, MTX, CST, FK | 1750 d | Total γδ, δ2 | >2, 100 d | NR | γδ T cells were significantly lowered in patients with aGVHD | NR | NR | NR | NR |
| Prinz et al (2013)31 | 1 | 1 (100) | 48 | HLA identical brother | NR | CLL (1) | NR | NR | 1 y | Total γδ, Vδ1, Vγ9 | NR | NR | NR | NR | NR | 1 (100) | CMV reactivation is associated with the expansion of Vδ1 |
| Farnault et al (2013)32 | 1 | 0 (0) | 14 | MUD | CB | ALL (1) | MAC | CSA. CST | 12 mo | Total γδ, Vδ1, Vδ2 | NR | NR | NR | NR | NR | 1 (100) | EBV infection resulted in significant Expansion of Vδ1+ cells |
| Lugthart et al (2014)33 | 131 | 88 (67) | ≃11 (0-19) | Related, MUD | BM (107) + PB (24) | Malignant (83), nonmalignant (48) | MAC (100%) | NR | 363 d (302-478) | Total γδ | >2, 100 d | 18 (14) | NR | NR | NR | 46 (35) | γδ T cell levels were twofold higher in patients with an early CMV reactivation |
| Airoldi et al (2015)34 | 27 | 15 (55) | 6 (0-17) | Related | αβ/CD19-depleted PB | ALL (9), AML (6), SCID (4), SDS (1), others (7) | MAC, RIC, NMA | None | Up to 7 mo | Total γδ, Vδ1, Vδ2 | NR | NR | NR | NR | NR | 15 (55) | Associated with the expansion of high-cytotoxic Vδ1 population between 1 and 3 mo after HSCT |
| Gao et al (2016)35 | 48 | NR | NR | NR | NR | NR | NR | NR | NR | Total γδ, Vδ1, Vδ2, FoxP3, gene expression | NR | 24 (50) | High total γδ, Vδ2, and FoxP3+ γδ/Vδ1/Vδ2 T cells in non-aGVHD patients | NR | NR | NR | NR |
| Hu et al (2017)36 | 62 | 41 (66) | 30 (15-48) | MUD (14), related (21), haplo (17), mismatched (10) | NR | ALL (30), AML (19), CML (5), MDS (6), lymphoma (2) | MAC, RIC | NR | 41.7 mo | Total γδ, FoxP3 | lcGvHD and ecGvHD | 41 (66) | Increased γδ Treg in non-cGvHD group | NR | NR | NR | NR |
| Laberko et al (2017)37 | 182 | 124 (68) | 6 (0-23) | MUD (124), Related (58) | αβ/CD19-depleted PB | ALL (46), AML (45), JML (9), NHL (9), MDS (5), nonmalignant (68) | MAC, RIC, NMA | FK, MTX, CSA, Abatacep, MMF, bortezomib | 27 mo | Total γδ | >2, 100 d | 73 (40) | NR | 67 (37) | NR | 93 (51) | CMV reactivation leads to higher absolute numbers of γδ T cells |
| Ravens et al (2017)12 | 33 | 19 (58) | 49 (18-69) | MUD (25), related (5), mismatched (3) | PB (32) + BM (1) | ALL (4), AML (16), CML (6), HL (1), MM (2), MDS (2), NHL (2) | MAC (10) + RIC (23) | NR | 180 d | TRG and TRD NGS, FACS anti-TCR γδ, Vδ2, Vγ9 | NR | NR | NR | NR | NR | 12 (36) | Proliferation of distinct γδ T-cell clones after reactivation of CMV |
| de Witte et al (2018)38 | 54 | 37 (38) | 50 (2-72) | MUD/SIB | PB (28), CB (26) | AML/MDS (29), other malignant (24), nonmalignant (1) | NR | CSA, MTX, CST, FK, sirolimus | 68 d (54-106) | Total γδ, Vδ1, Vδ2 | 2-4, <3 mo | 24 (44) | NR | 11 (20) | NR | 27 (50) | CMV reactivation is associated with Vδ1 expansion between 2-3 mo after HSCT |
| Winstead et al (2018)39 | 17 | 7 (41) | 2.4 (0.4-33.9) | MUD | BM (3) + CB (14) | Nonmalignant | RIC | MMF, FK | 180 d | TRG and TRD Spectratype (complexity score) | >2, 100 d | 4 (24) | Decreased TCR diversity in aGVHD patients | NR | NR | NR | NR |
| Kawanishi et al (1997)40* | 273 | 161 (59) | 15.4 (1-52) | SIB (62), MUD (157), related (54) | TCD BM | ALL (95), AML (54), CML (49), MDS (15), AA (25), lymphoproliferative syndromes (25), other (10) | MAC | CSA | 2.2 y (5 mo-4.9 y) | Total γδ | >2, 100 d | 75 (27) | No association between γδ T-cells number and aGvHD | 71 (26) | No association between γδ T-cell number and relapse | NR | NR |
| Xuan et al (2011)42* | 20 | 11 (55) | NR | SIB | PB | NR | NR | NR | NR | TRGV and TRDV spectratype (complexity score) | 1-4 | 8 (40) | The invariable clonality of TRDV1 gene repertoire is associated with low incidence of GVHD in recipients | NR | NR | NR | NR |
| Sairafi et al (2016)43* | 14 | 8 (57) | 49 (30-64) | SIB (100%) | PB (100%) | AML (4), ALL (2), CLL (1), MDS (5), solid tumor (2) | MAC (100%) | CsA + MTX (85) other (15) | 3 mo | Total γδ | 2-4 <3 mo | 7 (50) | No-aGvHD group presented higher γδ T-cell percentage | NR | NR | NR | NR |
| Nilsson et al (2017)44* | 21 | NR | 48 (1-68) | MUD (81%), SIB (19%) | PB (76%) + BM (24%) | Acute leukemia (14), MDS (4), lymphoma (1), myeloma (1), other (1) | NR | NR | 1 y | Total γδ | 1-3, <3 mo | 5 (24) | NR | 6 (28) | NR | 9 (43) | No association between intragraft γδ T-cell percentage and infection |
| Arruda et al (2019)45* | 20 | 7 (35) | 59.5 (20-71) | MUD (85%), SIB (15%) | PB (100%) | AML (20) | MAC (25%), RIC (75%) | CsA + MTX (100) | 32.7 mo | Total γδ, Vγ9, δV1, Vδ2, γ-chain NGS | 1-4, 100 d | 12 (60) | No association between TRG distribution nor percentage of γδ, γ9, δ1, or δ2 T-cells and aGVHD incidence Public sequences and V-J pairing changes were associated with clinical improvement | 8 (40) | The intragraft percentage of γδ, γ9, δ1, or δ2 T cells were not associated with relapse | NR | CMV+ donors presented a more restricted TRG repertoire and private sequences |
ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; ATG, antithymocyte globulin; BM, bone marrow; CAMPATH, anti-CD52 (alemtuzumab); cond., conditioning; CDR3, complementarity-determining region 3; CB, cord blood; CLL, chronic lymphoid leukemia; GIT, gastrointestinal tract; cGVHD, chronic GVHD; CsA, cyclosporin; CST, corticosteroids; ecGVHD, extensive cGVHD; FK, tacrolimus; haplo, haploidentical; HL, Hodgkin lymphoma; IHC, immunohistochemistry; IF, immunofluorescence; JMML, juvenile myelomonocytic leukemia; lcGVHD, limited cGVHD; MAC, myeloablative conditioning; MRD, minimal residual disease; MDS, myelodysplastic syndrome; MMF, mycophenolate; MTX, methotrexate; MUD, matched unrelated donor; MPAL, mixed phenotype acute leukemia; MDS-RCC, myelodysplastic syndrome-refractory cytopenia of childhood; MPD, methylprednisolone; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; NR, nonreported; OKT3, muromonab-CD3; PB, peripheral blood; PTCy, posttransplantation cyclophosphamide; RIC, reduced intensity conditioning; SAA, severe aplastic anemia; SIB, matched sibling; SCID, severe combined immunodeficiency; SDS, Shwachman-Diamond syndrome; TCD, T-cell depleted; TRG, T-cell receptor γ-chain; TRD, T-cell receptor δ-chain.
*
Studies that only evaluated graft samples.