Page 1822 - Hematology_ Basic Principles and Practice ( PDFDrive )

1624 Part X Transplantation

A fourth approach involves infusing virus-specific cytotoxic T-cell
Refinements to the TCD Platform to Improve lines for the prevention or treatment of viral infections. These T
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Immune Reconstitution cells expand in vivo following infusion and exert antiviral effects
without causing GVHD and might also have antitumor activity. 101,102
Early studies of T cell–depleted, megadose HLA-haploidentical SCT Another approach involves infusing donor lymphocytes expressing
were characterized by low rates of graft failure and GVHD but a high suicide genes that could be activated if GVHD developed. 103,104 In a
incidence of NRM, mostly due to infection. These outcomes spurred study of 50 patients, use of this treatment strategy markedly acceler-
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efforts to improve immune reconstitution after TCD haploSCT. The ated immune reconstitution. When GVHD did occur, it could be
Tübingen and Memphis groups introduced CD3/CD19 depletion abated effectively by induction of the suicide gene. However, NRM
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rather than positive selection of CD34 cells to produce a graft still occurred in 40% of the patients.
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containing other CD34 progenitors (such as NK cells, monocytes,
dendritic cells, and other myeloid cells) that might enable immune
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recovery without inciting GVHD. This approach was used in Blood Versus Marrow From Filgrastim-Primed Donors:
combination with RIC in an attempt to lower treatment-related the “GIAC” Protocol
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toxicity. In one study, all but 1 of 29 patients engrafted; however,
grades II–IV acute GVHD occurred in 48% of patients, 8 patients Treatment of bone marrow donors with G-CSF before donation
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(28%) still had NRM, 7 died as a result of infection, and 1 died as increases marrow CD34 cells and granulocyte-macrophage colony-
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a result of GVHD. In a study of 46 children receiving CD3- and forming units, reduces total lymphocytes, and reverses the CD4 /
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CD19-depleted grafts after myeloablative conditioning, successful CD8 T-cell ratio (Fig. 106.3). To enhance engraftment by increasing
engraftment after 5 years of follow-up was shown in 88% of patients, the dose of transplanted HSCs, 15 patients with high-risk leukemia
and grades II–IV acute GVHD occurred in 20%, grades III–IV acute received myeloablative conditioning with cytarabine; cyclophospha-
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GVHD in 7%, chronic GVHD in 21%, and NRM in 20%. In this mide; and 1000-cGy TBI; G-CSF–primed bone marrow from hap-
latter study, relapse occurred in 63% of patients after 2 years of loidentical donors; and GVHD prophylaxis with rabbit ATG (5 mg/
follow-up, although 43% of patients undergoing transplant had kg/day on days −4 through −1), CsA, MTX, and mycophenolate
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active disease at the time of treatment. Overall, the use of CD3/ mofetil (MMF). At the time of reporting, all 15 patients had
CD19 depletion may reduce NRM, but at the cost of a higher risk prompt trilineage hematopoietic engraftment; the cumulative inci-
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of GVHD compared with CD34 selection. dence of GVHD was 33%; and 9 of 15 patients were alive at a median
The increased risk of infection seen after TCD haploSCT may be follow-up of 22 months (range, 13–35 months). On the basis of
due to the depletion from the adult donor graft of pathogen-specific these results, Lu et al compared the outcomes of 293 patients with
memory T cells that provide protection from infection until new leukemia receiving HLA-matched sibling (n = 158) or HLA-
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donor T cells differentiate from hematopoietic precursors in the haploidentical related grafts (n = 135) from G-CSF–primed donors.
recipient thymus. Research has been focused on infusing grafts Patients undergoing haploidentical SCT were conditioned with
containing selected populations of T cells to enhance immune cytarabine, oral busulfan, cyclophosphamide, and methyl-CCNU
reconstitution without substantially increasing the risk of GVHD. (1-[2-chloroethyl]-3-[4-methylcyclohexyl]-1-nitrosourea); received
Adding back low numbers of T cells that have been depleted of G-CSF primed bone marrow on day 0 (n = 134) and/or G-CSF–
alloreactive cells or that have been anergized by IL-10 is a straight- primed peripheral blood on day 1 (n = 131); and received GVHD
forward and promising approach to improving immune reconstitu- prophylaxis with ATG 2.5 mg/kg/day on days −4 through −1, CsA,
tion without exacerbating GVHD. 89,90 MTX, and MMF. This protocol is now termed the GIAC protocol:
A second approach is focused on depleting only T cells expressing (1) G-CSF stimulation of the donor; (2) intensified immunosuppres-
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the αβ T-cell receptor (TcRαβ). TcRγ δ (γδ ) T cells have been sion, including CsA, MMF, and MTX; (3) antithymocyte globulin;
found to mediate virus-specific responses to both CMV and Epstein- and (4) combination of peripheral blood and bone marrow allografts.
Barr virus, 91–93 both of which cause substantial posttransplant mor- All but two haploidentical SCT patients on the GIAC protocol had
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bidity and mortality. Furthermore, γδ T cells have antitumor sustained engraftment of donor neutrophils. The cumulative inci-
activity 91,92,94 while potentially also posing a lower risk for initiating dence of acute grades II–IV, grades III–IV, and chronic GVHD in
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GVHD than αβ T cells. 95,96 Following successful clinical scale deple- recipients of matched versus mismatched SCT were 32% versus 40%
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tion of αβ but not γδ T cells, results of a small study of 23 (p = .13), 11% versus 16% (no p value provided), and 56% versus
pediatric patients with nonmalignant disorders were published in 55% (p = .90). Mismatched patients had a higher incidence of CMV
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2014. The researchers in this study used combined depletion of αβ antigenemia (65% vs. 39%; p < .001) and hemorrhagic cystitis (35%
T cells and B cells and detected GVHD rates similar to those seen vs. 13%; p < .001) but not of CMV disease. Two-year rates of relapse
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in patients who received CD34 -selected TCD haploBMT, but with and NRM were 13% versus 18% (p = .40) and 14% versus 22%
an encouragingly low NRM of 9.3%. 98 (p = .10) for recipients of matched versus mismatched transplants,
Another approach, reported by the Perugia group, involves infus- respectively. The 2-year probability of LFS was 71% versus 64% and
ing immunomagnetically selected Tregs 4 days before transplant that of OS was 72% versus 71% (p = .72) in the matched and mis-
and infusing conventional T cells on the same day as the TCD matched cohorts, respectively. In a follow-up report of 157 consecu-
allograft. 99,100 In the first study of 28 patients, 26 successfully tive recipients of G-CSF–primed bone marrow plus peripheral blood
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engrafted. Only two patients developed grades II–IV acute GVHD, from haploidentical related donors, recipients of CD3 T-cell doses
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and both received the highest T-cell doses in the study cohort; no higher than the median (1.77 × 10 /kg) had a significantly lower
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chronic GVHD was observed. T-cell reconstitution was markedly NRM, better LFS, and better OS. The Beijing results are extremely
improved, including expanded T-cell repertoires and improved encouraging. Novel aspects of the regimen that may contribute to the
pathogen-specific responses. No patients developed CMV-associated low rates of graft failure and GVHD may be the use of low-dose
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disease. Unfortunately, NRM still occurred in 13 patients (50%), rabbit ATG ; the use of G-CSF–mobilized bone marrow plus
8 of whom died following infection. An updated report of an peripheral blood 82,109 ; and the combination of CSP, MTX, and MMF.
expanded cohort of patients showed similar results and suggested Two other Chinese research groups reported very similar results
that, in both mouse and human models, the infusion of Tregs did not of retrospective studies comparing outcomes of patients who received
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seem to affect graft-versus-tumor immunity. Indeed, relapse rates haploBMT with those of patients who received HLA-matched sibling
in patients treated in this study, using add-back of low numbers of or HLA-matched unrelated alloBMT. 110,111 Researchers in a prospec-
Tregs and conventional T cells, were strikingly lower than those in tive, multicenter study of haploBMT (n = 231) versus HLA-matched
historical control subjects. Still, NRM remained high, particularly sibling (n = 219) alloBMT using biologic randomization based on
death as a result of infection, despite laboratory evidence of improved donor availability confirmed similar outcomes between the two
immune reconstitution. groups. 112