Page 1823 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 106 Haploidentical Hematopoietic Cell Transplantation 1625

Several groups have attempted to reduce the incidence of GVHD to the fourth posttransplant day, with the optimal effectiveness of this
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seen with use of the GIAC protocol. In a Korean study, researchers treatment being at 2 days posttransplant. This work was continued
used a modification of this platform with RIC and only G-CSF- by a number of other investigators, but it was most fully explored by
PBSC allografts, and their results showed lower rates of grades II–IV a Kyushu University group whose results were published in a series
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acute (20%) and chronic (34%) GVHD. The Air Force General of 13 related reports from 1984 to 1987, with related mechanistic
Hospital group modified its protocol, which used TBI-based condi- studies continuing into the mid-1990s. 125,126 By administering donor
tioning and only GCSF-primed bone marrow, by adding basiliximab spleen cells followed 48–72 hours later by cyclophosphamide, long-
for further GVHD prophylaxis. 114,115 This approach resulted in a lasting tolerance to MHC-compatible, but not MHC-incompatible,
markedly lower rate of grades II–IV acute GVHD of 11%; although skin allografts was established. Three primary mechanisms of post-
chronic GVHD was still seen in most patients, it was mostly limited transplant cyclophosphamide (PTCy)-induced tolerance were delin-
in severity. The Rome Transplant Network employed this same eated in this model: (1) direct elimination of host T cells responding
GVHD prophylaxis approach in 97 patients and had encouraging to donor antigens in the periphery, (2) intrathymic clonal deletion of
results in terms of GVHD (grades II–IV and grades III–IV acute donor-reactive host T cells, and (3) generation of tolerogen-specific
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GVHD of 31% and 9%, respectively, and extensive chronic GVHD host suppressor T cells. Suppressor T cells were found to inhibit
of 12%), but 1-year NRM was 32%. 116 responses to both major and minor histocompatibility antigens
Survival outcomes of patients with acute leukemia who received through active suppression but not clonal deletion of alloreactive T
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haploBMT using the GIAC protocol have been particularly encour- cells. Induction of tolerance by PTCy was disrupted by the admin-
aging. In fact, results of one study suggested that even patients treated istration of CsA or corticosteroids before adoptive cell transfer and
for very high-risk acute leukemia with haploBMT had better out- cyclophosphamide treatment, 129,130 but it was not affected by the
comes than patients receiving HLA-matched sibling alloBMT, owing administration of G-CSF starting the day after PTCy treatment. 131
primarily to a much lower incidence of relapse in the haploBMT Subsequently, the PTCy approach was extended to alloBMT. In
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group (26% vs. 49%; p = .008). In 2009, the Peking University MHC-mismatched mouse models, treatment with PTCy reduced the
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research group reported the results of a study of 250 consecutive dose of radiation required to induce reliable engraftment and also
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patients with acute leukemia, 108 of whom had AML and 142 of prevented GVHD and prolonged survival. Graft failure could be
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whom had ALL. Survival outcomes of patients with AML were further reduced by the use of antilymphocyte globulin, and radia-
particularly favorable, with 3-year OS outcomes of 73% and 56% tion in the conditioning regimen could be replaced entirely by
reported for standard-risk and high-risk groups, respectively. Similarly fludarabine, although high levels of donor chimerism required at least
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excellent outcomes were seen in a second study of adult patients with 100 cGy of TBI. The resultant mixed chimeras were tolerant to
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AML in CR1. However, outcomes of patients with high-risk ALL both donor and host but maintained reactivity against third-party
appear poor because of very high rates of NRM (51% after 3 years alloantigens in mixed lymphocyte culture. 132–134 This tolerogenic
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of follow-up) and relapse (49% after 3 years of follow-up). Patients effect allowed skin and heart allografts from the MHC-mismatched
with standard-risk ALL, however, had an encouraging 3-year OS of donor strain to survive, whereas MHC-disparate third-party grafts
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60%. Two other studies have confirmed excellent survival of were rejected. 132,135
patients with ALL in CR1 treated with haploBMT using the GIAC Parallel to the effects seen on host T cells in skin allograft models,
protocol. 112,118 Researchers in another study retrospectively investi- in mouse alloBMT models treatment with PTCy inhibited GVHD
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gated adult patients with ALL who had high-risk disease and were in through elimination of alloreactive donor T cells. Donor T cells
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CR1 but lacked an HLA-matched sibling or HLA-matched URD. exposed to antigen on day 0 were largely depleted by PTCy, whereas
Consolidation with either 2 years of chemotherapy (n = 104) or nonalloreactive donor T cells, which divided more slowly in a lym-
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haploBMT (n = 79) was chosen by the patients; those who received phopenic environment, were relatively spared (Fig. 106.4).
haploBMT had markedly better 3-year disease-free survival (DFS) However, destruction of alloreactive donor T cells was necessary but
(64% vs. 21%), OS (72% vs. 27%), and cumulative incidence of not sufficient for PTCy-induced tolerance. The role of Tregs in induc-
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relapse (19% vs. 61%) than chemotherapy-treated patients. In ing, as opposed to maintaining, tolerance is controversial. In mouse
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multivariate analyses, treatment with haploBMT was the only factor models of MHC-matched alloBMT in which donor CD4 T cells
associated with less relapse and better OS. promote GVHD, donor Tregs were necessary to prevent lethal
In these studies of haploBMT using the GIAC protocol, the GVHD after PTCy treatment, 137,138 an effect consistent with the
extent of HLA disparity did not affect OS. 110,120,121 Although findings results from skin allograft models. In these mouse and human studies,
of a later study suggested that HLA-B mismatching was associated donor Tregs were resistant to PTCy-induced cytotoxicity, owing to
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with higher acute GVHD and NRM as well as worse DFS and OS, increased expression of aldehyde dehydrogenase, the enzyme primar-
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the Peking University group’s latest analysis did not confirm this ily responsible for in vivo detoxification of cyclophosphamide,
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finding. In an analysis of the effects of donor characteristics on upon allogeneic stimulation in a lymphopenic environment. 137,138 In
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patient outcomes, the lowest NRM and highest OS were seen when contrast, PTCy can induce tolerance in alloreactive CD8 T cells in
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using younger, male donors. Less acute GVHD was seen when the the absence of CD4 T cells, including CD4 Tregs. Other studies
donor was the patient’s child or an HLA-haploidentical relative who have shown that Tregs are not required for cyclophosphamide-induced
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was mismatched for noninherited maternal HLA antigens (NIMA); tolerance of tumor-reactive T cells or for transplant tolerance
however, neither of these donor types was associated with improved induced by bendamustine. 141
survival. By contrast, use of maternal donors was associated with PTCy is the most commonly employed approach to selective
higher acute and chronic GVHD and worse survival. Overall, the alloreactive TCD, although ex vivo approaches also have been
authors suggested that a NIMA-mismatched male child was the best explored. These strategies include using mixed lymphocyte cultures
possible donor for haploBMT using the GIAC protocol, whereas use to eliminate alloactivated cells that either express the activation
of older mothers and noninherited paternal antigen-mismatched marker CD25 or retain a dye that becomes highly cytotoxic upon
donors should probably be avoided. 121 activation with visible light. 142–144 This latter photodepletion approach
also spares Tregs and has reportedly shown promise in ongoing clini-
cal studies. 145,146
Posttransplant Cyclophosphamide
The effects of cyclophosphamide, one of the oldest chemotherapeutic Clinical Outcomes of HaploSCT With PTCy
agents, on immunologic tolerance have been studied since the early
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1960s. High-dose cyclophosphamide was found to be effective in In a phase I study of 13 patients at the John Hopkins Hospital
prolonging the survival of MHC-mismatched mouse skin allografts (JHH), patients received PTCy 50 mg/kg 3 days after receiving TCR
only when the drug was given shortly after allograft placement or up haploBMT using RIC with fludarabine and low-dose (200 cGy) TBI