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370 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 371

the endoscopist has experience in evaluating allogeneic HCT recipi- differed somewhat, but did not impact TRM. Interestingly, there was a
ents, but biopsies remain essential to rule out CMV enteritis and other strong trend toward a higher incidence of chronic GVHD in the SRL-
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etiologies. Mucosal denudation is a particularly concerning endo- containing arm (53 percent vs. 45 percent, p = 0.06).
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scopic finding, and is associated with a grim prognosis. Donor T-cell depletion has been explored as a means of GVHD
Hepatic GVHD presents with abnormal liver function tests, most prevention, using either mechanical ex vivo T-cell depletion or in
commonly elevated bilirubin and alkaline phosphatase. Liver biopsy is vivo T-cell depletion in the form of ATG or alemtuzumab. T-cell-
required for definitive diagnosis, but is rarely performed because of the depletion strategies have generally been successful in reducing GVHD,
low pretest likelihood of hepatic GVHD in the modern era and because but in many instances the reduction in donor T cells contributes to an
of procedural risk. When biopsies are performed, the most common increased incidence of graft rejection, infection, and relapse which may
finding associated with hepatic GVHD is bile-duct injury and loss negate the advantage of GVHD prevention. A recent randomized clin-
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resulting in cholestasis. Numerous other etiologies can cause abnor- ical trial of ATG versus placebo added to standard CSP/MTX GVHD
mal liver function tests in allogeneic HCT recipients, including SOS, prophylaxis reported lower rates of acute and chronic GVHD in the
viral hepatitis, regimen-related hepatotoxicity, and medication-related ATG arm, although TRM and overall survival were not improved.
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hepatotoxicity (particularly with triazoles and CSP). Hepatic GVHD is Longer followup from this study confirmed a significantly lower rate of
relatively uncommon except in the setting of severe multisystem acute chronic GVHD in the ATG arm (45 percent vs. 12 percent, p <0.0001).
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GVHD. However, ATG was associated with an increased risk of PTLD, a compli-
cation that is virtually nonexistent after T-cell-replete allogeneic HCT.
In fact, there were 4 deaths from PTLD in the ATG arm (versus none in
Pathophysiology the placebo arm). Perhaps as a result, the study did not show improve-
The current model of acute GVHD requires three steps. In step 1, the ments in TRM or overall survival with ATG. A subsequent randomized
transplantation conditioning regimen damages host tissue, leading to clinical trial aimed at replicating and extending these results with ATG
increased secretion of inflammatory cytokines such as TNF-α and IL-1. has been completed in the United States.
These cytokines enhance alloreactivity of donor T cells by upregulating In the setting of reduced-intensity allotransplantation, a number of
the expression of major and minor host tissue histocompatibility anti- immunosuppressive regimens have been used, the most common being
gens and also affect other molecules on host antigen-presenting cells CSP plus MMF. 177,185 Posttransplant CY has demonstrated impressive
(APCs). Regimen-related damage to the GI tract results in leakage of efficacy in the setting of HLA-haploidentical HCT, and has been stud-
endotoxins such as lipopolysaccharides into the systemic circulation, ied in the setting of HLA-matched allotransplantation as well. 375,376 The
where they serve as additional inflammatory stimuli. In step 2, resting combination of TLI and ATG is associated with very low rates of acute
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donor T cells become activated in secondary lymphoid organs by host and chronic GVHD even with standard CSP/MMF postgrafting immu-
or donor APCs, which present alloantigens to the T-cell receptor in the nosuppression, 184,185 suggesting that protective conditioning can play a
context of MHC. Costimulatory signals are required for full T-cell acti- significant role in GVHD prevention.
vation. Donor T-cell activation is characterized by cellular proliferation Several laboratories have reported that naïve (CD62L+) T cells
and predominance of Th1 cells and the secretion of IL-2 and IFN-γ. induce experimental acute GVHD, whereas effector memory (CD62L–)
In step 3, cellular effectors mediate tissue injury and destruction in the T cells do not. 377,378 Based on this insight, depletion of naïve donor T
target organs, resulting in the clinical manifestations of acute GVHD. cells has been investigated as a means of preventing acute GVHD in
This step involves the continued release of inflammatory cytokines that humans. Murine models of marrow transplantation show that simul-
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direct specific antihost donor-derived T cells to migrate to the target taneous infusions of T limited the proliferation and clonal expansion
reg
tissues of acute GVHD, namely, skin, liver, and gut. Neutrophils and of activated donor T cells and protected against acute GVHD develop-
mononuclear phagocytes contribute to local tissue injury by amplifying ment in murine models. Pilot studies of T infusions in humans have
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the proinflammatory response. reg
demonstrated safety and some efficacy in preventing GVHD, 145,146,380
although larger trials are required to confirm these preliminary find-
Prevention ings. Importantly, relapse rates did not appear to be increased by the
Without some form of GVHD prophylaxis, virtually all patients under- addition of T , consistent with murine models. 144,146
reg
going allogeneic HCT would develop severe or fatal acute GVHD. Another investigational avenue in GVHD prevention involves
Immunosuppressive drugs are the mainstay of acute GVHD prevention, inhibition of lymphocyte trafficking through CCR5 blockade. A
and all patients undergoing allogeneic HCT with a T-cell-replete graft recent trial combining the CCR5 antagonist maraviroc with standard
require prophylaxis. On the basis of randomized clinical trials pub- GVHD prophylaxis demonstrated low rates of acute GVHD, partic-
lished in the 1980s, the most commonly used regimen in myeloablative ularly GI GVHD. The BMT-CTN is currently conducting a three-
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allogeneic HCT is the combination of a calcineurin inhibitor (CSP or arm randomized clinical trial comparing novel approaches to GVHD
tacrolimus [TAC]) with a short course of MTX, generally given on days prophylaxis: posttransplant CY; maraviroc; and bortezomib-based
+1, +3, +6, and +11 after allotransplantation. 368,369 The addition of pred- immunosuppression.
nisone to this backbone paradoxically increased the risk of acute GVHD
in a randomized clinical trial, and thus glucocorticoids are rarely used Treatment
for GVHD prophylaxis. Two randomized studies demonstrated that The standard first-line therapy for acute GVHD requiring systemic
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TAC was superior to CSP in preventing acute GVHD after myeloabla- treatment is methylprednisolone or prednisone, at a dose of 1 to 2 mg/
tive allogeneic HCT, 371,372 and thus TAC has largely supplanted CSP in kg/day with subsequent tapering once disease activity resolves. Higher
this setting. A recent randomized clinical trial conducted by the BMT- doses of methylprednisolone (10 mg/kg per day) do not prevent evo-
CTN compared TAC/sirolimus (TAC/SRL) to the standard TAC/MTX lution to grades III to IV acute GVHD or improve survival. Patients
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regimen as GVHD prophylaxis after myeloablative allogeneic HCT. The with acute GVHD grade II or less can be safely treated with a starting
primary endpoint (day +114 survival free of acute GVHD grades II to dose of 1 mg/kg/day of methylprednisolone, an approach that reduces
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IV) was not significantly different in the two arms, nor were overall or overall glucocorticoid exposure and toxicity. Complete resolution of
progression-free survival. The toxicity profiles of the two regimens acute GVHD is reported in less than 50 percent of patients after first-line
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