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Chapter 108 Graft-Versus-Host Disease and Graft-Versus-Leukemia Responses 1663

(sCD13); sBAFF and anti-dsDNA also may be elevated in patients However, in patients classified as high-risk on the basis of platelet
with late-onset chronic GVHD, but these biomarkers need to counts below 100,000/µL, treatment with prednisone alone resulted
be validated in much larger cohorts before definitive conclusions can in only 26% 5-year survival. When a similar group of patients was
be drawn. treated with alternating-day CSA and prednisone, 5-year survival
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exceeded 50%. A randomized study of patients with extensive
GVHD found no difference when prednisone alone was compared
THERAPY FOR CHRONIC GRAFT-VERSUS-HOST DISEASE with prednisone plus CSA. For chronic GVHD that recurs or fails
24
to respond to initial therapy, there is no standard treatment. A small
Chronic GVHD has a major impact on both quality of life and sur- recent study has shown that an 8 week administration of low dose,
vival, frequently involves multiple organs, and necessitates prolonged subcutaneous IL-2 ameliorated several manifestations of chronic
360
immunosuppressive therapy. One report noted that 15% of cancer- GVHD that was resistant to steroids, particularly in the skin. 9,368 This
free patients were still receiving immunosuppressive therapy after 7 improvement was associated with an increase in Tregs. This increase
361
years. The more severe forms of chronic GVHD are clearly associ- was caused by enhanced, proliferation, thymic export and resistance
ated with a lower disease-free survival. Thus the potential benefit of a to apoptosis. 10,171 Randomized clinical trials of this approach are
GVL effect is shadowed by significant treatment-related mortality. 361 currently being conducted. Other experimental therapies include
Current therapies for chronic GVHD are of limited efficacy, and psoralen plus ultraviolet light A, MMF, thalidomide, total lymphoid
there is no long-term satisfactory regimen for patients who do not irradiation, Plaquenil, extracorporeal photopheresis, pentostatin, and
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respond to front-line steroid-based therapy. Indeed, no medication acetretin. (see Table 108.4, for list of the commonly used GVHD
has been approved by the Food and Drug Administration for use in drugs and their side effects.)
chronic GVHD. The lack of standardized response criteria to measure
therapeutic efficacy poses a major obstacle to pursuing therapeutic
trials in chronic GVHD. Overall survival and/or discontinuation of Transfusion-Associated Graft-Versus-Host Disease
systemic immunosuppression are accepted long-term endpoints in
chronic GVHD trials. The recent NIH-sponsored consensus project Most blood products administered to immunocompromised patients
provided, for the first time, a set of standardized measures and defini- are now irradiated or at least leukocyte-depleted to avoid the transfu-
tions to use as response criteria in chronic GVHD. 341,342 Nonetheless, sion of viable alloreactive T cells. With most homologous blood
these recommendations are yet to be tested and validated in prospec- products, the MHC incompatibility between donor and recipient
tive studies. The NIH consensus conference has defined response results in rapid clearance of transfused T cells by the recipient’s
measures that are classified in two main groups: clinician-assessed and immune system. However, occasionally, transfusions from donors
patient-reported (Table 108.5). 348 who are homozygous for one of the recipient’s MHC haplotypes are
The prevention of acute GVHD has not consistently resulted in not recognized as foreign by the recipient. 369–371 These cells can
a lower incidence of chronic GVHD. A clear example is the use of survive, “engraft,” and mount an immunologic attack against the
reduced-intensity transplants, consistently associated with a lower unshared haplotype in the patient, resulting in transfusion-induced
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incidence of acute GVHD but with no major impact on chronic GVHD. Transfusion-associated GVHD differs from GVHD
GVHD. 362,363 The extended use of GVHD prophylaxis with cyclo- occurring after transplantation in terms of kinetics and manifesta-
sporine, or variations in the cyclosporine dosage used, showed no tions (i.e., with transfusion-associated GVHD, the recipient marrow
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beneficial effects on the incidence of chronic GVHD. 360,364 The addi- is a major target). Since the number of stem cells in the offending
tion of thalidomide to cyclosporine and methotrexate prophylaxis, blood product is inadequate, there is no hemopoietic recovery from
the administration of intravenous immunoglobulin, and early treat- donor cells. This syndrome is generally fatal as a result of refractory
ment based on biopsy findings of subclinical GVHD in an attempt pancytopenia and/or other organ involvement.
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to preemptively treat chronic GVHD were unsuccessful. A ran-
domized placebo- controlled study in Europe showed that the addi-
tion of ATG Fresenius resulted in a significant reduction in the GRAFT-VERSUS-LEUKEMIA RESPONSES
severity and incidence of chronic GVHD. 8,365
The most commonly used therapies to treat chronic GVHD are The GVL response after allogeneic HCT results from the immuno-
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cyclosporine A (CSA) and prednisone. Sullivan and colleagues logic attack of the host tissue and, by extension, the leukemia (i.e.,
reported that prednisone alone is superior to prednisone plus azathio- the tumor). This response represents a potent form of immunotherapy
prine for primary treatment of patients with chronic GVHD. that circumvents some of the “immunoediting” mechanisms used by
tumor cells to develop in the hosts. The power of the alloimmune
response to eliminate malignancy was first reported more than 50
1
years ago in experimental models by Barnes et al. However, GVL as
TABLE National Institutes of Health Chronic Graft-Versus- its own entity and its close association with GVHD were not estab-
108.5 Host Disease Measures lished until another 15 years later. GVL responses demonstrate the
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Measure Clinician-Assessed Patient-Reported clearest and arguably to date, the most potent demonstration of the
Chronic GVHD Specific Core Measures power to harness the immune system to eradicate malignant diseases.
Signs Organ-specific measures Not applicable The critical and direct evidence of GVL effect in clinical transplanta-
tion has been provided by the use of DLI to treat relapses after
Symptoms Clinician-assessed Patient-reported symptoms allogeneic HCT. 373–375 Kolb and colleagues first reported three patients
symptoms with relapsed chronic myeloid leukemia (CML) who achieved com-
Global rating Mild, moderate, or severe Mild, moderate, or severe plete cytogenetic remission after treatment with IFN-α and DLI from
376
0–10 severity scale 0–10 severity scale the original donors. Subsequently, these findings have been con-
377–379
7-point change scale 7-point change scale firmed in several reports.
The most recent and dramatic effect of the GVL effect has been
Chronic GVHD Nonspecific Ancillary Measures demonstrated using genetic engineering to create tumor antigen-
Function Grip strength Patient-reported function
specific T cells (CAR T-cell therapy). Most discussion below is geared
2-minute walk time towards biology of GVL responses after allo-BMT. The mechanisms
Quality of life — Patient-reported health- of GVL responses after CAR T-cell therapy while seemingly evident
related quality of life (antigen-specific T cells eliminating leukemia and other cells express-
GVHD, Graft-versus-host disease. ing the antigen), the mechanisms for failure and complications are
just being explored.