Page 397 - Williams Hematology ( PDFDrive )

372 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 373

treatment with glucocorticoids, and the likelihood for long-term sur- the understanding of its pathobiology and restricting the study of novel
vival is low among individuals who develop glucocorticoid-refractory therapies. Efforts continue to develop more relevant murine models,
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acute GVHD. Various approaches, including third-party mesenchy- although translational success remains elusive.
mal stem cells, MMF, and TNF blockade, have been combined with glu- Although chronic GVHD is frequently preceded by acute GVHD,
cocorticoids in upfront treatment of acute GVHD, but none has proven progress in reducing the incidence of acute GVHD has generally not
superior to glucocorticoids alone. 385,386 translated into a reduction in the incidence of chronic GVHD. If any-
There is no standard second-line therapy for patients with glu- thing, the incidence of chronic GVHD is likely increasing, as a result of
cocorticoid-refractory acute GVHD. Practices vary widely, although the increasing use of PBPC as a graft source and the increasing at-risk
groups such as the ASBMT have published guidelines in an effort to pool of long-term survivors of allogeneic HCT. The only approaches
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codify and standardize treatment. Even though many agents have proven to prevent chronic GVHD are the use of marrow as a graft
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been used in this setting, none has proven superior or even reliably source rather than PBPC, and the use of ex vivo or in vivo T-cell deple-
effective. Options include enrollment on a clinical trial, treatment with tion (which carries increased risks of infection, PTLD, and relapse). 373,400
a second-line agent of choice, and palliative care. Agents that have been It has been suggested that posttransplant CY may prevent chronic
studied include daclizumab, SRL, MMF, ABX-CBL (a CD147-specific GVHD, as low rates have been reported in single-arm studies, 375,376 but
monoclonal antibody), anti-TNF agents, visilizumab, ruxolitinib, 388,389 this comparison is confounded by graft source (predominantly marrow
and ATG, among others. In the absence of comparative clinical trial in trials of posttransplant CY) and requires confirmation in randomized
data, the choice of second-line agent is often guided by institutional clinical trials. Recipient statin use has been associated with a signifi-
experience, physician preference, and side-effect profiles. Outcomes cantly reduced risk of chronic GVHD, but a higher risk of relapse, in
with second-line therapy remain poor, and novel treatments for gluco- patients receiving CSP-based GVHD prophylaxis regimens. Rituxi-
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corticoid-refractory acute GVHD are needed. mab has been studied as a prophylactic agent because of the demon-
strated role of B cells in the genesis of chronic GVHD. Results have been
CHRONIC GRAFT-VERSUS-HOST DISEASE mixed; a clinical trial performed at Stanford University demonstrated
that rituximab potently abrogated B-cell alloimmunity, but did not lead
Chronic GVHD is the major determinant of quality of life in long- to a statistically significant reduction in chronic GVHD incidence. A
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term survivors of allogeneic HCT. 390,391 Despite its impact, however, it nonrandomized study from the Dana-Farber Cancer Institute reported
remains poorly understood and treatment options remain limited and that rituximab decreased glucocorticoid-requiring chronic GVHD (but
largely empiric. Historically, any form of GVHD occurring beyond day not overall chronic GVHD incidence) in comparison with a concurrent
+100 after allogeneic HCT was defined as chronic GVHD. However, control cohort, a finding which requires confirmation in randomized
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with an increasing appreciation of the biologic differences between clinical trials.
acute and chronic GVHD and the recognition that late acute GVHD Despite decades of investigation of novel therapies, the standard
occurs beyond day +100 with RIC, chronic GVHD was redefined on of care for initial systemic treatment of chronic GVHD remains pred-
the basis of pathognomonic clinical and histologic criteria by a National nisone 1 mg/kg/day, with or without a calcineurin inhibitor. Numer-
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Institutes of Health (NIH) consensus conference in 2005. The NIH ous investigational agents have demonstrated promise in uncontrolled
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consensus criteria include global and organ-specific scoring to evaluate phase II clinical trials. However, these agents have uniformly proven
the severity of chronic GVHD, and these staging tools have been vali- disappointing when subjected to randomized phase III studies. At least
dated to correlate with clinical severity and outcomes. 392,393 The Center six large randomized trials conducted over the past 20 years testing
for International Blood and Marrow Transplant Research (CIBMTR) various alternate regimens, including azathioprine, thalidomide, MMF,
has also developed a chronic GVHD risk-stratification algorithm that and hydroxychloroquine, have failed to demonstrate the efficacy of any
identifies age, donor–recipient gender mismatch, serum bilirubin, plate- novel regimen for treatment of established chronic GVHD. 405–410
let count, donor type, and performance status, among other factors, as Patients with chronic GVHD typically require prolonged courses
predictors of outcome in patients with chronic GVHD. The presence of immunosuppressive therapy. The median time to discontinuation
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of chronic GVHD is consistently associated with more potent GVT of all systemic immunosuppression in patients with chronic GVHD
effects and a lower risk of posttransplantation relapse, 177,395 although the resolution is approximately 2 years. Approximately half of patients
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negative impact of chronic GVHD on TRM may outweigh the benefit with chronic GVHD will fail to respond to glucocorticoids and require
against relapse. 177 second-line therapy. As with acute GVHD, there is no single standard
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In contrast to acute GVHD, which is limited to the skin, gut, and of care for glucocorticoid-refractory chronic GVHD, and enrollment on
liver, chronic GVHD has diverse manifestations which can affect nearly a clinical trial should be strongly considered. Treatment choice depends
any organ system and which overlap considerably with those of autoim- on patient and physician preference, side-effect profile, and institutional
mune disorders such as scleroderma, lichen planus, Sjögren syndrome, priorities, as there are no data to guide a more systematic approach.
and dermatomyositis. The most common clinical features of chronic Typical second-line agents include extracorporeal photopheresis (ECP),
GVHD include lichenoid skin lesions that may progress to generalized SRL, thalidomide, pentostatin, rituximab, and imatinib, among oth-
scleroderma, keratoconjunctivitis sicca, lichenoid oral lesions, esoph- ers. ECP is logistically cumbersome but can be effective and causes
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ageal and vaginal strictures, intestinal abnormalities, chronic liver relatively few adverse effects ; this approach is currently being studied
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disease, and bronchiolitis obliterans. Comprehensive assessment of in a randomized clinical trial conducted by the BMT-CTN. Low-dose
chronic GVHD requires a detailed history and physical examination, IL-2 has been reported to facilitate T expansion and homeostasis in a
reg
but can be performed in the clinic in less than 20 minutes. Instruc- small single-center study of patients with chronic GVHD, 414,415 although
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tional videos and training tools demonstrating clinical assessment of the degree of T expansion was not significantly associated with clinical
reg
chronic GVHD are available. 397 response. Nonetheless, therapies targeting T are under active inves-
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regs
The pathophysiology of chronic GVHD remains poorly under- tigation in the treatment of chronic GVHD, as is the Bruton tyrosine
stood. In contrast to acute GVHD, where there is a track record of kinase inhibitor ibrutinib. More effective prevention and treat-
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translation from relevant animal models to humans, existing murine ment of chronic GVHD remains a crucial research need in allogeneic
models of chronic GVHD suffer from serious shortcomings, limiting HCT.
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