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`
`Leukemia (2005) 19, 1532–1535
`& 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00
`
`www.nature.com/leu
`
`KEYNOTE ADDRESS
`
`Chronic graft-versus-host disease: where is promise for the future?
`
`DJ Weisdorf1
`
`1Blood and Marrow Transplantation Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
`
`Leukemia (2005) 19, 1532–1535. doi:10.1038/sj.leu.2403856;
`published online 30 June 2005
`
`Introduction
`
`Chronic graft-versus-host disease (GVHD) remains a troubling
`and dangerous complication of allogeneic stem cell transplanta-
`tion with little prospect of a simple solution. The frequency of
`chronic GVHD over the last 12 years has increased. Data from
`the Fred Hutchinson Cancer Research Center indicate that in
`1990, chronic GVHD incidence was about 40%; currently, the
`incidence is 65–80%.1,2 This increase can be attributed to a
`greater number of patients surviving transplant, and to older
`patients being transplanted with unrelated or alternative donor
`grafts.2 Even though chronic GVHD may promote graft-versus-
`leukemia effects, large observational studies have shown that
`chronic GVHD is still the leading cause of nonrelapse death
`2 years after transplantation.3 Patient selection plays an im-
`portant role in the outcome of chronic GVHD treatment trials,4
`as demonstrated by widely varying response rates to prednisone,
`cyclosporine, azathioprine, or combination regimens.5,6
`Chronic GVHD has been attributed to T-lymphocyte activa-
`tion and overexpansion of autoreactive subsets, or both. Data
`from a large randomized trial
`in about 400 patients who
`received unrelated donor transplantation with either T-cell-
`depleted or unmodified grafts showed similar risks of chronic
`GVHD and nearly 20% chronic GVHD-related mortality
`(Pavletic SZ et al. Blood 2003; 102: 154a; abstract). This
`incidence is similar to that for sibling donor transplants.7–9 Only
`about 50% of those who developed chronic GHVD in this trial
`were alive at 3–4 years following the transplant. In general,
`neither unmodified grafts nor T-cell depletion alter
`the
`incidence of chronic GVHD or improve overall survival.
`
`Preventing chronic GVHD
`
`Treatment regimens intended to prevent chronic GVHD have
`included early administration of high- or low-dose cyclosporine
`and trials to determine the optimum duration of
`therapy.
`Extended cyclosporine therapy (24 months) was compared to
`a conventional 6-month course (n ¼ 162),10 and 6 months to 60
`
`Correspondence: Dr DJ Weisdorf, Blood and Marrow Transplantation
`Program, Department of Medicine, University of Minnesota, MMC
`480, 420 Delaware Street SE, Minneapolis, MN 55455, USA;
`Fax: þ 1 612 625 6919; E-mail: weisd001@umn.edu
`This paper is part of a series of keynote addresses to be published in
`Leukemia. They were presented at the Acute Leukemia Forum San
`Francisco, Friday April 16, 2004
`Received 12 April 2005; accepted 27 April 2005; published online 30
`June 2005
`
`days of cyclosporine therapy in patients with no active acute
`GVHD (n ¼ 103).11 Extended therapy yielded no difference in
`outcomes.10,11 Randomized trials have also evaluated cyclos-
`porine and methotrexate with or without
`thalidomide and
`showed no difference in the resolution of chronic GVHD.12–14
`The addition of thalidomide to cyclosporine was hypothesized
`to pre-emptively treat chronic GVHD, but
`in fact
`it was
`associated with more acute GVHD and worse survival. In two
`randomized trials of intravenous (i.v.) immunoglobulin, one vs
`placebo (n ¼ 250) and one comparing several different dose
`levels that had been reportedly associated with reduced GVHD
`(n ¼ 627),15 there was no difference in the incidence of chronic
`GVHD. Even though patients who develop chronic GVHD may
`have a lower risk of relapse, particularly those with mild-
`to-moderate disease, chronic GVHD substantially increases
`treatment-related mortality and regularly worsens disease-free
`survival.16 There are no specific effective interventions at this
`time to prevent chronic GVHD.
`
`Treating chronic GVHD
`
`A major long-term morbidity of chronic GVHD is the ongoing
`need for prednisone or other immunosuppressive agents. One
`strategy is to control symptoms early, and then slowly taper
`patients off the immunosuppressants. In a study of 159 patients
`at the University of Minnesota, bolus steroid induction therapy
`was administered for 8 weeks followed by alternate day
`prednisone 0.5 mg/kg and cyclosporine. Patients were followed
`for a median of 8 (range 1–13) years. Of those who responded,
`about 2/3 did so in the first 6 months, with over 50% still
`responding at a year. GVHD flares occurred primarily within the
`(Table 1).17 Although conventional steroids and
`first year
`cyclosporine can control chronic GVHD, additional continued
`immunosuppression is often needed. However, it is unclear that
`more intense immunosuppression will be more effective.
`Conventional predictors of favorable chronic GHVD (platelets
`4100 000/ml, age o20 years, and the absence of gastrointest-
`inal (GI) involvement) each independently indicate a greater
`likelihood of a good response to initial therapy. In patients with
`de novo chronic GVHD or quiescent chronic GVHD (whose
`
`response with bolus steroid induction
`Frequency of
`Table 1
`therapy (methylprednisolone i.v. 15 mg/kg/week  8 weeks, +predni-
`sone 0.5 mg/kg qod) and cyclosporine
`
`Response
`
`6 months, n (%)
`
`1 year, n (%)
`
`2 years, n (%)
`
`CR+PR
`NR
`Flare
`NR+flare
`
`95 (61)
`60 (39)
`
`F
`
`60 (39)
`
`Adapted from Arora et al.17
`
`78 (53)
`53 (36)
`17 (12)
`70 (47)
`
`71 (50)
`64 (45)
`6 (4)
`70 (50)
`
`

`

`Chronic GVHD: where is promise for the future?
`DJ Weisdorf
`
`1533
`
`Table 2
`
`New agents in chronic GVHD
`
`Agents
`
`Function
`
`Tacrolimus
`MMF
`Tacrolimus/MMF
`Thalidomide
`Hydroxychloroquine
`Clofazimine
`Etretinate
`PUVA
`ECP
`Etanercept
`Infliximab
`Daclizumab
`Rituximab
`
`Immunosuppressant
`Immunosuppressant
`
`Suppression of TNF-alpha modulation of interleukins
`Blocks antigen presentation
`Immunosuppressant and antimicrobial
`
`TNF-alpha blocker
`TNF-alpha blocker
`Humanized anti-CD25 MoAb
`anti-CD20 chimeric MoAb
`
`Adapted from Farag et al (745/id).28
`
`N
`
`86
`30
`26
`244
`32
`22
`27
`40
`110
`10
`26
`4
`8
`
`Complete response
`
`Partial response
`
`12 (14%)
`6 (20%)
`2 (8%)
`47 (19%)
`3 (9%)
`0
`0
`16 (40%)
`15 (14%)
`0
`16 (62%)
`1 (25%)
`0
`
`17 (20%)
`16 (53%)
`10 (38%)
`49 (20%)
`14 (44%)
`12 (55%)
`20 (74%)
`15 (38%)
`24 (22%)
`7 (70%)
`2 (8%)
`2 (50%)
`4 (50%)
`
`acute disease had resolved), favorable responses were also seen,
`resulting in improved long-term survival. In all, 50% survive
`10–15 years later.17
`A scoring system for chronic GVHD-specific survival was
`developed based on the high-risk features of the extent (450%)
`of skin involvement, progressive onset of chronic GVHD, and a
`low platelet count.2,18 Those who had low-risk disease but still
`needed systemic therapy had 80% survival at 10 years, whereas
`those with higher risk features had only 40–50% survival at 10
`years. A third of patients resolved their chronic GVHD in the
`first 6 months, but more than a third still had active disease
`beyond 2 years. At 4 years, nearly 70% of those with high-risk
`chronic GVHD were still being treated with immunosuppression
`vs only 30% of those with standard-risk disease.2
`Another study examined nonrelapse mortality and survival in
`long-term follow-up of patients enrolled in a randomized trial
`comparing prednisone with or without cyclosporine for mana-
`ging standard- or
`low-risk chronic GVHD (platelet counts
`4100 000/ml).19 The authors concluded that although the
`addition of cyclosporine may reduce steroid-related toxicity,
`treatment-related mortality showed little difference over 10
`years. A slight, but not statistically significant improvement in
`treatment-related mortality with combination therapy was
`observed. There was no disease-free survival improvement with
`combination therapy.19 In all, 28% died while still receiving
`immunosuppression. Cumulative incidence of recurrent malig-
`nancy at 5 years was 39% in the cyclosporine plus prednisone
`arm compared with 37% in the prednisone alone arm. Survival
`without recurrent malignancy at 5 years was 61% in the
`cyclosporine plus prednisone arm compared with 71% in the
`prednisone arm. A statistically significant higher composite risk
`for transplantation-related mortality or recurrent malignancy in
`the cyclosporine plus prednisone arm resulted in a lower
`probability of survival in remission. Thus, there was no net
`advantage for combination chemotherapy. Standard therapy can
`produce control of GVHD for 50 or 60% of patients in 2–3
`years, but
`the burden of ongoing immunosuppression is
`substantial.19
`
`Newer therapies for chronic GVHD
`
`Small pilot studies have suggested several new drugs as effective
`in managing chronic GVHD. Sirolimus plus tacrolimus was
`
`tested in a phase II study of 29 steroid-refractory patients at the
`MD Anderson Cancer Center. Patients received sirolimus (6 mg
`loading dose) with maintenance at 2 mg/day (levels 7–12 ng/ml)
`plus tacrolimus (levels 7–12 ng/ml). The overall response rates
`were 68% (18/29), with five complete responses and 13 partial
`responses. Response rates in the skin, mouth, eye, and GI tract
`were similar. Of 24 patients with skin GVHD, 8/24 (30%) had
`scleroderma and six (75%) responded to treatment. In patients
`with visceral involvement, responses were less frequent. None
`with lower GI tract GVHD responded.
`Another sirolimus trial included 19 patients.20 In all, 15 of 16
`responded, five stopped due HUS or nephrotoxicity, and most
`others flared. The trial closed early.
`Extracorporeal photopheresis (ECP) is another new therapy. A
`retrospective study of ECP was conducted in 32 patients who
`were beyond day 100 with steroid-dependent or steroid-
`refractory cutaneous chronic GVHD.21 The study was limited
`to those receiving ECP for 4 weeks or more. These patients had
`extensive chronic GVHD and were treated an average of 36
`sessions over 5 months. The total response rate was about 50%.
`Of seven with complete response, 5/7 had continuing complete
`response. Of 28 patients on systemic corticosteroid therapy at
`the start of ECP, 18 achieved 50% dose reduction, yielding a
`64% steroid-sparing response rate. In total, 11 (34%) patients
`died due to visceral chronic GVHD or chronic GVHD-related
`infectious complications after ECP, and 66% of the patients
`survive, although all require continuing immunosuppression.
`Another report showed that ECP recipients had skin softening
`and improvement
`in liver
`function enzymes early in the
`treatment.22 ECP is a cumbersome intervention offering similar
`response rates, but has some steroid-sparing potential. However,
`chronic GVHD-related morbidity and mortality remain high and
`most patients continue to require immunosuppressive therapy.
`Another treatment alternative, a combination of tacrolimus
`plus steroids, was studied in 104 patients and suggested no
`major advantage to the combination.23 These patients had a
`70% response rate with 79% in the skin and 76% in the mouth,
`but much lower response rate in visceral disease: 41% in the GI
`tract and 29% in the liver. The mortality rate was 48% and
`chronic GVHD-specific mortality was 34%.
`Other alternative agents have been used with variable
`outcome. The response rates for various agents are shown in
`Table 2. The studies were all conducted in different types of
`patients over varying time periods, but all patients had chronic
`GVHD. In most studies, the overall response rates were under
`
`Leukemia
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`•
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`1534
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`Leukemia
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`Chronic GVHD: where is promise for the future?
`DJ Weisdorf
`
`50%, suggesting only limited efficacy. For example, tacrolimus
`given to 86 patients in several small studies had an overall
`response rate of 34%. Mycophenolate mofetil (MMF) might be a
`potentially promising drug because the cumulative response
`from two studies is 73%, and it has only limited toxicity.24,25
`However, tacrolimus with MMF as salvage therapy produced a
`lower response of approximately 38%.26 Prospective multi-
`center testing of prednisone plus or minus MMF is underway.
`Thalidomide is a widely studied agent, including its use as
`secondary therapy for chronic GVHD,12,27 with an overall
`response nearly 40% (Table 2). Two randomized trials
`used thalidomide for initial management of chronic GVHD.
`Neither study showed any response or survival advantage for
`thalidomide.28
`Hydroxychloroquine has shown nearly 50% responses in a
`small number of patients and is being tested in an ongoing
`randomized trial.29 Two other drugs, clofazimine and etretinate,
`yield promising partial responses and might be worthy of more
`study.30,31 PUVA and ECP therapy only favorably affect skin
`disease, and both have variable responses.32
`include
`New agents
`reported in only a few patients
`etanercept, infliximab, daclizumab, and rituximab. Etanercept
`showed 70% response in 10 patients,33 infliximab had over 50%
`response rate,34 and daclizumab showed a response in 3/4
`patients.35 Of note, a recently completed trial in acute GVHD
`showed a survival disadvantage with daclizumab, a finding that
`suggests caution in its future use.36 Rituximab has been tried in
`three small studies; one included eight patients with some
`manifestations of chronic GVHD that resolved simultaneously
`(Cutler C et al. Biol Blood Marrow Transplant 2005; 11: 10;
`abstract).37,38
`
`Summary
`
`the key to
`that
`is apparent
`it
`From these various studies,
`improving management of chronic GVHD remains elusive.
`Heterogeneity of patients and disease manifestations and even
`uncertainty in diagnosis of chronic GVHD confound all these
`studies. At one referral center, 15–20% of the patients referred
`for management of chronic GVHD were found to have no signs
`the disease.39 Treating physicians are inconsistent
`of
`in
`recognizing the protean manifestations of
`this syndrome.
`If
`patients with varying symptoms are included in heterogeneous
`pilot studies, interpretation of their findings may be misleading.
`Future studies of chronic GVHD need carefully defined
`eligibility, consistent
`therapy, and clearly defined response
`criteria. At present, there are two prospective randomized trials
`underway for treatment of chronic GVHD. One is a multicenter
`trial
`for
`standard-risk patients comparing prednisone and
`cyclosporine with or without MMF. The Children’s Oncology
`Group is comparing the addition of hydroxychloroquine to
`initial therapy of chronic GVHD. The outcome from these two
`trials will be important in offering prospective and clear data,
`even if the either agent is not a big advance.
`An essential component of chronic GVHD medical manage-
`ment
`is ongoing supportive care over the whole length of
`therapy. This must
`include infection prophylaxis, hydration,
`nutrition, and careful follow-up. New strategies for abatement of
`chronic GVHD are essential, but more critical are new ideas to
`manage the immune deficiency associated with chronic GVHD,
`discipline in designing and executing studies, clinical caution in
`interpreting the outcomes, and new support systems to help
`patients bear the ongoing burdens accompanying this lengthy
`chronic illness.
`
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`Leukemia
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