`
`Consensus Conference on Clinical Practice in Chronic
`GVHD: Second-Line Treatment of Chronic
`Graft-versus-Host Disease
`Daniel Wolff/ Michael Sch/euning, 2 Stephanie von Harsdor(;3 Ulrike Bacher, 4
`Armin Gerbitz,5 Michael Stadler, 6 Francis Ayuk,4 Alexander Kiani, 7 Rainer Schwerdtfeger, 2
`Georgia B. Vogelsang, 8 Guido Kobbe, 9 Martin Gramatzki, 10 Anita Lawitschka, 1 1
`Mohamad Mohty, 12 Steven Z. Pavletic, 13 Hildegard Greinix, 14 Ernst Holler1
`
`Steroid refractory chronic graft-versus-host disease (cGVHD) is associated with a significant morbidity and
`mortality. Although first-line treatment of cGVHD is based on controlled trials, second-line treatment is
`almost solely based on phase II trials or retrospective analyses. The consensus conference on clinical practice
`in cGVHD held in Regensburg aimed to achieve a consensus on the current evidence of treatment options as
`well as to provide guidelines for daily clinical practice. Treatment modalities are the use of steroids and
`calcineurin inhibitors as well as immunomodulating modalities (photopheresis, mTOR-inhibitors, thalido(cid:173)
`mide, hydroxychloroquine, vitamin A analogs, clofazimine), and cytostatic agents (mycophenolate mofetil,
`methotrexate, cyclophosphamide, pentostatin). Recent reports showed some efficacy of rituximab, alemtu(cid:173)
`zumab, and etanercept in selected patients. Moreover, tyrosine kinase inihibitors such as imatinib came into
`the field because of their ability to interfere with the platelet-derived growth factor (PDGF-R) pathway in(cid:173)
`volved in fibrosis. An other treatment option is low-dose thoracoabdominal irradiation. Although different
`treatment options are available, the "trial-and-error system" remains the only way to identify the drug effec(cid:173)
`tive in the individual patient, and valid biomarkers are eagerly needed to identify the likelihood of response to
`a drug in advance. Moreover, the sparse evidence for most treatment entities indicates the urgent need for
`systematic evaluation of second-line treatment options in cGVHD.
`Biol Blood Mairow Trnnsplant 17: 1-17 (2011) © 2011 Amei-ican Society for Blood and Mairow Transplantation
`KEY WORDS: Allogeneic hematopoietic stem cell transplantation, Chronic GVHD, Bone marrow transplan(cid:173)
`tation, lmmunosuppressive therapy
`
`INTRODUCTION
`
`Chronic graft-versus-host disease
`(cGVHD)
`remains the leading cause for late morbidity and
`mortality after allogeneic hematopoietic stem cell
`transplantation (HSCT). Although half of the patients
`
`respond to first-line treatment, prognosis of steroid
`refractory cGVHD remains poor [1-3]. Primary
`treatment of cGVHD is based on controlled trials
`and consists of prednisone given with or without
`a calcineurin inhibitor (CNI). In contrast, evidence
`in steroid refractory cGVHD is
`limited almost
`
`From the 1Department of Hematology and Clinical Oncology,
`University of Regensburg, Germany; 2DKD, Wiesbaden,
`Germany; 3Department of Internal Medicine III, University of
`Ulm, Germany; "Interdisciplinary Clinic for Stem Cell Trans(cid:173)
`plantation, University Cancer Center Hamburg (UCCH),
`Germany; 5Department of Internal Medicine III, Campus Ben(cid:173)
`jamin Franklin, Charite-University Hospital Berlin, Germany;
`6Department of Hematology, Hemostasis, Oncology and
`Stem Cell Transplantation, Hannover Medical School, Hann(cid:173)
`over, Germany; 7Department oflnternal Medicine I, University
`of Dresden, Germany; 8Johns Hopkins Oncology Center,
`Baltimore, Maryland; 9Department of Hematology, University
`of Duesseldorf, Germany; 10Department of Hematology, Uni(cid:173)
`versity of Kiel, Germany; 11St. Anna Children's Hospital,
`
`Vienna, Austria; 12Department of Hematology, University of
`Nantes, France; 13Experimental Transplantation and Immunol(cid:173)
`ogy Branch, Center of Cancer Research, National Cancer Insti(cid:173)
`tute, Bethesda, Maryland; and 14Department of Internal
`Medicine I, Medical University of Vienna, Austria.
`Finnncinl disclosure: See Acknowledgments on page 13.
`Correspondence and
`reprint requests: Daniel Wolff, MD,
`Department of Hematology and Oncology, University of
`Regensburg, F.J. Strauss Allee 11, 93053 Regensburg, Germany
`(e-mail: daniel.wolff@klinik.uni-regensburg.de).
`Received February 12, 2010; accepted May 17, 2010
`© 2011 American Society for Blood and Marrow Transplantation
`1083-8791/$36.00
`doi:10.1016/j.bbmt.2010.05 .011
`
`Pharmacyclics Exhib[t 2050
`Sandoz v. Pharmacyclics
`1PR2019-00865
`
`
`
`2
`
`D. Wolff et al.
`
`Biol Blood Marrow Transplant I 7: I-I 7, 20 I I
`
`q
`
`exclusively to phase II trials or retrospective analyses.
`Until recently, no valid criteria for the diagnosis and
`staging of cGVHD severity were available, which
`limits the value of most reported trials on treatment
`of cGVHD. Moreover, most of the reported trials
`did not use uniform criteria for response and did not
`provide details on severity of cGVHD. An additional
`problem is the heterogeneity of the patients included
`in the analyses, because, for some treatment options,
`results in children differ substantially from results
`achieved in adults. Although not yet validated in
`a prospective fashion, the National Institutes of
`Health (NIH) consensus criteria on diagnosis and
`staging of cGVHD as well as on treatment response
`criteria, reported in 2005, now provide defined
`criteria that should improve the validity of future
`results on treatment of cGVHD [4-9].
`The Consensus Conference on Clinical Practice in
`Chronic GVHD held in the fall of 2009 in Regens(cid:173)
`burg, Germany (complete program provided at
`www.gvhd.de), aimed to summarize the current avail(cid:173)
`able evidence for second-line treatment and to provide
`practical guidelines for the use of treatment modalities.
`The presented consensus was based on a review of
`published evidence and a survey on the current clinical
`practice in transplant centers from Germany, Austria,
`and Switzerland, with 31 of 3 7 centers responding to
`the survey. The results of the survey are shown in
`Table 1. Moreover, the consensus was circulated
`among all centers performing allogeneic HSCT in
`Germany, Austria, and Switzerland and was discussed
`during the Consensus Conference meetings. The
`Consensus Conference was organized under the aus(cid:173)
`pices of the German Working Group on Bone Marrow
`and Blood Stem Cell Transplantation (DAG-KBT)
`and the German Society of Hematology and Oncology
`(DGHO), the Austrian Stem Cell Transplant Work(cid:173)
`ing Group of the Austrian Society of Hematology
`and Oncology, the Swiss Blood Stem Cell Transplan(cid:173)
`tation Group (SBST), and the German-Austrian
`Paediatric Working Group on HSCT.
`The evaluation of evidence and the subsequent
`the
`to
`recommendations were graded according
`system used by Couriel [10]. Because the evidence of
`the majority of treatment options in cGVHD is sparse
`and therefore the strength of recommendation falls
`into category C for most of the therapeutic options, cat(cid:173)
`egory C and evidence III level were further specified as
`shown in Tables 2 and 3. Strength of recommendation
`and evidence levels were first rated by an expert panel
`and subsequently rated by all participants of the
`consensus process. Only evidence from the use in
`cGVHD was included in the evaluation. We mainly
`focus on reported clinical trials and retrospective
`analyses. The literature search was performed by the
`working group on second-line treatment within the
`Consensus conference using the Pubmed database.
`
`Only English literature was considered. Abstracts
`from the Bone Marrow Transplantation Tandem meet(cid:173)
`ings, the European Bone Marrow Transplantation
`meetings, and the American Society of Hematology
`meetings were cited but were not included in the
`evidence rating.
`
`PRINCIPLES OF SECOND-LINE TREATMENT
`OFCGVHD
`
`Currently no uniformly accepted definition of
`steroid refractory cGVHD is available, and generally
`accepted criteria include (1) progression on predni(cid:173)
`sone at 1 mg/kg/day for 2 weeks, (2) stable disease
`on 2:0.5 mg/kg/day of prednisone for 4-8 weeks, and
`(3) inability to taper prednisone below 0.5 mg/kg/
`day. Treatment duration may vary depending on clin(cid:173)
`ical manifestation (eg, sclerosis requires longer to re(cid:173)
`spond) or toxicity of the agent (eg, shorter duration
`in the presence of significant toxicity) [3, 7]. Although
`different treatment options are available for salvage
`therapy of steroid refractory cGVHD, the "trial-and(cid:173)
`error system" remains to date the only way to
`identify the drug or drug combination effective in an
`individual patient. In principle, initial secondary
`treatment should include agents with an adequate
`safety profile and well-documented activity like CNI,
`extracorporeal photopheresis (ECP), mTOR inhibi(cid:173)
`tors, or mycophenolate mofetil (MMF), whereas
`agents with significant side effects should be reserved
`to third- or fourth-line treatment. In addition, steroid
`sparing should be an important goal of salvage therapy
`of cGVHD. Because no predictors of response are yet
`available either for single immunosuppressive agents
`or combination therapies, most patients receive empir(cid:173)
`ical treatment in daily clinical practice and changes of
`therapeutic components in case oflack of response are
`performed at the individual clinician's discretion.
`Nevertheless, at time of initiation of secondary or
`any further treatment, it is suggested not to change
`more than 1 drug at once, because adding several drugs
`at once may interfere with identification of the active
`component and might lead to prolonged use of inac(cid:173)
`tive components. This does not apply to patients
`showing rapid progression of cGVHD, indicating
`complete failure of treatment, or the need to withdraw
`agents because of toxicity. In the presence oflack of re(cid:173)
`sponse, continuation of at least 1 drug during the
`change period is suggested because there is a risk to
`end up with a new combination without individual ef(cid:173)
`ficacy, which would leave the patient without effective
`immunosuppression.
`As in first-line treatment, response to salvage ther(cid:173)
`apy should be assessed after 8-12 weeks. If patients
`have progression of cGVHD after 4 weeks, a new
`treatment option should be offered. However, patients
`should be exposed to therapeutic drug levels for an
`
`
`
`Biol Blood Marrow Transplant 17: 1-17, 20 I I
`
`Second-Line Treatment of Chronic GVHD
`
`3
`
`Table I. Results of the Survey on Second-Line Treatment of cGVHD (n = 30)
`
`Agent
`
`Frequently
`Used
`
`Occasionally
`Used
`
`Infrequently
`Used
`
`Not Used but Regarded as
`Treatment Option
`
`Not Regarded
`as Treatment Option
`
`No Report
`on the Use
`
`Steroids
`Cyclosporine
`Tacrolimus
`Photopheresis
`Mycophenolat Mofetil
`Mycophenolic acid
`Sirolimus
`Everolimus
`Pentostatin
`MTX
`lmatinib
`Rituximab
`Hydroxychloroquine
`Clofazimine
`Thoracoabdominal irradiation
`Pulse of steroids
`Thalidomide
`Azathioprine
`Retinoids (Acitretin/lsotretinoine)
`Alemtuzumab
`Cyclophosphamide
`Etanercept
`
`30
`22
`9
`13
`13
`8
`6
`2
`
`2
`
`5
`
`2
`
`6
`8
`9
`9
`8
`6
`9
`
`6
`13
`
`3
`II
`2
`I
`I/ I
`8
`3
`3
`
`7
`5
`5
`3
`7
`3
`7
`II
`6
`6
`3
`2
`
`6
`2
`3
`0 I I
`
`5
`
`5
`
`9
`9
`10
`9
`4
`7
`5
`9
`5
`8
`2
`13
`10
`7 / 10
`7
`9
`10
`
`2
`7
`8
`7
`
`9
`II
`II
`5
`9
`9
`12 / 9
`9
`10
`6
`
`2
`
`4
`7
`6
`4
`3
`9
`12
`8
`
`4
`6
`10 / 9
`5
`7
`4
`
`MTX indicates methotrexate.
`Thirty of 37 transplant centers performing allogeneic HSCTwithin Germany (n = 34), Austria (n = 3), and Switzerland (n = I) responded to the paper-
`based survey on second-line treatment sent via e-mail to representatives of the centers. (One center responded only for first-line treatment and was
`excluded from the analysis of second-line treatment.)
`
`adequate length of time (at least 4 weeks) before con(cid:173)
`cluding treatment failure. Patients with sclerotic skin
`lesions may require substantially longer for responses
`(up to 6 months) and treatment may be continued pro(cid:173)
`vided that the patient is closely monitored to recognize
`progression of cGVHD. In principle, less immunosup(cid:173)
`pressive therapy is preferable when treating cGVHD,
`and thus, agents being identified as ineffective should
`be discontinued to avoid side effects. In addition, im(cid:173)
`munosuppression should be reduced as soon as disease
`control has been achieved. Thus far, no controlled trial
`showed evidence for a beneficial impact of a 3-agent
`treatment in first-line therapy [11-13]. Moreover,
`a retrospective analysis performed by Mitchell et al.
`[14] demonstrated a decline of quality of life in the
`presence of multiagent (2::2) treatment independent
`of severity of cGVHD. These findings, however, do
`not necessarily imply that novel immunosuppressive
`agents when used in combination would have the
`same negative impact on patients' outcome, as data
`in this regard are lacking.
`In pediatric patients, systemic steroid therapy can
`be deleterious on a growing child. Therefore, addition
`of an effective steroid-sparing agent is of crucial
`importance for long-term patient outcome. More(cid:173)
`over, topical therapy should be offered in mild cases
`both early in the course of cGVHD as well as at the
`end of systemic steroid taper. However, topical ste(cid:173)
`roids or topical CNI may lead to significant systemic
`drug levels if applied to large areas in small infants,
`and thus, their use should be restricted to limited
`areas.
`
`Although no predictors of response for a single agent
`are yet available, the side effects of specific agents may
`limit their use in individual situations. CNI may
`be used with caution in case of significant renal
`impairment. Thoracoabdominal irradiation as well as
`pentostatin may not be given to patients with altered
`marrow function [15-17]. mTOR inhibitors had
`a lower response rate in patients with low platelets, but
`it is unknown whether this is a drug specific effect or
`an indicator for cGVHD severity as suggested by the
`risk score developed by Akpek et al. and Courie! et al.
`[2,18].
`From the efficacy standpoint, most of the immuno(cid:173)
`suppressive agents are used for treatment of a broad
`spectrum of symptoms of cGVHD. However, some
`agents may be more relevant in specific indications be(cid:173)
`cause of a specific mode of action. This is the case in
`retinoids, which have been solely applied to sclerotic
`skin lesions because of their interference with collagen
`synthesis [19]. On the other hand, rituximab may be
`considered in immune thrombocytopenia because of
`its directed efficacy on B cells [20-22].
`Although currently no valid recommendation can
`be made for an individual patient, certain combination
`of drugs should be avoided because of overlapping tox(cid:173)
`icities. With regard to myelosuppressive capacity, cau(cid:173)
`tion is required when considering thoracoabdominal
`irradiation or pentostatin in combination with mTOR
`inhibitors [16-18,23]. Moreover, the combination of
`mTOR inhibitors with CNis has been associated with
`a significant rate of transplantation-associated rnicroan(cid:173)
`giopathia (TAM) [18,24,25].
`
`
`
`4
`
`D. Wolff et al.
`
`Biol Blood Marrow Transplant 17: 1-17, 20 I I
`
`Table 2. Strength of Recommendation of Treatment
`
`Strength of
`Recommendation Level
`
`A
`B
`C
`
`C-1
`C-2
`
`C-3
`
`C-4
`
`D
`
`Definition of Recommendation Level
`
`Should always be offered
`Should generally be offered
`Evidence for efficacy is insufficient to support for
`or against, or evidence might not outweigh
`adverse consequences, or cost of the
`approach. Optional
`Use in second-line treatment justified
`Use in greater than second-l ine treatment
`justified
`Use because of increased risk profile limited to
`specific circumstances
`Experimental , use only in clinical trials or
`individual cases
`Moderate evid ence for lack of efficacy or for
`adverse outcome supports
`a recommendation against use. Should
`generally not be offered
`
`During long-term immunosuppression adequate
`monitoring for infectious complications including
`screening for viral reactivation and fungal infections
`is recommended. Moreover, antifungal prophylaxis
`should be considered, especially in patients receiving
`a multiagent immunosuppressive regimen or with
`a history of invasive fungal infections. Steroids require
`monitoring for steroid-induced osteoporosis and
`diabetes mellitus. MTOR inhibitors require monitor(cid:173)
`ing of drug levels, signs for TAM, hyperlipidemia, and
`blood counts. C:i\Tis require monitoring of drug levels,
`arterial blood pressure, and renal function. Moreover,
`interactions of certain irmnunosuppressive agents with
`comedications such as azole derivates for antifungal
`prophylaxis need to be taken into account.
`
`EVALUATING EFFICACY OF TREATMENT
`OFCGVHD
`
`In the absence of a single approved immunosup(cid:173)
`therapy of cGVI-ID
`pressrve agent for salvage
`
`Table 3. Quality of Evidence Supporting the Recommenda(cid:173)
`tion
`
`Strength of
`Evidence Level
`
`Definition of Evidence Level
`
`Evidence from 2: I properly randomized, controlled
`trials
`Evidence from > I well-designed clinical trial without
`randomization, from cohort or case-controled
`analytic studies (preferable from > I center) or from
`multiple time series, or dramatic results from
`uncontrolled experiments
`Evidence from opinions of respected authorities based
`on clinical experience, descriptive stud ies or reports
`from expert committies
`Several reports from retrospective evaluations or smal l
`uncontrolled clinical trials
`Only I report from small uncontrolled clinical trial or
`retrospective evaluations
`Only case reports available
`
`Ill
`
`Ill- I
`
`Ill - 2
`
`Ill - 3
`
`clinicians must resort of trying "off label" drugs. To
`be confident about success or failure of each irmnuno(cid:173)
`suppressive agent applied, the Consensus Conference
`advised that a baseline l\TIH-style comprehensive or(cid:173)
`gan assessment be obtained to serve as a comparison
`for follow-up evaluations. In addition, reasons for
`treatment changes including progression of symp(cid:173)
`toms, toxic side effects, or patient's request should be
`documented.
`The German version of the modified cGVI-ID stag(cid:173)
`ing form can be downloaded on www.gvhd.de or
`www.gvhd.eu. Although most of the organs like oral
`and ocular manifestations can be assessed easily and
`are frequently reported by the patients, it is of impor(cid:173)
`tance to ask for manifestations infrequently reported
`to prevent prolonged
`like vaginal manifestations,
`suffering and irreversible damage. The same applies
`for screening of lung manifestations, because mild
`involvement can be only detected by evaluation of
`lung function. Because moderate lung manifestations
`already interfere significantly with quality of life and
`physical activity, early intervention seems preferable to
`avoid progression to more severe stages taken into ac(cid:173)
`count, that prospective evaluation of this approach has
`not been performed yet (26].
`
`SECOND-LINE TREATMENT OPTIONS
`IN CGVHD (TABLE 4)
`
`Prednisone (B 111-1)
`Corticosteroids have traditionally been the back(cid:173)
`bone of cGVHD tl1erapy. Although the use of steroids
`in first-line treatment is based on controlled trials,
`their role in second-line therapy remains less clear be(cid:173)
`cause of a lack of data. In many studies on second-line
`treatment of cGVI-ID drugs like MMF, sirolimus or
`ECP were combined with continuous steroid adminis(cid:173)
`the contribution of
`tration (18,23,27-30]. Thus,
`steroids to the reported response rates in tl1ese
`studies remains uncertain. Because steroid-sparing is
`an important goal in cGVI-ID patients, tl1eir dose is
`usually reduced once symptoms of cGVI-ID are re(cid:173)
`solved and steroids may be stopped before dose reduc(cid:173)
`tion of other immunosuppressants. If cGVI-ID flares
`during steroid taper, increasing the dose by I or 2 taper
`steps may be enough to control symptoms. Consider(cid:173)
`ing the potential side effects of systemic steroids alone
`and even more so in combination with other immuno(cid:173)
`suppressive agents, regular monitoring for osteoporo(cid:173)
`sis, arterial hypertension, and steroid induced diabetes
`mellitus is recommended.
`
`Pulse of Steroids (C-2 111-2)
`Currently, only I publication evaluated the efficacy
`of high-dose corticosteroids. Akpek et al. [I] reported
`
`
`
`Biol Blo'od Marrow Transplant 17:/-17, 20/ I
`
`Second-Line Treatment of Chronic GVHD
`
`5
`
`Table 4. Second-line Treatment Options in cGVHD
`
`Agent
`
`Recommendation
`
`Evidence
`
`Side Effects
`
`Comments
`
`Steroids
`
`Photopheresis
`mTOR inhibitors
`
`CNI
`
`MMF
`
`Pentostatin
`
`MTX
`
`lmatinib
`
`Rituximab
`
`Hydroxychloroquine
`
`Clofazimine
`Thoracoabdominal irradiation
`
`Pulse of steroids
`
`Thalidomide
`Azathioprine
`Retinoids
`Alemtuzumab
`Alefacept
`Etanercept
`
`B
`
`C-1
`C-1
`
`C-1
`
`C-1
`
`C-2
`
`C-2
`
`C-2
`
`C-2
`
`C-2
`
`C-2
`C-2
`
`C-2
`
`C-3
`C-3
`C-3
`C-4
`C-4
`C-4
`
`111-1
`
`osteoporosis, avascular necrosis, diabetes
`
`111-1
`
`111-1
`
`111-1
`
`venous access required
`TAM, hyperlipidemia, hematotoxicity
`
`renal toxicity, hypertension
`
`GI complaints, infectious and relapse risk
`
`II
`
`Hematotoxicity, infectious risk
`
`111-1
`
`111-1
`
`II
`
`111-2
`
`111-2
`111-2
`
`111-2
`
`II
`111-1
`111-2
`111-3
`111-3
`111-3
`
`Hematotoxicity
`
`Fluid retention
`
`Infectious risk
`
`GI complaints
`
`GI complaints, skin hyperpigmentation
`Hematotoxicity
`
`Infectious risk
`
`Neurotoxicity, sedation, constipation
`Hematotoxicity, infectious risk
`Skin toxicity, Hyperlipidemia
`Infectious risk
`Infectious risk
`Infectious risk
`
`important but need to spare steroids because of
`side effect profile
`spares steroids, excellent safety profile
`increased risk for TAM in combination with CNI,
`lower efficacy in thrombocytopenia, requires
`frequent monitoring
`spares steroids, should be avoided in renal
`impairment
`increased risk for viral reactivation, spares
`steroids, GI toxicity may mimic GVHD
`clinically and histologically
`best results in children, caution in presence of
`impaired marrow function, long-term
`immunosuppression
`best response in mucocutaeous cGVHD, spares
`steroids
`best results in sclerotic skin lesions, potentially
`effective in mild and moderate BO
`effective in auto-antibody mediated
`manifestations as well as cutaneous and
`musculosceletal cGVHD
`best results in mucocutaneous and liver
`involvement
`best results in mucocutaneous cGVHD
`best results in fasciitis or steroid dependent
`mucocutaneous cGVHD, caution in presence
`of impaired marrow function
`rapid control of symptoms, identification of
`steroid resistance
`may be used in concomitant relapse of MM
`increased risk for oral malignancies
`effective in sclerotic skin lesions
`last resort
`last resort
`may be used in overlap syndrome with GI
`manifestations
`
`TAM indicates transplantation-associated microangiopathia; CIN, calcineurin inhibitor; cGVHD, chronic graft-versus-host disease; BO, bronchiolitis
`obliterans.
`
`results in 61 patients with severe refractory cGVHD,
`who were treated with methylprednisolone at 10 mg/
`kg/day for 4 consecutive days followed by stepwise
`dose reductions. After 4 days, all patients received
`a course of additional immunosuppressive therapy.
`Twenty-seven patients (48%) showed a major response
`with substantial improvement of cGVHD manifesta(cid:173)
`tions, including softening of the skin, increased range
`of motion, and improved performance status; 15 patients
`(27%) showed a minor response, defined as improve(cid:173)
`ment in some but not all symptoms of cGVHD. The
`treatment was well tolerated with no serious adverse
`events. Although all patients received additional immu(cid:173)
`nosuppressive agents through their later course interfer(cid:173)
`ing with the evaluation of the impact ofhigh dose steroids
`on the extend of response, the results demonstrate that
`high-dose methylprednisolone allows rapid clinical re(cid:173)
`sponse in patients with prior uncontrolled cGVHD, re(cid:173)
`quiring rapid control of symptoms. An additional
`advantage of a pulse of high dose steroids is the immedi(cid:173)
`ate identification of steroid resistance especially in cuta(cid:173)
`neous manifestations of cGVHD.
`
`Calcineurin Inhibitors (C-1 111-1)
`As in clinical practice, C:t\TJs (either cyclosporine
`[CsA] or tacrolimus) are frequently employed in
`addition to corticosteroids as the initial treatment of
`cGVHD, however, only limited experience exists on
`their use as salvage therapy. In 2 small studies investi(cid:173)
`gating the effect of tacrolimus in patients with refrac(cid:173)
`tory cGvHD, overall response rates ranged between
`35% and 46% [31,32]. In a study of 39 patients
`receiving CsA already as part of their first-line treat(cid:173)
`ment, a change of CsA to tacrolimus offered some
`benefit only in a small subset of patients [33].
`In all, CNis may represent a reasonable option
`for patients with refractory or progressive cGVHD,
`provided they have not been part of the first-line
`therapeutic regimen or have shown prior therapeutic
`activity. Moreover, a subset of patients may remain
`CNI dependent by showing repeated flares of symptoms
`of cGVHD after withdrawal of CNI. Tacrolimus
`clearance is age dependant in pediatric patients, and
`especially children younger than 6 years of age have
`
`
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`6
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`D. Wolff et al.
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`Biol Blood Marrow Transplant 17: 1- 17, 201 I
`
`a rugher clearance [34]. In contrast, a change from 1
`Cl\TI to another is unlikely to improve efficacy, but
`may be justified for the presence of certain side effects
`(eg, hyperlipid emia , h.irsuitism, neurotoxicity). In gen(cid:173)
`eral, however, the toxicity profile ofboth available drugs
`is usually overlapping ( eg, nephrntoxicity, risk of micro(cid:173)
`angiopathy). If chosen, the mod e of administration
`and plasma trough level targets of both Cl\Tis in
`second-line treatment are usually similar to those em(cid:173)
`ployed in first-line treatment. Beca use long-tenn renal
`toxicity is of concern, both substances may be applied
`with plasma trough level targets at the lower therapeutic
`limit.
`
`Extracorporeal Photopheresis (C-1 II)
`During the last years a substantial number of pa(cid:173)
`tients have been treated with ECP for steroid(cid:173)
`dependent or steroid-refractory cGVHD [29,35-46].
`The mechanisms of action are complex including
`leukocyte subsets,
`.in all
`induction of apoptosis
`inhibition of proinflammatory cytokine production,
`increase .in anti-inflammatory cytokine product.ion,
`reduced stimulation of effector T cells, and induction
`of donor-derived regulatory T cells (Tregs) [45,47].
`Most of the clinical experience in ECP treatment of
`is based on
`steroid-refractory cGVHD patients
`retrospective analyses with a limited number of patients
`[29,35-38,40,41,43,44,46-50] with consistently high
`complete responses in up to 80% of patients with
`cutaneous manifestations and significant improvement
`in sclerodermatous skin involvement [29,46]. Courie]
`[38] reported in 71 patients with steroid(cid:173)
`et al.
`refractory severe cGVHD a response rate of 61 %,
`with an inferior outcome in patients with thrombocyto(cid:173)
`penia and a trend toward a higher response rate in de
`novo cGVHD. Kanold et al. [44] acruved an overall re(cid:173)
`sponse rate of 63 % in 63 children given ECP. Improve(cid:173)
`ment in visceral and lung manifestations of cGVHD to
`ECP has been less consistent [29,35,37,38,40,43,46].
`Two studies demonstrated, tl1at earlier initiation of
`ECP ( < 1 year) revealed better response rates in skin,
`liver, and mucosa! cGVHD [37,50]. The latter was not
`confirmed by Foss et al. [40] and Apisamthanarax et al.
`[35] . So far, no treatment schedule (weekly versus 2
`weekly) has reportedly revealed superior response rates.
`However, because of tl1e variety of ECP schedules, tl1e
`impact of dose intensity (number of cycles per montl1)
`and length of treatment (number of cycles) cannot be as(cid:173)
`sessed accurately. Recently, Flowers et al. [28] reported
`results of a prospective randomized phase II study in 95
`patients with steroid-refractory/ dependent/intolerant
`cGVHD given ECP for 12 to 24 weeks in combination
`witl1 conventional immunosuppressants acrueving no
`significant difference in improvement of total skin score
`(TSS) at week 12, but a significantly rugher rate of com(cid:173)
`plete and partial responses of skin cGVHD as assessed
`
`by tl1e nonblinded investigator in the ECP ann
`compared to tl1e control arm. In addition, significantly
`more patients in tl1e ECP ann had at least a 50%
`reduction of steroid dose and at least a 2 5 % decrease
`ofTSS at week 12. Of note, a steroid-sparing effect of
`ECP has also been reported by other investigators
`[29,38,40,43,49]. Significantly improved survival rates
`and improvementsin quality of life have been reported
`in ECP responders [28,29,50]. Therefore, ECP may
`be a reasonable first choice in certain clinical scenarios
`of steroid-refractory cGVHD. It requires a venous ac(cid:173)
`cess tl1at may be difficult in patients with sclerotic skin
`lesions and may occasionally require a central venous
`line associated with increased risk for infections and
`venous tlnombosis.
`Numerous investigators reported results on ECP
`for treatment of cGVHD in children and adolescents
`witl1 rugh response rates in skin, liver, and oral mani(cid:173)
`festations of cGVHD and improved survival rates of
`steroid-refractory patients [3 9, 48-5 4].
`
`MMF (C-1 111-1)
`Since the first publication of a case series with 26
`patients at Johns Hopkins, MMF is increasingly used
`in salvage therapy for refractory cGVHD [55,56].
`Reported response rates in case series using different
`definitions range between 40% and 75%, and no
`randomized trial is available to prove the efficacy of
`second-line MMF in cGVHD alone or in combination
`witl1 other immunosuppressive drugs. Most of the
`improvements have been observed in patients witl1
`limited disease [30,5 7-62] and steroid sparing was
`observed [59].
`Nevertheless, some limitations for the use ofMMF
`as salvage therapy have to be considered such as side
`effects, including gastrointestinal discomfort and diar(cid:173)
`rhea, wruch require dose reduction and may become
`a reason for drug discontinuation. In addition, MMF
`treatment can result in rustopathologic changes of the
`gut mucosa, which may mimic intestinal GVHD [63].
`Hematologic toxicity such as leukopenia and thrombo(cid:173)
`cytopen.ia were observed especially in combination with
`herpes virus infections [64]. Grade II hematologic
`toxicity was reported for 6 of 21 pediatric patients and
`other reports showed an incidence of neutropen.ia or
`tlu·ombocytopenia up to 10% [58,60,62] . Infectious
`complications were observed in several case series
`ranging from 10% to 50%. Baudard eta!. [58] reported
`serious infectious complications such as aspergillosis,
`septicemia, and CMV reactivation in 6 of 15 patients in(cid:173)
`cluding 3 deaths in patients givenMMF either as a single
`agent or in combination. Krejci et al. [60,62] observed
`multiple serious infections in 14 of 21 pediatric
`patients, whereas others recently published serious
`infections in only 3 of 2 3 adult patients, respectively.
`Interestingly, in tl1e latter study, 5 of 2 3 patients died
`
`
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`Biol Blo'od Marrow Transplant 17: 1-17, 20/ I
`
`Second-Line Treatment of Chronic GVHD
`
`7
`
`from noninfectious respiratory failure, a problem not
`mentioned in other studies [60]. One potential explana(cid:173)
`tion for the different rates of infectious complications
`reported in association with MMF may be differences
`in severity of cGVHD, differences in the intensity of
`immunosuppression, as well as comorbidities and the
`use of prophylactic antifungal drugs.
`Both in prophylaxis studies as well as the randomized
`trial mentioned, it became evident, that the use oflvIMF
`potentially increases the relapse risk in myelogenous ma(cid:173)
`lignancies if used as part of a triple agent regimen [13].
`The published data on MMF as second-line therapy
`for cGVHD provide very little information in this re(cid:173)
`spect. Baudard et al. [58] reported on 2 relapses in 20 pa(cid:173)
`tients with both acute GVHD (aGVHD) and cGVHD,
`and Furlong et al. [ 60] observed 2 relapses in 2 3 patients
`treated for cGVHD, respectively.
`Given the information available, MMF represents
`a second-line treatment option. A patient's risk of
`relapse should be considered and may influence a deci(cid:173)
`sion to use Mll1F as part of a multiagent regimen.
`
`Inhibitors of the Mammalian Ta