HEMATOPOIETIC STEM CELL TRANSPLANTATION II: TOWARD SAFER ALLOGENEIC TRANSPLANTATION
`
`Are we making progress in GVHD prophylaxis and treatment?
`
`StevenZ.Pavletic1andDanielH.Fowler1
`
`1CenterforCancerResearch,NationalCancerInstitute,Bethesda,MD
`
`Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective immunotherapy for human cancer. More
`than 20 000 allo-HCTs are performed each year worldwide, primarily for the treatment of hematologic malignancies.
`Several technical innovations implemented in allo-HCT over past 2 decades have reduced NRM by 50% and improved
`overall survival. The allo-HCT practice has changed with the introduction of peripheral blood, cord blood, and
`haploidentical transplantations and reduced-intensity conditioning, and the patient population is also different
`regarding age and diagnosis. However, both acute and chronic GVHD remain serious barriers to successful allo-HCT
`and it is not clear that a major improvement has occurred in our ability to prevent or treat GVHD. Nevertheless, there is
`an increasing knowledge of the biology and clinical manifestations and the field is getting better organized. These
`advances will almost certainly lead to major progress in the near future. As the long list of new potential targets and
`respective drugs are developed, systems need to be developed for rapid testing of them in clinical practice. The current
`reality is that no single agent has yet to be approved by the US Food and Drug Administration for GVHD prevention or
`therapy. Although a primary goal of these efforts is to develop better therapies for GVHD, the ultimate goal is to
`develop treatments that
`lead to effective prevention or preemption of
`life-threatening and disabling GVHD
`manifestations while harnessing the desirable graft-versus-tumor effects.
`
`Introduction
`Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an
`effective immunotherapy for human cancer.1 More than 20 000 allo-
`HCTs are performed each year worldwide, primarily for the
`treatment of hematologic malignancies. Several technical innova-
`tions implemented in the past 2 decades have reduced nonrelapse
`mortality (NRM) by 50% and improved the overall survival (OS)
`after allo-HCT.2 Observed decreases in mortality could be due to
`better methods for the prevention and treatment of GVHD, but to
`many other advances, including: better treatment of infection, less
`toxic conditioning regimens, and better HLA matching of unrelated
`donors (URDs). Allo-HCT clinical practice has also changed over
`last 20 years and has departed from the uniform use of HLA-
`matched sibling donor BM transplantations and myeloablative
`conditioning to a much more complex field. The introduction of
`peripheral blood, cord blood, and haploidentical transplantations
`and reduced-intensity conditioning (RIC) regimens, an older patient
`population, and different diagnoses have modified and made it more
`difficult to study factors that affect the risks and incidence of GVHD
`in today’s era.3 Nevertheless, acute GVHD (aGVHD) and chronic
`GVHD (cGVHD) remain a major contributor to transplantation-
`related deaths and the most significant barrier to the success of
`allo-HCT.4-6 Despite prophylactic treatments with immunosuppres-
`sive agents, approximately 50% of transplantation recipients de-
`velop GVHD. Most GVH reactions are undesirable and affect
`multiple organs; however, GVH reactions against hematopoietic
`tissue targets are desirable and critical for the cure of hematologic
`malignancies (ie, the graft-versus-tumor effect [GVT]) and for
`donor immune-hematopoietic system engraftment. These disparate
`effects of GVH reactions are difficult to separate and any strategies
`directed against GVHD may adversely affect survival by increasing
`malignancy relapse or infections. This chapter examines the prog-
`ress made in GVHD prevention and therapy. Other areas of
`progress, such as GVHD’s impact on health-related quality of life
`
`and functional status and advances in basic research or trial designs,
`will also be discussed.
`
`Who gets GVHD and how is it diagnosed?
`GVHD is an immunological complication of allo-HCT caused by
`donor T cells recognizing the genetically disparate recipient who is
`unable to reject the donor graft.6 cGVHD is additionally compli-
`cated by disturbances in pathways of immunological reconstitution
`and failure to acquire immunological tolerance, thereby resulting in
`both alloimmune and autoimmune attacks on multiple host tissues.7
`
`aGVHD diagnosis should be confirmed by biopsy of an affected
`organ if possible; in addition, other non-GVHD complications
`involving the skin, liver, and GI tract should be ruled out.8 Although
`diagnostic biopsies are highly specific if current histopathology
`criteria are used, the sensitivity of these biopsies is only approxi-
`mately 60%; therefore, the ultimate aGVHD diagnosis and decision
`to treat systemically is based on careful integration of all available
`clinical information.9 There is clearly an unmet need for developing
`more accurate diagnostic tests for aGVHD.10 The severity of
`aGVHD is graded according to the Keystone 1994 consensus
`criteria (grades I-IV) or, less commonly, by the Center for Interna-
`tional Blood and Marrow Transplant Research (CIBMTR) criteria
`(grades A-D).11,12 The diagnosis of cGVHD is also primarily
`clinical and requires at least one diagnostic sign in a target organ per
`National Institutes of Health (NIH) criteria (ie, a sign found only in
`cGVHD) or at least one distinctive sign (ie, a sign highly suggestive
`of cGVHD) in combination with some other laboratory, biopsy, or
`other test confirmation in the same or another organ.7 Due to the
`frequent presence of typical clinical manifestations, biopsies are less
`commonly done for cGVHD diagnosis and are more often used to
`rule out other diagnoses such as infection, drug reactions, or cancer.
`
`The incidence of GVHD described in the available literature must
`be interpreted in light of new classifications that view GVHD as a
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`AcuteGVHD :
`Red skin rash , GI symptoms, liver
`
`Chronic GVHD
`Skin, eyes, mouth, gastrointestinal, liver,
`musculoskeletal, lung, genitourinary
`
`-Classic acute
`
`NIH
`Mild
`Moderate
`Severe
`
`Day 0
`
`50
`
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`180
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`2y
`
`Jy
`
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`Inflammation
`
`Injury
`
`Repair
`
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`
`Figure 1. GVHD classification after the NIH consensus conference.
`The current consensus is that clinical manifestations and not the time
`after transplantation determine whether the clinical syndrome is
`considered aGVHD or cGVHD. Retrospective and prospective studies
`reported wide ranges in the incidences of “late aGVHD” (3%-48%) and
`“cGVHD overlap” (13%-82%); more prospective cohort studies are
`needed.
`
`continuum process rather than as a strict separation of aGVHD and
`cGVHD by the previously used day-100 posttransplantation cutoff.
`(Figure 1) The current consensus is that clinical manifestations
`rather than time after transplantation should determine whether the
`clinical GVHD syndrome is considered acute or chronic.7 Some
`signs and symptoms are common to both aGVHD and cGVHD (ie,
`erythema, macular-papular rash, nausea, vomiting or diarrhea, and
`elevated liver function tests) and thus cannot be used to distinguish
`the two. Two main categories of GVHD are now recognized, each
`with 2 subcategories. The broad category of aGVHD includes:
`(1) classic aGVHD (ie, macular-papular erythematous rash, gastro-
`intestinal symptoms, or cholestatic hepatitis), occurring within
`100 days after transplantation or donor leukocyte infusion and
`(2) persistent, recurrent, or late aGVHD, occurring beyond
`100 days after transplantation or donor leukocyte infusion. To
`facilitate reporting in clinical trials, the arbitrary day-100 distinction
`is retained for the purpose of separating of these 2 aGVHD
`
`categories. Both aGVHD subentities occur without the presence of
`diagnostic or distinctive cGVHD manifestations. A second broad
`category is cGVHD, which encompasses: (1) classic cGVHD,
`which consists only of manifestations that can be ascribed to
`cGVHD; and (2) aGVHD and chronic overlap syndrome, in which
`features of both aGVHD and cGVHD appear together. With
`appropriate stratification, patients with persistent, recurrent, or late
`aGVHD or overlap syndrome can be included in clinical trials with
`patients who have cGVHD. The newly defined entities of “late-
`onset” aGVHD and overlap syndrome subset have been associated
`with poor survival in some studies but not in others.13-16 It remains
`to be determined whether the type or duration of immunosuppres-
`sive therapy should differ in patients with “classic” versus “late”
`aGVHD or “overlap cGVHD.”
`
`Historically, cGVHD severity was staged as “limited” (ie, localized
`skin involvement and/or liver dysfunction) or “extensive” (ie,
`generalized skin involvement, liver histology showing aggressive
`hepatitis, or involvement of any other target organ).17 This classifi-
`cation is relatively poorly reproducible across investigators and
`does not provide information about the number and extent of the
`organs involved or the severity of organ function impairments.18 A
`new cGVHD clinical staging system is now recommended for
`scoring of individual organs (scale, 0-3) that describes the severity
`for each affected organ/site at any given time and also measures
`functional impact.7 A global staging of severity (ie, mild, moderate,
`or severe) is derived by combining organ-specific scores, thereby
`replacing the “limited-extensive” nomenclature.7,17 The feasibility
`of using the NIH staging scale and the distribution of the individual
`organ scores and global severity stages has now been established in
`large prospective studies.16,19,20 In the largest study of
`several
`298 cGVHD patients enrolled into the cGVHD consortium, it was
`determined that 10%, 59%, and 31% of patients had mild, moderate,
`or severe cGVHD, respectively.19 This new and practical scoring
`system enhances the quality and level of detail of cGVHD data
`recording and can be used in clinical practice or investigational
`trials (Figure 2).
`
`Historically, several factors have been identified that predict the
`onset of aGVHD or cGVHD. However, in previous studies, aGVHD
`
`80
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`
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`
`Figure 2. Distribution of individual organ severity scores of cGVHD within global severity mild-moderate-severe staging categories. Data
`were obtained from the prospective study of the US cGVHD consortium (N ⫽ 298). The severity score accounts for both the magnitude of clinical
`manifestations and the degree of functional impairment. Reprinted with permission from Arai et al.19
`
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`

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`Figure 3. Cumulative incidence of aGVHD grade B-D in related donors (A; n ⫽ 3191) and URDs (B; n ⫽ 2370) stratified by treatment category.
`The analysis was performed through the CIBMTR. PBSC indicates peripheral blood stem cell. Reprinted with permission from Jagasia et al.4
`
`and cGVHD were generally referred to as disease that occurred
`within the first 100 days or after 100 days after transplantation. A
`recent large retrospective study of 2941 patients transplanted after
`myeloablative conditioning at the Fred Hutchinson Cancer Research
`Center evaluated risk factors for aGVHD and cGVHD using
`patients reclassified according to new NIH criteria.21 Risk factors
`for aGVHD grades II-IV included transplantation from HLA-
`matched unrelated donor (MUD) or a mismatched related or URD,
`use of total body irradiation (TBI) in the conditioning, and use of a
`female donor for a male recipient. Factors associated with lower risk
`of aGVHD were the use of rabbit antithymocyte globulin (ATG) in
`pretransplantation conditioning and chronic myeloid leukemia diag-
`nosis. Grafting with growth-factor mobilized blood cells and
`patient/donor age were not associated with increased risk of grades
`II-IV aGVHD classified according to the NIH criteria. Risk factors
`for cGVHD scored by NIH criteria were similar to the aGVHD risk
`factors, with the exception of TBI in the conditioning. The use of
`growth factor–mobilized blood cells and donor or recipient age
`were also associated with cGVHD, suggesting that aGVHD and
`cGVHD are not entirely congruent processes. In a separate subanaly-
`sis, prior aGVHD grades III-IV were also associated with higher
`risk of cGVHD according to NIH guidelines.
`
`Compared with these extensive data in the myeloablative setting,
`there is a relative paucity of data in patients receiving RIC.
`However, a recent study from the CIBMTR analyzed risk factors for
`classic aGVHD (within 100 days after transplantation) in a cohort of
`5561 adult patients receiving transplantations between 1999 and
`
`2005 (approximately 20% received allo-HCT after a RIC regimen).4
`In the sibling donor cohort (n ⫽ 3191), the cumulative incidences of
`CIBMTR grades B-D and C-D aGVHD were 39% and 16%,
`respectively. In the URD cohort (n ⫽ 2370), the cumulative inci-
`dences of grades B-D and C-D aGVHD were 59% and 32%,
`respectively. Certainly, these data illustrate the magnitude of the
`aGVHD problem in a contemporary community– based cohort of
`patients. In an innovative way, this study analyzed the impact of the
`most common treatment packages currently used in transplantation
`protocols, because it took into account stem cell source, use of TBI,
`and conditioning intensity (Figure 3). A recent prospective study in
`206 patients with cGVHD enrolled in an NIH natural history study
`identified TBI, especially in the RIC setting, as a significant
`prognostic factor for sclerotic-type cGVHD of the skin (Figure 4).22
`Nevertheless, our current ability to predict aGVHD or cGVHD
`remains insufficiently reliable; however, it is possible that improved
`predictive criteria may be developed through integration of clinical
`and emerging biological markers.10,23
`
`Prognostic factors for outcomes in patients with
`GVHD
`The most established prognostic factors for poor survival and
`mortality in patients who develop aGVHD are grade III-IV severity
`and refractory disease.24-27 The characteristics most consistently
`associated with an increased risk of NRM among patients with
`cGVHD have been thrombocytopenia (⬍ 100 ⫻ 109/L) and progres-
`sive onset of cGVHD from aGVHD. Several other factors associ-
`ated with increased NRM in patients with cGVHD include: elevated
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`100
`
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`
`Figure 4. TBI is associated with an increased risk of development of sclerotic-type cGVHD. The association between TBI and sclerotic cGVHD
`was demonstrated most strongly among patients treated with RIC (P ⫽ .0114). Data are from the NIH study group prospective cohort. Reprinted with
`permission from Martires et al.22
`
`bilirubin, poor Karnofsky performance status, steroid therapy at the
`time of onset, diarrhea, weight loss, GI involvement, HLA mis-
`match, increased patient age, prior aGVHD, and lack of therapeutic
`response to cGVHD treatment.18,28-33 Recently, a prognostic score
`has been developed for cGVHD that is defined by traditional criteria
`derived from a large cohort of 5343 patients reported to the
`CIBMTR between 1995 and 2004. The study cohort included
`patients of all ages treated by all graft sources, donor sources, and
`both myeloablative and RIC regimens. This analysis showed an OS
`for the whole cohort of 72% at 1 year and 55% at 5 years.5 The
`cumulative incidence of NRM was 21% at 1 year and 31% at 5 years;
`6 risk groups were identified that had OS ranging from 15% to 90%.
`
`It is important to emphasize that most studies evaluating prognostic
`factors for NRM and survival in GVHD are retrospective, from
`various treatment eras, include heterogeneous patient populations,
`and did not use contemporary diagnosis and staging criteria.
`However, in a positive vein, prospective data are now emerging in
`
`newly diagnosed and advanced patients due largely to the efforts of
`the cGVHD consortium in the United States and some single-center
`studies.19,34 These studies confirmed the significance of some
`previously recognized prognostic factors, such as low platelet count,
`progressive disease onset, and Karnofsky performance status, and
`also identified new prognostic factors such as NIH global severity
`stage (mild vs moderate vs severe), overlap syndrome, NIH lung
`score, and lymphopenia (Figure 5).15,16,19,20 Recent studies estab-
`lished the association between NIH mild-moderate-severe global
`stages and health-related quality of life.35 It is also expected that
`integration of established clinical prognostic factors and emerging
`biomarkers will assist in better individualization of GVHD therapy
`depending on the risk stratification.36,37
`
`GVHD prophylaxis
`aGVHD
`The original aGVHD prophylaxis regimens developed during the
`1970s used the folate antagonist methotrexate (MTX) due to its
`
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`
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`
`Figure 5. Cumulative incidence of OS according to NIH global severity at enrollment. Graph shows 2-year survival estimates, 95% confidence
`intervals (in parentheses), and hazard ratios (HR). Data are from the prospective study of the US cGVHD consortium (N ⫽ 298). Reprinted with
`permission from Arai et al.19
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`ability to delete proliferating donor lymphocytes. The initial MTX
`dosing regimen of days 1, 3, 6, and 11 and then once weekly through
`day 102 yielded an incidence of grades III-IV aGVHD of approxi-
`mately 25%.38 Cyclosporine (CSA) entered clinical trials of GVHD
`prophylaxis in the late 1970s and showed equivalency with MTX in
`prospective studies.39 True progress in GVHD prevention occurred
`with combination regimens containing CSA and a short course of IV
`MTX (15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11),
`which showed synergism and a survival benefit in BM transplanta-
`tion from matched siblings and remains a commonly used regi-
`men.4,40,41 No improvements in cGVHD incidence were seen with
`these regimens, again suggesting divergent pathogenic mechanisms.
`Attempts to improve outcomes by adding prednisone to the
`MTX/CSA combination did not yield positive results.42,43 During
`the 1990s, another calcineurin inhibitor, tacrolimus (TAC) used in
`combination with short-course MTX was tested in 2 large North-
`American phase 3 clinical
`trials after related and URD BM
`transplantation.44,45 Both trials showed reductions in overall aGVHD
`incidence (but not cGVHD) among patients receiving TAC/MTX
`relative to recipients of CSA/MTX; however, OS was not different.
`These studies prompted some centers to more frequently use the
`TAC combination, particularly in URD transplantations.
`
`Mycophenolate mofetil (MMF), via its metabolite mycophenolic
`acid, inhibits proliferation of lymphocytes and is synergistic with
`calcineurin inhibitors in preventing GVHD. MMF also facilitates
`donor engraftment and is now widely used in RIC transplantations
`from related or URDs.38 Although GVHD prevention does not seem
`to be improved by use of MMF rather than MTX in calcineurin
`inhibitor– based regimens, there is a significant decrease in inci-
`dence and severity or oropharyngeal mucositis with the use of
`MMF.46,47
`
`Although the combinations of calcineurin inhibitors and MTX or
`MMF have resulted in satisfactory rates of aGVHD and survival
`outcomes, these regimens are not uniformly effective and many
`patients are still dying from GVHD and related complications.4
`Therefore, substantial efforts have been invested in attempts to
`improve on these calcineurin-inhibitor– based combinations. Anti–
`T-cell Abs have been explored as part of preparative regimens since
`the earliest days of allo-HCT; in uncontrolled studies, such Abs
`prevented GVHD but also increased risk of leukemia relapse,
`infections, non-relapse-related complications, and engraftment fail-
`ures.48 Interpretation of these data is complicated by the huge
`variability in the studies, particularly in regard to the form of Ab
`used (at least 4 different forms have been used), source of the stem
`cell, type of donor, and conditioning regimen intensity. The best
`evidence for in vivo Ab efficacy is for ATG in URD BM
`transplantation after myeloablative conditioning.49 In a large random-
`ized trial, patients who underwent allo-HCT from 8/8 MUDs
`(approximately 80% received peripheral blood stem cells) were
`randomly assigned to receive CSA/MTX with or without anti-Jurkat
`rabbit ATG. ATG recipients had significant reduction of grade II-IV
`and grade III-IV aGVHD from 51%-33% and from 24.5%-11.7%,
`respectively. ATG recipients also had a reduced 3-year incidence of
`extensive cGVHD (45.0% vs 12.2%).50 There was no statistically
`significant difference in relapse, NRM, mortality from infectious
`disease, or OS between groups. A smaller and older randomized
`study originally performed in the late 1990s showed similar
`short-term results.51 In addition, long-term follow-up showed re-
`duced late pulmonary disease in the ATG arm, suggesting a
`potential long-term impact of in vivo ATG on health-related quality
`of life.52 Randomized trials to address the role of ATG, especially in
`
`cGVHD prevention, are progressing in the United States and
`Canada (www.clinicaltrials.gov identifiers NCT01295710 and
`NCT01217723, respectively). The role of ATG in RIC allo-HCT
`has not been formally tested because the success of these transplan-
`tations in terms of controlling relapse is more dependent on intact
`GVT reactions. A large retrospective CIBMTR study involv-
`ing ⬎ 1400 patients confirm these concerns, because ATG recipi-
`ents after RIC had increased risk of malignancy relapse, more NRM,
`more EBV lymphoproliferative disease, and lower OS and disease-
`free survival.53 Prospective randomized trials are needed to define
`the role of optimal dose and timing of ATG administration in the
`RIC allo-HCT setting.54,55 In a related approach, potent and
`practical techniques for ex vivo T-cell depletion strategies have
`been evaluated to prevent GVHD. Recently, a phase 2 study in acute
`myeloid leukemia patients in remission (mostly in in first complete
`remission [CR1]) demonstrated feasibility of such an approach in
`related donor transplantations using myeloablative conditioning
`devoid of posttransplantation systemic immunosuppression.56 In
`that study, the incidences of aGVHD and cGVHD were low and
`relapse did not appear to be increased; however, survival rates were
`not different from historical controls.
`
`Another pharmacological approach to preventing GVHD has been
`developed by investigators at the Dana-Farber Cancer Institute
`through the use of sirolimus, an mTOR inhibitor, as an addition to
`TAC and MTX.57 In addition to effector T-cell inhibition, sirolimus
`can preserve regulatory T cells after transplantation, thereby adding
`to GVHD control. In a single-arm phase 2 study, the substitution of
`sirolimus for MTX in combination with TAC after myeloablative
`conditioning resulted in grade II-IV aGVHD of 20.5% and grade
`III-IV of 4.8%; no differences in outcomes were observed between
`recipients of related or URDs.58 This approach has been extended
`into the RIC setting, with results indicating that the addition of MTX
`to sirolimus and TAC is not necessary.59,60 These data support the
`utility of sirolimus as a second agent with TAC in GVHD
`prophylaxis. However, due to an increased risk of veno-occlusive
`disease, sirolimus should not be used with myeloablative doses of
`busulfan or in the TBI-based myeloablative regimens if combined
`with MTX.61
`
`Because long-term administration of calcineurin inhibitors has
`toxicities and impairs T-cell development, Johns Hopkins Univer-
`sity investigators are testing the use of high-dose posttransplantation
`cyclophosphamide (Cy) as sole prophylaxis for GVHD after
`HLA-matched related and URD T cell–replete BM transplanta-
`tion.62 Cy, when given early after transplantation, acts similarly to
`MTX in terms of deleting rapidly dividing alloreactive T cells.
`Hematopoietic stem cells contain high levels of aldehyde dehydro-
`genase, which converts 4-hydroxycyclophosphamide into a nonalky-
`lating metabolite, thus sparing stem cells from the antiproliferative
`activity of this agent. Cy was given at a dose of 50 mg/kg on days
`3 and 4 after transplantation with myeloablative Bu-Cy conditioning
`without addition of any other systemic immunosuppression.62 The
`median time to neutrophil engraftment was 23 and 25 days in
`matched related donor (MRD) and URD patients, respectively,
`without use of exogenous colony stimulating factors; in addition,
`there was a relatively low treatment-related mortality of 13% and
`21% at 2 years for MRD and MUD, respectively. Grade II-IV
`aGVHD incidence was 42% (MRD) and 46% (URD), with grade III
`and IV occurring in 12% and 8% of patients, respectively. Perhaps
`the most impressive clinical result of the Cy regimen was the low
`cumulative incidence of cGVHD, which was 10%. The potential
`advantage of this approach is selective elimination of host-reactive
`
`Hematology2012
`
`255
`
`

`

`Table 1. Prospective studies of aGVHD prevention
`
`Study
`Randomized
`Storb40
`
`Storb41
`
`Chao42
`
`Ratanatharathorn44
`
`Chao43
`
`Nash45
`
`Bolwell46
`
`Finke49
`
`Perkins47
`
`Regimen
`
`N
`
`Donor
`
`Transplantation
`
`Grade
`II-IV
`
`Grade
`III-IV
`
`cGVHD
`
`OS
`
`CSA
`CSA⫹MTX
`
`MTX
`CSA⫹MTX
`
`CSA⫹MTX⫹PDN
`CSA⫹PDN
`
`TAC⫹MTX
`CSA⫹MTX
`
`CSA⫹MTX
`CSA⫹MTX⫹PDN
`TAC⫹MTX
`CSA⫹MTX
`
`CSA⫹MMF
`CSA⫹MTX
`CSA⫹MTX⫹ATG
`CSA⫹MTX
`
`50
`43
`
`24
`22
`
`75
`74
`
`165
`164
`
`96
`90
`90
`90
`
`21
`19
`103
`98
`
`MSD
`
`MAC BMT
`
`MSD
`
`RIC BMT (AA)
`
`MSD
`
`MAC BMT
`
`MSD
`
`MAC BMT
`
`MSD
`
`URD
`
`MSD
`
`URD
`
`MAC BMT
`
`MAC BMT
`
`MAC BMT
`
`MAC ⬃ 80% BMT
`⬃ 20% BSC
`
`TAC⫹MMF
`TAC⫹MTX
`
`42 MSD and
`47
`URD
`
`MAC
`
`54%
`33%
`P ⫽ .014
`53%
`18%
`P ⫽ .012
`9%
`23%
`P ⫽ .02
`32%
`44%
`P ⫽ .01
`20%
`18%
`56%
`74%
`P ⫽ .0002
`48%
`37%
`33%
`51%
`P ⫽ .011
`78%
`79%
`
`26%
`7%
`
`37%
`0%
`
`NA
`
`13%
`17%
`
`10%
`6%
`18%
`15%
`
`38%
`37%
`
`25%
`41%
`
`57%
`60%
`
`56%
`59%
`
`45%
`43%
`76%
`70%
`
`NA
`
`63%
`64%
`31%
`12%
`59%
`24%
`P ⫽ .054 P ⬍ .0001
`19%
`38%
`4%
`45%
`P ⫽ .03
`
`55% @ 1.5 y
`80%
`P ⫽ .042
`60% @ 2 y
`82%
`P ⫽ .062
`64% @ 3 y
`59%
`(DFS)
`47% @ 2 y
`57%
`P ⫽ .02
`65% @ 2 y
`72%
`54% @ 2 y
`50%
`
`52% @ 6 mo
`68%
`59% @ 2 y
`52%
`
`54% @ 3 y
`42%
`
`13%
`
`42%
`
`52% @ 1 y
`
`Single arm
`Antin57
`
`Cutler58
`
`Aleya59
`
`Ho60
`Koreth64
`
`Luznik62
`
`Devine56
`
`Reshef65
`
`TAC⫹SIRO⫹MTX
`
`TAC⫹SIRO
`
`TAC⫹SIRO⫹MTX
`
`TAC⫹SIRO
`TAC⫹MTX⫹
`bortezomib
`High-dose CY⫹
`no systemic IS
`High-dose CY⫹
`no systemic IS
`Ex vivo TCD⫹
`no systemic IS
`TAC⫹MTX⫹maraviroc
`
`41
`
`83
`
`91
`
`29
`23
`
`78
`
`39
`
`51
`
`38
`
`URD
`mmSD
`53 MSD
`30 URD
`46 MSD
`45 URD
`MRD
`URD (mm)
`
`MRD
`
`URD
`
`MRD
`
`13 MRD
`25 URD
`
`MAC BMT
`
`MAC BSC
`
`RIC BSC
`
`RIC
`RIC BSC
`
`MAC BMT
`
`MAC BMT
`
`MAC
`
`RIC
`
`26%
`
`20%
`
`16%
`
`17%
`13%
`
`42%
`
`46%
`
`23%
`
`24%
`
`5%
`
`7%
`
`NA
`7%
`
`12%
`
`8%
`
`5%
`
`6%
`
`59%
`
`72% @ 2 y
`
`59% @ 2 y
`
`76% @ 2 y
`75% @ 1 y
`
`55% @ 2 y
`
`55% @ 2 y
`
`56% @ 3 y
`
`47% @ 2 y
`
`49%
`(extensive)
`74%
`41%
`
`9%
`
`11%
`
`19%
`
`24%
`(moderate/
`severe)
`
`Pvalues are reported only in cases when the difference was statistically significant.
`MSD indicates HLA matched sibling donor; BMT, BM transplantation; AA, aplastic anemia; MAC, myeloablative conditioning; PDN, prednisone or equivalent dose of another
`corticosteroid (most commonly, IV methylprednisolone); SIRO, sirolimus; mm, HLA mismatch; and IS, immunosuppression.
`
`donor lymphocytes within days after transplantation, with relatively
`rapid recovery of other immunologic functions and without pro-
`tracted exposure to calcineurin inhibitors (which may interfere with
`the induction of posttransplantation tolerance). Comparative prospec-
`tive studies should define the risk of malignancy relapse after using
`the posttransplantation Cy approach.
`
`Several additional agents are of potential interest or are in the early
`stages of clinical development for GVHD prevention.63 A phase 1/2
`study demonstrated promise in aGVHD prevention using the
`proteasome inhibitor bortezomib in addition to TAC and low-dose
`MTX.64 A strikingly low incidence of gastrointestinal and liver
`aGVHD was observed in a recent phase 1/2 study using maraviroc, a
`
`well-tolerated oral CCR5 antagonist.65 Prospective studies for
`aGVHD prevention are summarized in Table 1.
`
`cGVHD
`Due to a relatively limited understanding of cGVHD pathogenesis,
`developing preventive strategies specifically for this complication
`of allo-HCT has been more difficult. None of the current calcineurin-
`inhibitor– based pharmacological approaches that successfully pre-
`vent aGVHD has a major impact on cGVHD (Table 1). Whether the
`development of calcineurin-inhibitor–free aGVHD prevention meth-
`ods would have better impact on cGVHD remains to be deter-
`mined.66 Although cGVHD can be reduced by methods that
`quantitatively eliminate donor T cells by in vivo or ex vivo T-cell
`
`256
`
`American Society of Hematology
`
`

`

`depletion or posttransplantation high-dose Cy, the success of such
`approaches is constrained by a higher rate of malignancy relapse or
`infections, thereby leading to lack of a survival advantage or even
`reduced survival.48,53 Two randomized trials were specifically
`designed to prevent cGVHD with study drugs added to the standard
`calcineurin inhibitor– based aGVHD prevention. One placebo-
`controlled randomized trial tested hydroxychloroquine administered
`on days 21-365 after transplantation in 95 patients and did not show
`effects on aGVHD or cGVHD or on survival.67 The other random-
`ized placebo-controlled trial that tested thalidomide in 59 patients
`showed detrimental effects due to an increased rate of cGVHD
`flares and impaired survival in the experimental arm.68 The reasons
`for the discrepancy in cGVHD prevention between pharmacological
`suppression and T-cell depletion strategies are not clear, and a better
`understanding of these processes may aid in the development of new
`treatments to prevent cGVHD and hopefully harness GVT effects.
`Based on the recent information about the role of B cells in cGVHD,
`anti-CD20 Ab strategies are currently being tested for their potential
`in preventing cGVHD.69
`
`GVHD treatment
`aGVHDfrontlinetherapy
`The current model of aGVHD development includes 3 phases:
`(1) tissue damage induced by the preparative regimen; (2) priming
`and activation of donor T cells, with CD8 T cells being stimulated
`by residual host APCs and CD4 T cells being stimulated by donor
`APCs presenting host-derived antigens; and (3) target tissue damage
`induced directly by cytotoxic T cells and indirectly by inflammatory
`cytokines.6 Therefore, modulation of donor-alloreactive effector
`T cells remains a major focus of current therapies for aGVHD.
`Nonetheless, other cell populations including regulatory T cells,
`dendritic cells, natural killer T cells, and B cells or other mecha-
`nisms such as modulation of tissue or vascular endothelium damage
`signals may represent future targets for novel approaches to GVHD
`therapy.63 Although several agents have been tested over the last
`30 years for the systemic therapy of aGVHD, no product
`is
`approved by the US Food and Drug Administration (FDA) for use in
`aGVHD or cGVHD. Poor standardization of GVHD clinical studies
`has been identified as a major obstacle to the progress of clinical
`trials and the development of new treatments.70 Recent recommen-
`dations of the American Society of Blood and Marrow Transplanta-
`tion (ASBMT) recognize this fact and raise the bar required for
`study implementation and publications of future studies in aGVHD.27
`
`Patients with aGVHD requiring systemic therapy (grades II-IV) are
`typically started o