Abstract
In 2014, the National Institutes of Health sponsored the second Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-vs-Host (GVHD). The purpose was to update recommendations about key elements of chronic GVHD research, including definitions for diagnosis, severity scoring, and response measures, based on empirical data published since the first 2005 Consensus Conference. The most significant modifications were to the response assessments, since studies demonstrated difficulty with the first consensus definitions. The Response Measures Validation study is a multi-center, prospective cohort study of patients who are starting initial or subsequent treatments for chronic GVHD. The aim of the study is to evaluate the performance of the 2014 response measures and see if any other combination of assessments is superior. Clinical data, clinician assessments, patient-reported outcomes and research samples are collected at enrollment, and 3, 6, and 18 months later, and if another chronic GVHD systemic treatment is added. The target enrollment of 368 evaluable patients from 12 transplant centers has been reached. This report describes the rationale, design, and methods of the Chronic GVHD Response Measures Validation study, and invites other investigators to collaborate with the Consortium to analyze data or specimens.
Keywords: chronic graft-versus-host disease, allogeneic hematopoietic cell transplantation, prospective longitudinal observational study, biorepository, response assessment
INTRODUCTION
Chronic graft-versus-host disease (GVHD) occurs in 20–50% of patients after allogeneic hematopoietic cell transplantation (HCT) and is the major cause of non-relapse mortality in two-year disease free survivors.1–5 Chronic GVHD is also associated with worse quality of life (QOL), worse functional status and inability to return to work, and increased symptom burden.6–11.
Chronic GVHD requires long-term treatment with immunosuppressive agents. Initial treatment usually includes corticosteroids at doses of 0.5–1.0 mg/kg/day. If chronic GVHD worsens or recurs when steroids are tapered, there are more than 35 agents that have reported activity in patients who need additional treatment.12 In August 2017, ibrutinib was the first agent approved by the U.S. Food and Drug Administration (FDA) for treatment of steroid-refractory chronic GVHD.13 The approval was based on the overall response rate (complete plus partial response) according to the 2005 National Institutes of Health (NIH) consensus conference on Criteria for Clinical Trials in Chronic GVHD recommended response criteria. Improvement in patient-reported symptoms as measured by the Lee Symptom Scale is also included in the FDA label.
The overall goal of this multicenter, observational, prospective, longitudinal study is to further develop and validate endpoint measures that accurately and holistically capture patient response to chronic GVHD treatment. A secondary goal is to determine whether any chronic GVHD characteristics predict response to specific therapy. The purpose of this paper is to provide a description of the study to facilitate collaboration and use of data and samples by the broader research community.
METHODS
Objectives
The study has 3 main objectives: (1) develop and validate the Chronic GVHD-Activity index (CGVHD-AI) that uses clinician-reported, patient-reported and laboratory measures to quantify treatment response, correlating changes in the CGVHD-AI to clinically significant changes reported by patients and physicians; (2) develop and validate the Chronic GVHD Failure-Free Survival Score (CGVHD-FFS) as a predictor of failure-free survival, defined as an absence of death, relapse, and requirement for new therapy; (3) determine if the CGVHD-AI and CGVHD-FFS can predict disability-free survival, defined as being alive, without relapsed malignancy, and no worsening of disability status, as measured by the Human Activities Profile.14 Standardized data are collected prospectively from clinicians and patients and supplemented by the information obtained from medical chart review.
Population
Allogeneic HCT recipients 7 years or older were eligible for the study independent of graft source, donor type, and GVHD prophylaxis if they had a diagnosis of chronic GVHD according to the criteria of the diagnosis and scoring group of the NIH consensus conference. In addition, because this study focused on evaluating response criteria, participation was limited to patients who either initiated a new systemic treatment for chronic GVHD in the past 4 weeks or subsequent 4 weeks, since these patients are the ones who would be considered for therapeutic clinical trials. Systemic treatment was defined as any medication or intervention that has intended systemic effects, including extracorporeal photopheresis, regardless of prior lines of therapy or prior treatment with the agent(s). Patients restarting a prior treatment must have been off that therapy for at least 4 weeks before restarting. Concurrent acute GVHD manifestations were allowed if patients also met the diagnostic criteria for chronic GVHD. Patients were excluded if they had evidence of persistent or progressive malignancy at the time of enrollment, were unable to comply with the study procedures and evaluation schedule, or already had complete resolution of their chronic GVHD at the time of enrollment, having previously started a new treatment in the past 4 weeks. The protocol was approved at all participating sites by an institutional review board (IRB) and all study participants provided written informed consent prior to enrollment. This study was registered at www.clinicaltrials.gov as NCT01902576. Participating transplantation centers and investigators are listed in the Appendix.
At Fred Hutchinson Cancer Research Center (FHCRC), a limited number of patients without chronic GVHD were enrolled as a control group (n=43, enrollment ongoing). Control participants were eligible beginning 6 months after HCT if they had no evidence of chronic GVHD and were confirmed to be free of chronic GVHD at least 3 months after enrollment. They completed the same assessments that study cases did, except the walk test, as well as also providing a research blood sample. Controls could still be receiving systemic immune suppression for GVHD prophylaxis or acute GVHD treatment.
Study Design
This is an observational, prospective, longitudinal study at 12 participating sites. Sample size was determined by the number of patients needed to address the 3 primary objectives. Study visits and data collection occur at the time of enrollment, at 3, 6, and 18 months after enrollment, and when another systemic treatment is added. Standardized information about chronic GVHD organ involvement and symptoms are collected from the patients and clinicians, and research blood samples are collected at each research visit. Objective medical data are captured via chart review, including laboratory results, ancillary testing, medical complications, comorbidities, and concomitant medications (Table 1). If a patient relapses with their primary disease and is treated, data collection from the patient and clinician ceases and no additional research samples are obtained. The patient continues to be followed for the other endpoints: discontinuation of immunosuppression and death. All participants are now in long-term follow up for data collection by chart review for relapse, death, and discontinuation of immunosuppressive medications.
Table 1.
Data collection for the Response Measures study.
| Data element | Data source | Description |
|---|---|---|
| Clinician assessment form | Clinical providers | NIH organ scores, NIH response measures, Carpenter photographic range of motion, overall cGVHD severity, reason for adjusting treatment, rare clinical manifestations |
| Patient assessment form | Patients | Lee symptom scale, FACT-G, SF-36, HAP, overall cGVHD severity, changes in cGVHD since enrollment, sociodemographic information |
| Functional assessments | Patients | 2-minute walk test, pulmonary function tests |
| Chart review | Institutional database or medical records | Sociodemographics, patient, donor, and transplant characteristics, immunosuppressive medications, comorbidity, relapse, death, resolution of cGVHD |
| Biological samples | Peripheral blood mononuclear cells, heparin plasma |
Abbreviations: GVHD, graft-versus-host disease; FACT-BMT, Functional assessment of cancer therapy – bone marrow transplant version 4.0; SF-36, Short form-36 v2.0; HAP, Human activities profile
Data Collection
Data are entered into an online electronic database maintained at the Coordinating Center at FHCRC using only a study identification number (ID). Data cleaning is conducted every 4–6 months using customized programs for range and logic checking and by random audits comparing data entered to the source documents.
Clinician assessment form
The clinician-reported variables include all the measures recommended by the 2014 NIH conference.15,16 The 7 clinician-reported NIH organ severity scores (skin, eye, mouth, vulvo-vaginal, gastrointestinal, lung, and joint) are collected along with the NIH response measures, and the clinician overall severity scores (0–10 scale and mild, moderate, severe). Liver severity is calculated from liver function tests. Clinicians also report the change in chronic GVHD activity since enrollment on an 8-point scale, ranging from completely gone, very much better, moderately better, a little better, stable, a little worse, moderately worse, very much worse. The clinician form takes approximately 10 minutes to complete.
Patient assessment form
The patient-reported variables assessed include all the patient-reported measures identified in the 2014 NIH consensus conference as predictive of patient perceptions of change, non-relapse mortality, survival or failure-free survival. If a subscale was predictive, the entire scale is included. At each standard study visit, including enrollment, the patient assessment includes the following items to record patients’ symptoms, global severity scores, perceptions of change, quality of life (QOL), and functional status: the Lee Symptom Scale, a 30-item instrument rating how much patients are bothered by their chronic GVHD symptoms over the past month;17 the Functional Assessment of Cancer Therapies v4 (FACT-G, a 27-item multidimensional quality of life instrument used in HCT research to assess 4 domains of wellbeing: physical, emotional, social, and functional; the SF-36 v2, a 36-item self-report questionnaire that assesses health and functioning by evaluating physical functioning (PF), role functioning-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role functioning-emotional (RE), and mental health (MH); the Human Activity Profile (HAP), a 94-item survey assessing functional ability that measures disability-free survival, defined as a modified HAP scale score that is not more than 0.5 standard deviation below the score at enrollment.14 Patients also report their overall chronic GVHD symptoms, skin itching, skin and/or joint tightening, mouth sensitivity, and genital discomfort on a 0–10 scale from “not present” to “as bad as you can imagine” over the past week, and at follow-up study visits score the changes in their chronic GVHD since enrollment on the same 8-point scale employed by the clinician assessment form. Sociodemographic information is also collected by the patient-assessment at enrollment. The patient assessment forms take 15–20 minutes to complete.
Laboratories/functional tests
Study staff record the laboratory tests and functional status measures that include: liver function tests (alkaline phosphatase, ALT, AST, total bilirubin, and albumin), LDL, and complete blood counts with differential. Pulmonary function test results are recorded when available. The 2-minute walk test requires the patient to walk up and down a flat 25 foot surface to measure the total distance covered in two minutes.
Medical record abstraction
Data collected from institutional databases and chart review includes transplant and disease-specific information. The details of the patient’s diagnosis, transplant course, chronic GVHD onset, current status, adjustments to chronic GVHD treatment, and complications are captured. Variables include disease history and status at transplantation, conditioning regimen, donor information, HLA-match, GVHD prophylaxis, occurrence of acute GVHD, prior exposure to infectious agents, co-morbidities, and other major clinical events (relapse, donor lymphocyte infusion, or death). Note that information on chimerism results and concurrent infections is not captured in the database, unless the infection solely accounted for organ dysfunction as captured on the clinician assessment form.
Biological samples
At all study visits, biological research samples are collected and banked in a biorepository housed at the National Marrow Donor Program, Minneapolis, MN. Adults donate 30 mL in green-top, heparinized tubes that are processed locally into peripheral blood mononuclear cells (PBMC) and plasma. Pediatric patients <20 kg donate 2 mL/kg up to 30 mL. Pathology specimens from biopsies taken as part of patients’ routine care may also be reviewed for research purposes.
Biostatistical Considerations
Data are presented descriptively. Medians, interquartile ranges (IQR) or means and standard deviations are reported as appropriate.
RESULTS
As of December 5, 2017 a total of 382 subjects have been enrolled in this prospective cohort study from 12 transplantation centers. Patient, disease and transplant characteristics are shown in Table 2. Of the 382 enrolled patients, 364 had baseline assessments and samples plus at least one response assessment, and 351 had baseline assessments, both baseline and follow up samples plus at least one response assessment (Figure). Almost all (99%) were adults and 89% were White. The median age was 56 years. About half were transplanted for acute leukemia with 64% receiving unrelated donor grafts and 91% getting peripheral blood. Fred Hutchinson enrolled 43% of the patients. Table 3 shows the chronic GVHD characteristics and the number of available specimens.
Table 2.
Enrollment socio-demographic, chronic GVHD, and transplantation characteristics
| N (%) | ||||
|---|---|---|---|---|
| Characteristic | Category | All enrolled (N=382) | Baseline research sample and response assessment (N=354) | Baseline and follow up research samples and response assessment (N=351) |
| Adult | 380 (99%) | 352 (99%) | 349 (99%) | |
| Age | Median (range) | 56.0 (12.0–79.0) | 56.0 (12.0–78.0) | 56.0 (12.0–78.0) |
| Sex | Male | 239 (63%) | 221 (62%) | 221 (63%) |
| Female | 143 (37%) | 133 (38%) | 130 (37%) | |
| Race | American Indian/Alaska Native | 4 (1%) | 4 (1%) | 4 (1%) |
| Asian | 13 (3%) | 13 (4%) | 13 (4%) | |
| Black/African American | 11 (3%) | 11 (3%) | 10 (3%) | |
| Native Hawaiian | 3 (1%) | 3 (1%) | 3 (1%) | |
| Caucasian | 341 (89%) | 315 (89%) | 313 (89%) | |
| Multi-race | 2 (1%) | 1 (0%) | 1 (0%) | |
| Unknown | 6 (2%) | 5 (1%) | 5 (1%) | |
| Other | 2 (1%) | 2 (1%) | 2 (1%) | |
| Ethnicity | Hispanic | 19 (5%) | 17 (5%) | 17 (5%) |
| Not hispanic | 358 (94%) | 332 (94%) | 329 (94%) | |
| Unknown | 5 (1%) | 5 (1%) | 5 (1%) | |
| Diagnosis | Acute myeloid leukemia | 148 (39%) | 132 (37%) | 130 (37%) |
| Acute lymphoblastic leukemia | 39 (10%) | 37 (10%) | 37 (11%) | |
| Chronic myeloid leukemia | 18 (5%) | 17 (5%) | 17 (5%) | |
| Chronic lymphcytic leukemia | 16 (4%) | 15 (4%) | 15 (4%) | |
| Myelodysplastic syndrome | 55 (14%) | 53 (15%) | 52 (15%) | |
| Non-hodgkins lymphoma | 43 (11%) | 41 (12%) | 41 (12%) | |
| Hodgkin lymphoma | 9 (2%) | 8 (2%) | 8 (2%) | |
| Myeloproliferative neoplasm | 15 (4%) | 15 (4%) | 15 (4%) | |
| Multiple myeloma | 10 (3%) | 9 (3%) | 9 (3%) | |
| Aplastic anemia | 7 (2%) | 5 (1%) | 5 (1%) | |
| Other | 22 (6%) | 22 (6%) | 22 (6%) | |
| Disease status1 | Early | 178 (47%) | 162 (46%) | 160 (46%) |
| Intermediate | 150 (39%) | 143 (40%) | 142 (40%) | |
| Advanced | 53 (14%) | 49 (14%) | 49 (14%) | |
| Transplant source | Peripheral blood | 347 (91%) | 322 (91%) | 320 (91%) |
| Bone marrow | 24 (6%) | 22 (6%) | 21 (6%) | |
| Cord blood | 9 (2%) | 8 (2%) | 8 (2%) | |
| Missing* | 2 (1%) | 2 (1%) | 2 (1%) | |
| Transplant type | Myeloablative | 178 (47%) | 168 (47%) | 166 (47%) |
| Reduced intensity | 111 (29%) | 102 (29%) | 101 (29%) | |
| Non-myeloablative | 92 (24%) | 83 (23%) | 83 (24%) | |
| Missing* | 1 (0%) | 1 (0%) | 1 (0%) | |
| Patient CMV serology | Negative | 185 (48%) | 175 (49%) | 174 (50%) |
| Positive/equivocal | 191 (50%) | 174 (49%) | 172 (49%) | |
| Missing* | 6 (2%) | 5 (1%) | 5 (1%) | |
| Donor CMV serology | Negative | 230 (60%) | 214 (60%) | 213 (61%) |
| Positive/equivocal | 145 (38%) | 134 (38%) | 132 (38%) | |
| Missing* | 7 (2%) | 6 (2%) | 6 (2%) | |
| Donor type | HLA matched relative | 127 (33%) | 122 (34%) | 121 (34%) |
| HLA mismatched relative | 8 (2%) | 7 (2%) | 7 (2%) | |
| Unrelated donor | 246 (64%) | 224 (63%) | 222 (63%) | |
| Missing* | 1 (0%) | 1 (0%) | 1 (0%) | |
| Transplant center | Fred Hutchinson Cancer Research Center | 165 (43%) | 150 (42%) | 149 (42%) |
| Vanderbilt University | 42 (11%) | 41 (12%) | 39 (11%) | |
| Cleveland Clinic | 30 (8%) | 27 (8%) | 27 (8%) | |
| Roswell Park Cancer Institute | 27 (7%) | 26 (7%) | 26 (7%) | |
| Dana-Farber Cancer Institute | 25 (7%) | 24 (7%) | 24 (7%) | |
| University of British Columbia | 23 (6%) | 23 (6%) | 23 (7%) | |
| University of Minnesota | 21 (5%) | 19 (5%) | 19 (5%) | |
| H. Lee Moffitt Cancer Center | 19 (5%) | 16 (5%) | 16 (5%) | |
| MD Anderson | 11 (3%) | 10 (3%) | 10 (3%) | |
| Stanford University | 10 (3%) | 10 (3%) | 10 (3%) | |
| Duke University | 7 (2%) | 7 (2%) | 7 (2%) | |
| Ohio State University | 2 (1%) | 1 (0%) | 1 (0%) | |
| Donor gender | Female into male | 97 (25%) | 87 (25%) | 87 (25%) |
| Other | 280 (73%) | 262 (74%) | 259 (74%) | |
| Male and female (cord blood) | 2 (1%) | 2 (1%) | 2 (1%) | |
| Missing* | 3 (1%) | 3 (1%) | 3 (1%) | |
| Marital status | Married/living with partner | 231 (60%) | 219 (62%) | 218 (62%) |
| Single, never married | 46 (12%) | 42 (12%) | 42 (12%) | |
| Divorced, separated | 37 (10%) | 33 (9%) | 32 (9%) | |
| Widowed | 6 (2%) | 5 (1%) | 5 (1%) | |
| Other | 2 (1%) | 1 (0%) | 1 (0%) | |
| Missing | 60 (16%) | 54 (15%) | 53 (15%) | |
| Highest education | Grade school | 5 (1%) | 5 (1%) | 4 (1%) |
| Some high school | 10 (3%) | 9 (3%) | 9 (3%) | |
| High school graduate | 53 (14%) | 50 (14%) | 50 (14%) | |
| Some college | 98 (26%) | 90 (25%) | 89 (25%) | |
| College graduate | 93 (24%) | 88 (25%) | 88 (25%) | |
| Post graduate degree | 60 (16%) | 56 (16%) | 56 (16%) | |
| Missing | 63 (16%) | 56 (16%) | 55 (16%) | |
| Annual family income | < $15,000 | 17 (4%) | 17 (5%) | 16 (5%) |
| $15,000–$24,999 | 14 (4%) | 12 (3%) | 12 (3%) | |
| $25,000–$49,999 | 49 (13%) | 45 (13%) | 44 (13%) | |
| $50,000–$74,999 | 61 (16%) | 57 (16%) | 57 (16%) | |
| $75,000–$99.999 | 55 (14%) | 53 (15%) | 53 (15%) | |
| $100,000+ | 96 (25%) | 91 (26%) | 91 (26%) | |
| Missing | 90 (24%) | 79 (22%) | 78 (22%) | |
One patient missing disease status
7 patients were transplanted at outside institutions; data are not available
Abbreviations: CMV, cytomegalovirus; HLA, human leukocyte antigen
Figure.
Number of informative patients
Baseline = data collection at enrollment; FU visit = data collection at 3, 6, 18 months or when another systemic agent was added; response known = complete response (CR), partial response (PR), non-CR/PR response calculated from baseline and FU data; baseline sample = research sample collected at enrollment; FU sample = research sample collected at FU visit
Table 3.
Chronic GVHD characteristics
| Characteristic | Chronic GVHD (n=382) |
|---|---|
| n (%) | |
| Case type | |
| Incident | 161 (42%) |
| Prevalent | 221 (58%) |
| Chronic GVHD severity1 | |
| Mild2 | 33 (9%) |
| Moderate | 200 (52%) |
| Severe | 148 (39%) |
| Organs involved at enrollment | |
| Skin | 288/380 (76%) |
| Fascia/joint | 197/380 (52%) |
| Mouth | 232/381 (61%) |
| Eye | 236/380 (62%) |
| Upper GI | 59/381 (15%) |
| Lower GI | 45/379 (12%) |
| Esophagus | 60/381 (16%) |
| Any GI | 123/380 (32%) |
| Liver | 168/370 (45%) |
| Lung | 115/381 (30%) |
| Genital | 44/229 (19%) |
| Line of treatment | |
| Initial | 150 (39%) |
| Secondary | 104 (27%) |
| Tertiary | 61 (16%) |
| Fourth line or greater | 67 (18%) |
| Index treatment | |
| Prednisone +/− other | 155 (41%) |
| Calcineurin inhibitor +/− others, no prednisone | 17 (4%) |
| Sirolimus +/− others, no prednisone or CNI | 40 (10%) |
| Extracorporeal photopheresis | 58 (15%) |
| Rituximab | 33 (9%) |
| Methotrexate | 13 (3%) |
| Other | 66 (17%) |
| Research sample collected before index treatment started | 101 had their sample collected before the index medication started; 87 had sample collection on the date the index medication started; 184 were collected after the index medication started |
| Months from transplant, median, IQR | 19.0 (10.0–38.0) |
| Months since diagnosis of chronic GVHD, median, IQR | 6.0 (0.4–23.6) |
| Follow up of surviving patients, median, IQR (months) | 27.0 (23.8, 29.8) |
| Sample availability, n (% compliance) | |
| Enrollment | 372/382 (97%) |
| 3 months (N/A = 34) | 342/348 (98%) |
| 6 months (N/A = 50) | 311/332 (94%) |
| 18 months (N/A =172) | 185/210 (88%) |
| New treatment (N/A = 321) | 52/61 (85%) |
| Relapse3 | 15 (4%) |
| Death3 | 46 (12%) |
One missing severity
Includes 4 in the mild category with NIH calculated severity 0
Includes 7 who relapsed and died
DISCUSSION
This Chronic GVHD Consortium Response Measures Validation study aims to develop and validate new outcome assessment tools in chronic GVHD. The cohort has completed enrollment and is waiting for the outcomes to mature prior to analysis of the primary objectives. However, we are inviting the HCT community to partner with us to make full use of these clinical data and specimens given the wealth of information and high completeness of data. Investigators interested in the clinical data, research forms, database structure, or research samples available from this cohort study should contact the Consortium for procedures on how to apply for access (chronicGVHDstudies@fredhutch.org).
This cohort differs from a previous Chronic GVHD Consortium Cohort study by the requirement that participants have just started a new systemic treatment. However, the characteristics of the present cohort are actually remarkably similar to the prior cohort,18 specifically in age, graft source, conditioning intensity, and chronic GVHD severity. The study has some limitations.
The study population is heterogeneous and therefore generalizable but includes different chronic GVHD organ involvement and severity, a broad range of prior and current chronic GVHD treatments, and varying clinical practices. Given that the study assessments were integrated into the clinical practice at multiple sites with different workflows, they did not always occur within the protocol-permitted windows. It also proved more difficult to capture data and research samples when patients started additional treatments, but compliance at this time point is still 85%.
In conclusion, this large, multicenter, prospective cohort with careful chronic GVHD assessments is a very valuable resource for diverse types of research, and we invite potential collaborators to contact us. Potential studies include: diagnostic and predictive biomarker analyses to look for biologic correlates of chronic GVHD onset, phenotypes, response to specific treatments and ultimate outcomes;19 secondary analysis of clinical information such as clinical predictors of response to specific treatments or correlation between patient-reported outcomes and clinical assessments; health services research such as practice variation; and any other study that will advance our understanding of chronic GVHD or other transplant outcomes.
Acknowledgments
Financial disclosure:
Funded by CA118953
Appendix. Participants in the Chronic GVHD Consortium Response Measures Validation study
Fred Hutchinson Cancer Research Center: Stephanie J. Lee, Mary E.D. Flowers, Barry Storer, Lynn Onstad, Chareeni Kurukulasuriya
Vanderbilt University Medical Center: Madan Jagasia
Cleveland Clinic: Betty Hamilton
Roswell Park: George Chen
Dana-Farber Cancer Institute: Corey Cutler
Vancouver, B.C.: Raewyn Broady
University of Minnesota: Mukta Arora
Moffitt Cancer Center: Joseph Pidala
MD Anderson: Amin Alousi
Stanford University: Sally Arai
Duke University: Stefanie Sarantopoulos
The Ohio State University: Samantha Jaglowski
Footnotes
Conflicts of interest:
SJL: Advisory board: Amgen, Incyte. Travel and speaking honoraria: Mallinckrodt
MJ: Advisory board/speaker: Janssen, Mallinckrodt. Research funding: Janssen, Mallinckrodt
CC: Advisory board/consulting: Bristol-Myers Squibb, Incyte
SS: Advisory board: Gilead, Pharmacyclics; Research funding: Gilead
MF: Advisory board/consultant: Pharmacyclics; Research funding: Speaker honoraria/travel: Incyte, Astellas, Mallinckrodt
BH, JP, AA, CK, LO, GC, RB, MA, SA: none
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