Reply to J.J. Boelens et al Soiffer, Robert J; Chen, Yi-Bin A; Jagasia, Madan H
Journal of clinical oncology,
04/2018, Letnik:
36, Številka:
11
Journal Article
PURPOSE:To validate the International Chronic Ocular GVHD Consensus Group (ICCGVHD) diagnostic criteria for chronic ocular chronic graft-versus-host disease (GVHD), by comparing results with ...comprehensive ophthalmic evaluation after allogeneic hematopoietic stem cell transplantation.
METHODS:A single-institution retrospective chart review was conducted on patients who underwent hematopoietic stem cell transplantation at Vanderbilt University Medical Center in Nashville, TN, from January 1, 2002, through April 17, 2014. A total of 344 patients were eligible for the study. Data collected include the Schirmer test score, corneal fluorescein staining, Ocular Surface Disease Index, conjunctival injection, and presence or absence of systemic GVHD. The diagnosis of chronic ocular GVHD in each participant and determination of the overall severity score were determined based on the newly proposed ICCGVHD diagnostic criteria and compared with the best clinical practice (BCP) score.
RESULTS:Chronic ocular GVHD was diagnosed in 141/344 (41%) participants, of these, 86 (61%) had complete charts. Based on the BCP score, 1.2% had none, 38.4% mild, 47.7% moderate, and 12.8% had severe chronic ocular GVHD. Based on the ICCGVHD, 34.8% had none, 59.3% mild/moderate, and 5.8% had severe chronic ocular GVHD. The clinical diagnostic stages of chronic ocular GVHD by BCP and ICCGVHD criteria had slight agreement (kappa statistic 0.187, with 95% confidence interval 0.049–0.321), with a higher correlation seen in those with severe chronic ocular GVHD.
CONCLUSIONS:The newly proposed ICCGVHD diagnostic criteria can be used reproducibly for the diagnosis and determination of severity of chronic ocular GVHD. However, larger prospective studies are needed to further validate it.
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Introduction: Belumosudil (KD025) is a novel oral selective rho-associated coiled-coil kinase 2 (ROCK2) inhibitor specifically designed for the treatment of cGVHD, an immune-mediated inflammatory ...and fibrotic disorder. In a previous dose-finding study (KD025-208, N=54), two-thirds of patients, including those with fibrotic and inflammatory manifestations, achieved a partial or complete response with belumosudil. Herein, we report on the top-line results (6 months after the last patient in) from the pivotal phase 2 trial (ROCKstar KD025-213, N=132).
Methods: This phase 2, open-label, randomized, multicenter study evaluated belumosudil 200 mg QD (n=66) and BID (n=66) in patients with cGVHD who received 2 to 5 prior lines of therapy (LOT). Treatment continued until clinically significant progression of cGVHD. The primary end point was overall response rate (ORR), defined per the 2014 National Institutes of Health Consensus Criteria. Additional end points included duration of response (DOR), Lee Symptom Scale (LSS) score, failure-free survival (FFS), corticosteroid (CS) dose reductions and overall survival. The study was powered such that the lower bound of the 95% confidence interval (CI) excludes 30%, with appropriate multiplicity adjustment.
Results: At enrollment, the median age was 56 years, the median time from cGVHD diagnosis to enrollment was 29 months, 67% of patients had severe cGVHD, 52% had ≥4 organs involved, 72% had received ≥3 prior LOT (including ibrutinib n=46 or ruxolitinib n=38) and 73% were refractory to their last LOT. The baseline characteristics of both arms were well balanced.
With a median follow-up of 8 months, the ORR (95% CI) with belumosudil 200 mg QD and BID was 73% (60%-83%) and 74% (62%-84%), respectively (Table 1). In patients who previously received ruxolitinib (29%), the ORR with belumosudil 200 mg QD and BID was 65% (41%-85%) and 72% (47%-90%), respectively. In patients who previously received ibrutinib (35%), the ORR with belumosudil 200 mg QD and BID was 73% (50%-89%) and 71% (49%-87%), respectively. High ORRs were seen in all patient subgroups, regardless of length of time from diagnosis to treatment, including those with severe cGVHD, involvement of ≥4 organs and a refractory response to prior LOT (Figure 1). The response rate was similar across all affected organs.
The median time to response was 4 weeks. Of responders, 49% have maintained response for ≥20 weeks. The median DOR has not yet been reached. Clinically meaningful improvement (≥7-point reduction) in LSS score on consecutive assessments was observed in 39% and 33% of patients in the QD and BID groups, respectively. Both responders (43%) and nonresponders (17%) experienced a clinically meaningful improvement in LSS score.
FFS was 77% (69%-84%) at 6 months. CS and calcineurin inhibitor discontinuations were seen in 18% and 13% of patients, respectively.
Belumosudil was well tolerated, with >95% relative dose intensity in 83% of patients. Drug discontinuation occurred in 10% of patients due to possible drug-related adverse events (AEs), 3% due to progression of underlying disease and 12% due to progression of cGVHD. AEs were consistent with those expected in patients with cGVHD receiving CS and other immunosuppressants (Table 2). Common AEs included fatigue (32%), diarrhea (29%), nausea (26%), cough (24%), dyspnea (24%), upper respiratory tract infection (23%), peripheral edema (21%) and headache (20%). At least 1 serious AE occurred in 34% of patients. Twenty-three percent of patients had at least 1 liver-related investigation; the most common was increased gamma-glutamyltransferase (11%), and only 1 patient showed an increase in bilirubin. Eight patients died during the study; 5 due to AEs (1 possibly related to belumosudil) and 3 during long-term follow-up (>28 days after last dose). There were no reports of cytomegalovirus reactivation or infection.
Conclusion: Treatment with belumosudil at both doses resulted in high ORRs across key subgroups, meeting the primary end point of this pivotal randomized trial in cGVHD. Responses were durable and clinically meaningful, irrespective of patient and cGVHD characteristics, and were seen in patients who previously received ruxolitinib and ibrutinib. Belumosudil was well tolerated, with limited and manageable AEs. Further studies will evaluate its use earlier in disease management. The 12-month data analysis will be presented at ASH 2020.
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Cutler:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lee:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Amgen: Research Funding; Kadmon: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Syndax: Research Funding. Rotta:Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Ramakrishnan:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cigna: Honoraria. Eiznhamer:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Schueller:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Yang:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Green:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Aggarwal:Kadmon Corporation, LLC: Consultancy; Angiocrine Bioscience, Inc: Current Employment, Other: stock options. Blazar:BlueRock Therapeutics: Research Funding; BlueRock Therapeuetic: Consultancy; Fate Therapeutics Inc.: Research Funding; Magenta Therapeutics: Consultancy; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder. Jagasia:Ocugen: Other; Mallinckrodt: Research Funding; Janssen: Research Funding.
Omidubicel (nicotinamide-expanded cord blood) is a potential alternative source for allogeneic hematopoietic cell transplantation (HCT) when an HLA-identical donor is lacking. A phase I/II trial with ...standalone omidubicel HCT showed rapid and robust neutrophil and platelet engraftment. In this study, we evaluated the immune reconstitution (IR) of patients receiving omidubicel grafts during the first 6 months post-transplant, as IR is critical for favorable outcomes of the procedure. Data was collected from the omidubicel phase I-II international, multicenter trial. The primary endpoint was the probability of achieving adequate CD4+ T-cell IR (CD4IR: > 50 × 10
/L within 100 days). Secondary endpoints were the recovery of T-cells, natural killer (NK)-cells, B-cells, dendritic cells (DC), and monocytes as determined with multicolor flow cytometry. LOESS-regression curves and cumulative incidence plots were used for data description. Thirty-six omidubicel recipients (median 44; 13-63 years) were included, and IR data was available from 28 recipients. Of these patients, 90% achieved adequate CD4IR. Overall, IR was complete and consisted of T-cell, monocyte, DC, and notably fast NK- and B-cell reconstitution, compared to conventional grafts. Our data show that transplantation of adolescent and adult patients with omidubicel results in full and broad IR, which is comparable with IR after HCT with conventional graft sources.
Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of ...this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor EGF receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.
•Under current treatment approaches, patients with LA GVHD have poor overall and failure-free survival.•Levels of AREG are elevated in LA GVHD, and the AREG/EGF ratio is predictive of overall survival and nonrelapse mortality in LA GVHD.
There are no validated criteria to measure skin response in chronic GVHD. In a prospectively assembled, multicenter cohort of patients with chronic GVHD (N = 458), we looked for correlation of change ...in several different scales recommended by the National Institutes of Health (NIH) Consensus with clinician and patient perception of change and overall survival. Of the clinician scales, the NIH composite 0-3 skin score was the only one that correlated with both clinician and patient perception of improvement or worsening. Of the patient-reported scales, the skin subscale of the Lee Symptom Scale was the only one that correlated with both clinician and patient perception of improvement or worsening. At study entry, NIH skin score 3 and Lee skin symptom score > 15 were both associated with worse overall survival. Worsening of NIH skin score at 6 months was associated with worse overall survival. Improvement in the Lee skin symptom score at 6 months was associated with improved overall survival. Our findings support the use of the NIH composite 0-3 skin score and the Lee skin symptom score as simple and sensitive measures to evaluate skin involvement in clinical trials as well as in the clinical monitoring of patients with cutaneous chronic GVHD.
Modern combinations of therapies for multiple myeloma have led to improvement in survival outcomes with near 100% overall response rate and 25% complete response rates, particularly with autologous ...hematopoietic cell transplant (AHCT). Minimal residual disease (MRD) assessment with multiparameter flow cytometry is a valid prognostic biomarker for progression-free survival (PFS) and overall survival (OS). However, few data exist regarding whether MRD positivity or negativity will meaningfully influence treatment decisions. We evaluated 433 patients who received induction therapy, followed by AHCT. Participants had MRD assessment by multiparameter flow cytometry before and at days +100 and +365 following AHCT. They also received either lenalidomide, bortezomib, or no maintenance therapy following AHCT. Maintenance treatment with lenalidomide improved MRD negativity at day +365 compared to bortezomib (92.9% vs 41.6%, p = 0.01), or no maintenance therapy (92.9% vs 24.4%, p = 0.012). The median PFS for patients who were MRD negative at day + 365 was 42 vs 17.5 months (p < 0.001) and median OS was 80.6 vs 59 months (p = 0.02). Maintenance therapy following AHCT for multiple myeloma improves the depth of response as assessed by MRD.
INTRODUCTION
There is an unmet need for quantitatively measuring skin sclerosis to track the progression of sclerosis in chronic cutaneous graft-versus-host disease (cGVHD). Two candidate ...technologies are the Myoton, a noninvasive device to assess soft tissue biomechanics, and the durometer, an industrial device measuring surface hardness. Both devices have been shown to have high reproducibility in the context of healthy skin,1 but the reproducibility of these devices in sclerotic cGVHD is critical missing information in designing longitudinal studies measuring sclerosis in cGVHD patients. We directly compared the interobserver reproducibility of these devices to measure skin stiffness and hardness in sclerotic cGVHD patients.
METHODS
The skin stiffness and hardness were measured in seven patients with sclerotic cutaneous cGVHD by three blinded observers with Myoton and durometer on 20 body sites. To estimate the clinical repeatability to differentiate amongst patients, the intraclass correlation coefficients (ICC) was calculated from a single measure, absolute agreement, linear mixed model on log scale. Mean coefficient of variation across the three observers and minimal detectable change (MDC95) were calculated to estimate device ability to track change within patients.
RESULTS
Patient overall hardness/stiffness interobserver ICCs were 0.92 0.82 - 1.00 for Myoton and 0.82 95% confidence interval 0.61 - 1.00 for durometry. The Myoton had superior reproducibility to durometry in calves and upper arms, but was inferior in the dorsal forearms. Coefficients of variation across observers were under 10% and the overall normalized MDC95 was 22 to 23% for both devices.
CONCLUSIONS
Both the Myoton and durometer devices exhibit high reproducibility to measure skin stiffness/hardness in sclerotic cutaneous cGVHD, and the Myoton trended towards higher reproducibility when compared to the durometer. The interobserver ICCs of both devices to measure sclerotic cGVHD patients is significantly higher than the typical range of ICCs (0.21-0.60)2 associated with clinical exam-based measurement of moveable sclerosis. Prospective longitudinal study following patients over time is warranted to validate the use of skin stiffness measurements to monitor disease progression and treatment response in cGVHD patients.
ACKNOWLEDGEMENTS
This work is partially supported by Career Development Award Number IK2 CX001785 from the United Sates Department of Veterans Affairs Clinical Science R&D (CSRD) Service.
REFERENCES Dellalana LE, Chen F, Vain A, Gandelman JS, Poldemaa M, Chen H, Tkaczyk ER. Reproducibility of the durometer and myoton devices for skin stiffness measurement in healthy subjects. Skin Research and Technology. 2019; 25(3): 289-293Mitchell SA, Jacobsohn D, Thormann Powers KE, et al. A multicenter pilot evaluation of the National Institutes of Health chronic graft-versus-host disease (cGVHD) therapeutic response measures: feasibility, interrater reliability, and minimum detectable change. Biol Blood Marrow Transplant. 2011;17(11):1619-1629.
Jagasia:Kadmon: Consultancy; Janssen: Research Funding; Incyte: Consultancy. Tkaczyk:Incyte: Consultancy.
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