Publications by authors named "Paul J Martin"

254 Publications

Murine Models Provide New Insights Into Pathogenesis of Chronic Graft--Host Disease in Humans.

Front Immunol 2021 3;12:700857. Epub 2021 Sep 3.

Riggs Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for hematologic malignancies, but its success is complicated by graft--host disease (GVHD). GVHD can be divided into acute and chronic types. Acute GVHD represents an acute alloimmune inflammatory response initiated by donor T cells that recognize recipient alloantigens. Chronic GVHD has a more complex pathophysiology involving donor-derived T cells that recognize recipient-specific antigens, donor-specific antigens, and antigens shared by the recipient and donor. Antibodies produced by donor B cells contribute to the pathogenesis of chronic GVHD but not acute GVHD. Acute GVHD can often be effectively controlled by treatment with corticosteroids or other immunosuppressant for a period of weeks, but successful control of chronic GVHD requires much longer treatment. Therefore, chronic GVHD remains the major cause of long-term morbidity and mortality after allo-HCT. Murine models of allo-HCT have made great contributions to our understanding pathogenesis of acute and chronic GVHD. In this review, we summarize new mechanistic findings from murine models of chronic GVHD, and we discuss the relevance of these insights to chronic GVHD pathogenesis in humans and their potential impact on clinical prevention and treatment.
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http://dx.doi.org/10.3389/fimmu.2021.700857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446193PMC
September 2021

Initial therapy of chronic graft vs. host disease: Analysis of practice variation and failure-free survival.

Blood Adv 2021 Sep 17. Epub 2021 Sep 17.

Fred Hutchinson Cancer Research Center, SEATTLE, Washington, United States.

Prior clinical trials largely considered prednisone 1mg/kg/day with or without calcineurin inhibitor as standard initial therapy for chronic graft vs. host disease (cGVHD) but uncertainty remains regarding the extent of practice variation and whether this affects subsequent outcomes. We assembled a cohort of 745 cGVHD patients treated with initial systemic immune suppressive (IS) therapy from three prior Chronic GVHD Consortium observational studies. Initial therapy was defined as first IS therapy started for cGVHD or prednisone increased to ≥ 0.4mg/kg/day from lower doses within 30 days before cGVHD diagnosis to any time afterward. Initial therapies were non-prednisone IS therapies (n=137, 18%), prednisone alone (n=411, 55%), or prednisone plus other IS therapy (n=197, 26%). In multivariate analysis, initial therapy group was not associated with FFS (failure-free survival, a composite of death, relapse, new IS therapy), overall survival (OS) or non-relapse mortality (NRM). Among the prednisone-based approaches, steroid dose (mg/kg/day) was <0.25 (9%), 0.25-0.74 (36%), 0.75-1.25 (42%), or >1.25 (13%). Prednisone dose within the steroid-treated patients was not significantly associated with FFS, OS, or NRM. No significant interactions were detected between overall cGVHD severity and either initial therapy group or prednisone dose for the outcomes of FFS, OS, or NRM. These observational data document heterogeneity in more contemporary cGVHD initial treatment practices, including prednisone dose and use of non-steroid approaches. This variation was not associated with FFS, OS, or NRM. Prospective trials are needed to verify efficacy of reduced-dose prednisone or prednisone-free initial therapy approaches.
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http://dx.doi.org/10.1182/bloodadvances.2021005286DOI Listing
September 2021

Genetic Variants Associated with Inflammatory Bowel Disease and Gut Graft-versus-host Disease.

Blood Adv 2021 Sep 17. Epub 2021 Sep 17.

University of Washington, United States.

Previous studies have identified genetic variants associated with inflammatory bowel disease (IBD). We tested the hypothesis that some of these variants are also associated with the risk of moderate to severe gut graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Associations were evaluated initially in a discovery cohort of 1980 HCT recipients of European ancestry with HLA-matched related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1294 HCT recipients. Among the 296 single nucleotide polymorphisms SNPs and 26 HLA alleles tested, we found that the recipient rs1260326 homozygous T allele in GCKR was associated with a higher risk of stage 2-4 gut GVHD. No other candidate variants were associated with stage 2-4 gut GVHD. The rs1260326 variant resides in an IBD-associated locus containing FNDC4, a gene that encodes a secreted anti-inflammatory factor that dampens macrophage activity and improves colitis in mice. Our results suggest that targeting inflammatory macrophages with recombinant FNDC4 offers an attractive avenue of clinical investigation for management of IBD and gut GVHD.
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http://dx.doi.org/10.1182/bloodadvances.2021004959DOI Listing
September 2021

Frequent Eczematous Dermatitis in Unrelated Cord Blood Hematopoietic Cell Transplant Recipients Compared With Other Donor Types.

Transplant Cell Ther 2021 Jul 29. Epub 2021 Jul 29.

Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington, Seattle, Washington; Seattle Cancer Care Alliance, Seattle, Washington. Electronic address:

We have consistently noticed in our clinical practice eczematous dermatitis (EcD) without other pathologic findings of graft-versus-host disease (GVHD) in recipients of unrelated cord blood transplantation (CBT). We hypothesized that the incidence of EcD was higher in CBT compared with other donor types, and our objective in this study was to compare the frequency, clinical course, and response to therapy of EcD between CBT and non-CBT recipients. We conducted a retrospective study of 720 consecutive adult recipients of allogeneic hematopoietic cell transplants from 2010 to 2016 from any donor type and with follow-up for at least 1 year after transplantation. After using keyword-based automated scanning to identify "eczema," "dermatitis," or "spongiosis" terms in medical records, we retrieved 217 cases for manual record review. We identified 23 EcD cases (12 in CBT recipients and 11 in patients with other types of donors) with a median onset at 8 months after transplantation. The 2-year cumulative incidence of EcD was 20% (95% confidence interval [CI], 11.2% to 31.5%) after CBT and 1.7% (95% CI, .90% to 2.90%) with other types of donors (P < .0001). Fifteen cases had a skin biopsy without distinctive pathologic features of GVHD. The most common EcD-involved sites in CBT recipients were face (75%), neck (50%), and antecubital fossae (50%). Compared with patients with other types of donors, EcD after CBT was more likely to involve three or more sites (10 of 12 vs. 2 of 10; P = .008) and had a more protracted course (lasting >6 months in 6 of 58 vs. 1 of 661; P < .0001). In both groups, EcD responded to topical therapy, and only a few cases required systemic therapy. EcD is a relatively frequent skin condition among recipients of unrelated CBT. Irrespective of donor type, most cases of EcD can be successfully managed with only topical therapy. These findings will help providers recognize EcD, avoid potentially harmful systemic therapy, and better counsel transplant recipients.
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http://dx.doi.org/10.1016/j.jtct.2021.07.022DOI Listing
July 2021

Genetic Variants Associated with Cytomegalovirus Infection after Allogeneic Hematopoietic Cell Transplantation.

Blood 2021 Jul 16. Epub 2021 Jul 16.

University of Washington, United States.

Human cytomegalovirus (CMV) reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Despite routine screening for CMV reactivation and early antiviral treatment, the rates of CMV-related complications after HCT remain high. Genetic variants in both the donor and recipient have been associated with the risk of CMV reactivation and disease after HCT, but these associations have not been validated and their clinical importance remains unclear. In this study, we assessed 117 candidate variants previously associated with CMV-related phenotypes for association with CMV reactivation and disease in a cohort of 2169 CMV-seropositive HCT recipients. We also carried out a genome-wide association study (GWAS) for CMV reactivation and disease in the same cohort. Both analyses used a pre-specified discovery and replication approach to control the risk of false-positive results. Among the 117 candidate variants, our analysis implicates only the donor ABCB1 rs1045642 genotype as a risk factor for CMV reactivation. This synonymous variant in P-glycoprotein may influence the risk of CMV reactivation by altering the efflux of cyclosporine and tacrolimus from donor lymphocytes. In the GWAS analysis, the donor CDC42EP3 rs11686168 genotype approached the significance threshold for association with CMV reactivation, although we could not identify a mechanism to explain this association. The results of this study suggest that most genomic variants previously associated with CMV phenotypes do not significantly alter the risk for CMV reactivation or disease after HCT.
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http://dx.doi.org/10.1182/blood.2021012153DOI Listing
July 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report.

Transplant Cell Ther 2021 Oct 10;27(10):817-835. Epub 2021 Jun 10.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.
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http://dx.doi.org/10.1016/j.jtct.2021.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478861PMC
October 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2020 Treatment of Chronic GVHD Report.

Transplant Cell Ther 2021 09 11;27(9):729-737. Epub 2021 Jun 11.

Clinical Division of Hematology, Medical University of Graz, Graz, Austria. Electronic address:

Positive results from recent clinical trials have significantly expanded current therapeutic options for patients with chronic graft-versus-host disease (GVHD). However, new insights into the associations between clinical characteristics of chronic GVHD, pathophysiologic mechanisms of disease, and the clinical and biological effects of novel therapeutic agents are required to allow for a more individualized approach to treatment. The current report is focused on setting research priorities and direction in the treatment of chronic GVHD. Detailed correlative scientific studies should be conducted in the context of clinical trials to evaluate associations between clinical outcomes and the biological effect of systemic therapeutics. For patients who require systemic therapy but not urgent initiation of glucocorticoids, clinical trials for initial systemic treatment of chronic GVHD should investigate novel agents as monotherapy without concurrently starting glucocorticoids, to avoid confounding biological, pathological, and clinical assessments. Clinical trials for treatment-refractory disease should specifically target patients with incomplete or suboptimal responses to most recent therapy who are early in their disease course. Close collaboration between academic medical centers, medical societies, and industry is needed to support an individualized, biology-based strategic approach to chronic GVHD therapy.
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http://dx.doi.org/10.1016/j.jtct.2021.05.004DOI Listing
September 2021

Relevance of Plasma Matrix Metalloproteinase-9 for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 09 12;27(9):759.e1-759.e8. Epub 2021 Jun 12.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.

Bronchiolitis obliterans syndrome (BOS) is a highly morbid form of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Several plasma proteins have been identified as biomarkers for BOS after lung transplantation. The relevance of these biomarkers in BOS patients after allogeneic HCT has not been examined. We hypothesized that biomarkers associated with BOS after lung transplantation are also associated with BOS after allogeneic HCT. We tested plasma samples from 33 adult HCT patients who participated in a phase II multicenter study of fluticasone, azithromycin, and montelukast (FAM) treatment for new-onset BOS (NCT01307462), and matched control samples of HCT patients who had non-BOS chronic GVHD (n = 31) and those who never experienced chronic GVHD (n = 29) (NCT00637689 and NCT01902576). Candidate biomarkers included matrix metalloproteinase-9 (MMP-9), MMP-3, and chitinase-3-like-1 glycoprotein (YKL-40). MMP-9 concentrations were higher in the patients with BOS compared with those with non-BOS chronic GVHD (P = .04) or no chronic GVHD (P < .001). MMP-3 concentrations were higher in patients with BOS (P < .001) or non-BOS chronic GVHD (P < .001) compared with those with no chronic GVHD. YKL-40 concentrations did not differ statistically among the 3 groups. MMP-9 concentrations before starting FAM therapy were higher in patients who experienced treatment failure within 6 months compared with those with treatment success (P = .006), whereas MMP-3 or YKL-40 concentrations did not differ statistically between these 2 groups. Patients with an MMP-9 concentration ≥200,000 pg/mL before starting FAM therapy had worse overall survival compared with those with lower MMP-9 concentrations. Our data suggest that plasma MMP-9 concentration could serve as a relevant biomarker at diagnosis of BOS after allogeneic HCT for prognostication of survival and for prediction of treatment response. Further validation is needed to confirm our findings.
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http://dx.doi.org/10.1016/j.jtct.2021.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403632PMC
September 2021

MR Imaging Findings in a Neonate With COVID -19-Associated Encephalitis.

Pediatr Neurol 2021 06 9;119:48-49. Epub 2021 Mar 9.

Pediatric Neuroradiologist, Department of Radiology, Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana. Electronic address:

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http://dx.doi.org/10.1016/j.pediatrneurol.2021.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942157PMC
June 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2020 Etiology and Prevention Working Group Report.

Transplant Cell Ther 2021 06 2;27(6):452-466. Epub 2021 Mar 2.

Division of Hematological Malignancies and Cellular Therapy, Department of Medicine, Duke Cancer Institute, Durham, North Carolina. Electronic address:

Preventing chronic graft-versus-host disease (GVHD) remains challenging because the unique cellular and molecular pathways that incite chronic GVHD are poorly understood. One major point of intervention for potential prevention of chronic GVHD occurs at the time of transplantation when acute donor anti-recipient immune responses first set the events in motion that result in chronic GVHD. After transplantation, additional insults causing tissue injury can incite aberrant immune responses and loss of tolerance, further contributing to chronic GVHD. Points of intervention are actively being identified so that chronic GVHD initiation pathways can be targeted without affecting immune function. The major objective in the field is to continue basic studies and to translate what is learned about etiopathology to develop targeted prevention strategies that decrease the risk of morbid chronic GVHD without increasing the risks of cancer relapse or infection. Development of strategies to predict the risk of developing debilitating or deadly chronic GVHD is a high research priority. This working group recommends further interrogation into the mechanisms underpinning chronic GVHD development, and we highlight considerations for future trial design in prevention trials.
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http://dx.doi.org/10.1016/j.jtct.2021.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217141PMC
June 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIa. The 2020 Clinical Implementation and Early Diagnosis Working Group Report.

Transplant Cell Ther 2021 07 9;27(7):545-557. Epub 2021 Apr 9.

Division of Stem Cell Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, Massachusetts.

Recognition of the earliest signs and symptoms of chronic graft-versus-host disease (GVHD) that lead to severe manifestations remains a challenge. The standardization provided by the National Institutes of Health (NIH) 2005 and 2014 consensus projects has helped improve diagnostic accuracy and severity scoring for clinical trials, but utilization of these tools in routine clinical practice is variable. Additionally, when patients meet the NIH diagnostic criteria, many already have significant morbidity and possibly irreversible organ damage. The goals of this early diagnosis project are 2-fold. First, we provide consensus recommendations regarding implementation of the current NIH diagnostic guidelines into routine transplant care, outside of clinical trials, aiming to enhance early clinical recognition of chronic GVHD. Second, we propose directions for future research efforts to enable discovery of new, early laboratory as well as clinical indicators of chronic GVHD, both globally and for highly morbid organ-specific manifestations. Identification of early features of chronic GVHD that have high positive predictive value for progression to more severe manifestations of the disease could potentially allow for future pre-emptive clinical trials.
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http://dx.doi.org/10.1016/j.jtct.2021.03.033DOI Listing
July 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIb. The 2020 Preemptive Therapy Working Group Report.

Transplant Cell Ther 2021 08 6;27(8):632-641. Epub 2021 Apr 6.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Chronic graft-versus-host disease (GVHD) commonly occurs after allogeneic hematopoietic cell transplantation (HCT) despite standard prophylactic immune suppression. Intensified universal prophylaxis approaches are effective but risk possible overtreatment and may interfere with the graft-versus-malignancy immune response. Here we summarize conceptual and practical considerations regarding preemptive therapy of chronic GVHD, namely interventions applied after HCT based on evidence that the risk of developing chronic GVHD is higher than previously appreciated. This risk may be anticipated by clinical factors or risk assignment biomarkers or may be indicated by early signs and symptoms of chronic GVHD that do not fully meet National Institutes of Health diagnostic criteria. However, truly preemptive, individualized, and targeted chronic GVHD therapies currently do not exist. In this report, we (1) review current knowledge regarding clinical risk factors for chronic GVHD, (2) review what is known about chronic GVHD risk assignment biomarkers, (3) examine how chronic GVHD pathogenesis intersects with available targeted therapeutic agents, and (4) summarize considerations for preemptive therapy for chronic GVHD, emphasizing trial development, including trial design and statistical considerations. We conclude that robust risk assignment models that accurately predict chronic GVHD after HCT and early-phase preemptive therapy trials represent the most urgent priorities for advancing this novel area of research.
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http://dx.doi.org/10.1016/j.jtct.2021.03.029DOI Listing
August 2021

The Future of Chronic Graft-Versus-Host Disease: Introduction to the 2020 National Institutes of Health Consensus Development Project Reports.

Transplant Cell Ther 2021 06 2;27(6):448-451. Epub 2021 Mar 2.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Medical Oncology, University of Washington, Seattle, Washington.

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http://dx.doi.org/10.1016/j.jtct.2021.02.034DOI Listing
June 2021

Home Spirometry Telemonitoring for Early Detection of Bronchiolitis Obliterans Syndrome in Patients with Chronic Graft-versus-Host Disease.

Transplant Cell Ther 2021 07 26;27(7):616.e1-616.e6. Epub 2021 Mar 26.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington. Electronic address:

Early detection of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) depends on recognition of subclinical spirometric changes, which is possible only with frequent interval spirometry. We evaluated the feasibility of home monitoring of weekly spirometry via a wireless handheld device and a web monitoring portal in a cohort of high-risk patients for the detection of lung function changes preceding BOS diagnosis. In this observational study, 46 patients with chronic graft-versus-host disease or a decline in forced expiratory volume in 1 second (FEV) of unclear etiology after allogeneic HCT were enrolled to perform weekly home spirometry with a wireless portable spirometer for a period of 1 year. Measurements were transmitted wirelessly to a Cloud-based monitoring portal. Feasibility evaluation included adherence with study procedures and an assessment of the home spirometry measurements compared with laboratory pulmonary function tests. Thirty-six patients (78%) completed 1 year of weekly monitoring. Overall adherence with weekly home spirometry measurements was 72% (interquartile range, 47% to 90%), which did not meet the predetermined threshold of 75% for high adherence. Correlation of home FEV with laboratory FEV was high, with a bias of 0.123 L (lower limit, -0.294 L; upper limit, 0.541 L), which is within acceptable limits for reliability. Of the 12 patients who were diagnosed with BOS or suspected BOS during the study period, 9 had an antecedent FEV decline detected by home spirometry. Our data indicate that wireless handheld spirometry performed at home in a high-risk HCT cohort is feasible for close monitoring of pulmonary function and appears to facilitate early detection of BOS.
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http://dx.doi.org/10.1016/j.jtct.2021.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423348PMC
July 2021

IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice.

Nat Commun 2021 02 5;12(1):805. Epub 2021 Feb 5.

Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, CA, USA.

Efforts to improve the prognosis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) have suffered from poor understanding of its pathogenesis. Here we show that the pathogenesis of SR-Gut-aGVHD is associated with reduction of IFN-γ Th/Tc1 cells and preferential expansion of IL-17IL-22 Th/Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis in a Reg3γ-dependent manner. Transplantation of IFN-γ-deficient donor CD8 T cells in the absence of CD4 T cells produces a phenocopy of SR-Gut-aGVHD. IFN-γ deficiency in donor CD8 T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1 mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1 MNP results in full-blown Gut-aGVHD. Our results thus provide insights into SR-Gut-aGVHD pathogenesis and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in SR-Gut-aGVHD therapy.
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http://dx.doi.org/10.1038/s41467-021-21133-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865028PMC
February 2021

Tolerogenic anti-IL-2 mAb prevents graft-versus-host disease while preserving strong graft-versus-leukemia activity.

Blood 2021 04;137(16):2243-2255

Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, CA.

Donor T cells mediate both graft-versus-leukemia (GVL) activity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Development of methods that preserve GVL activity while preventing GVHD remains a long-sought goal. Tolerogenic anti-interleukin-2 (IL-2) monoclonal antibody (JES6-1) forms anti-IL-2/IL-2 complexes that block IL-2 binding to IL-2Rβ and IL-2Rγ on conventional T cells that have low expression of IL-2Rα. Here, we show that administration of JES6 early after allo-HCT in mice markedly attenuates acute GVHD while preserving GVL activity that is dramatically stronger than observed with tacrolimus (TAC) treatment. The anti-IL-2 treatment downregulated activation of the IL-2-Stat5 pathway and reduced production of granulocyte-macrophage colony-stimulating factor (GM-CSF). In GVHD target tissues, enhanced T-cell programmed cell death protein 1 (PD-1) interaction with tissue-programmed cell death-ligand 1 (PD-L1) led to reduced activation of protein kinase-mammalian target of rapamycin pathway and increased expression of eomesodermin and B-lymphocyte-induced maturation protein-1, increased T-cell anergy/exhaustion, expansion of Foxp3-IL-10-producing type 1 regulatory (Tr1) cells, and depletion of GM-CSF-producing T helper type 1 (Th1)/cytotoxic T cell type 1 (Tc1) cells. In recipient lymphoid tissues, lack of donor T-cell PD-1 interaction with tissue PD-L1 preserved donor PD-1+TCF-1+Ly108+CD8+ T memory progenitors and functional effectors that have strong GVL activity. Anti-IL-2 and TAC treatments have qualitatively distinct effects on donor T cells in the lymphoid tissues, and CD8+ T memory progenitor cells are enriched with anti-IL-2 treatment compared with TAC treatment. We conclude that administration of tolerogenic anti-IL-2 monoclonal antibody early after allo-HCT represents a novel approach for preventing acute GVHD while preserving GVL activity.
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http://dx.doi.org/10.1182/blood.2020006345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063091PMC
April 2021

Sitagliptin to Prevent Acute Graft-versus-Host Disease.

Authors:
Paul J Martin

N Engl J Med 2021 01;384(1):70-71

From the Division of Clinical Research, Fred Hutchinson Cancer Research Center, and the Department of Medicine, University of Washington - both in Seattle.

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http://dx.doi.org/10.1056/NEJMe2032581DOI Listing
January 2021

Tissue-resident PSGL1loCD4+ T cells promote B cell differentiation and chronic graft-versus-host disease-associated autoimmunity.

J Clin Invest 2021 01;131(1)

Diabetes and Metabolism Research Institute, the Beckman Research Institute of City of Hope, Duarte, California, USA.

CD4+ T cell interactions with B cells play a critical role in the pathogenesis of systemic autoimmune diseases such as systemic lupus and chronic graft-versus-host disease (cGVHD). Extrafollicular CD44hiCD62LloPSGL1loCD4+ T cells (PSGL1loCD4+ T cells) are associated with the pathogenesis of lupus and cGVHD, but their causal role has not been established. With murine and humanized MHC-/-HLA-A2+DR4+ murine models of cGVHD, we showed that murine and human PSGL1loCD4+ T cells from GVHD target tissues have features of B cell helpers with upregulated expression of programmed cell death protein 1 (PD1) and inducible T cell costimulator (ICOS) and production of IL-21. They reside in nonlymphoid tissues without circulating in the blood and have features of tissue-resident memory T cells with upregulated expression of CD69. Murine PSGL1loCD4+ T cells from GVHD target tissues augmented B cell differentiation into plasma cells and production of autoantibodies via their PD1 interaction with PD-L2 on B cells. Human PSGL1loCD4+ T cells were apposed with memory B cells in the liver tissues of humanized mice and cGVHD patients. Human PSGL1loCD4+ T cells from humanized GVHD target tissues also augmented autologous memory B cell differentiation into plasma cells and antibody production in a PD1/PD-L2-dependent manner. Further preclinical studies targeting tissue-resident T cells to treat antibody-mediated features of autoimmune diseases are warranted.
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http://dx.doi.org/10.1172/JCI135468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773409PMC
January 2021

Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation.

Blood Adv 2020 07;4(14):3224-3233

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.

Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.
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http://dx.doi.org/10.1182/bloodadvances.2020001927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391140PMC
July 2020

Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades.

Haematologica 2021 06 1;106(6):1599-1607. Epub 2021 Jun 1.

Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA, USA.

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.
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http://dx.doi.org/10.3324/haematol.2020.248187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168504PMC
June 2021

Dickkopf-related protein 3 is a novel biomarker for chronic GVHD after allogeneic hematopoietic cell transplantation.

Blood Adv 2020 06;4(11):2409-2417

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

To identify plasma biomarkers associated with fibrotic mechanisms of chronic graft-versus-host disease (GVHD), we used multiplex mass spectrometry with pooled samples for biomarker discovery in comparing proteomic profiles between patients with newly diagnosed sclerotic chronic GVHD (n = 21), those with newly diagnosed nonsclerotic chronic GVHD (n = 33), and those without chronic GVHD (n = 20). Immunoassay was used to measure protein concentrations of individual discovery samples and 186 independent verification samples. The discovery mass spectrometry analysis identified 2 candidate proteins with at least 1.5-fold difference in sclerotic GVHD: Dickkopf-related protein 3 (DKK3) and interleukin-1 receptor accessory protein (IL1RAP). Analysis of individual discovery samples by immunoassay showed that DKK3, a modulator of the Wnt signaling pathway, was a biomarker for both sclerotic and nonsclerotic chronic GVHD. Verification analysis of 186 patients confirmed that elevated plasma DKK3 concentrations were associated with chronic GVHD, regardless of the presence or absence of sclerosis, and that the area under the receiver operating characteristic curve was 0.85 for association of DKK3 concentrations with chronic GVHD. Multiple linear regression analysis showed that chronic GVHD with or without steroid treatment and patient age were independently associated with DKK3 concentrations. Patients with high DKK3 concentrations had a higher nonrelapse mortality than those with low concentrations. The lower IL1RAP concentrations in patients with sclerotic GVHD compared with other conditions in the discovery cohort were not confirmed in the verification cohort. DKK3 is a novel biomarker for chronic GVHD. Further studies are needed to determine the biological functions of DKK3 in the pathogenesis of chronic GVHD.
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http://dx.doi.org/10.1182/bloodadvances.2020001485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284089PMC
June 2020

How I treat steroid-refractory acute graft-versus-host disease.

Authors:
Paul J Martin

Blood 2020 05;135(19):1630-1638

Division of Clinical Research, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, WA.

Steroid-resistant or steroid-refractory acute graft-versus-host disease (SR-aGVHD) poses one of the most vexing challenges faced by providers who care for patients after allogeneic hematopoietic cell transplantation. For the past 4 decades, research in the field has been driven by the premise that persistent graft-versus-host disease (GVHD) results from inadequate immunosuppression. Accordingly, most efforts to solve this problem have relied on retrospective or prospective studies testing agents that have direct or indirect immunosuppressive effects. Retrospective studies far outnumber prospective studies, and no controlled prospective trial has shown superior results for any agent over others. Truth be told, I do not know how to treat SR-aGVHD. Preclinical work during the past decade has provided fresh insights into the pathogenesis of acute GVHD, and translation of these insights toward development of more effective treatments for patients with SR-aGVHD has at last begun. Given the limited state of current knowledge, this "How I Treat" review highlights the overriding imperative to avoid harm in caring for patients with SR-aGVHD. Prospective trials that are widely available are urgently needed to advance the field.
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http://dx.doi.org/10.1182/blood.2019000960DOI Listing
May 2020

Survival, Nonrelapse Mortality, and Relapse-Related Mortality After Allogeneic Hematopoietic Cell Transplantation: Comparing 2003-2007 Versus 2013-2017 Cohorts.

Ann Intern Med 2020 02 21;172(4):229-239. Epub 2020 Jan 21.

Fred Hutchinson Cancer Research Center, Seattle, Washington (G.S., T.A.G.).

Background: Allogeneic hematopoietic cell transplantation is indicated for refractory hematologic cancer and some nonmalignant disorders. Survival is limited by recurrent cancer and organ toxicity.

Objective: To determine whether survival has improved over the past decade and note impediments to better outcomes.

Design: The authors compared cohorts that had transplants during 2003 to 2007 versus 2013 to 2017. Survival outcome measures were analyzed, along with transplant-related complications.

Setting: A center performing allogeneic transplant procedures.

Participants: All recipients of a first allogeneic transplant during 2003 to 2007 and 2013 to 2017.

Intervention: Patients received a conditioning regimen, infusion of donor hematopoietic cells, then immunosuppressive drugs and antimicrobial approaches to infection control.

Measurements: Day-200 nonrelapse mortality (NRM), recurrence or progression of cancer, relapse-related mortality, and overall mortality, adjusted for comorbidity scores, source of donor cells, donor type, patient age, disease severity, conditioning regimen, patient and donor sex, and cytomegalovirus serostatus.

Results: During the 2003-to-2007 and 2013-to-2017 periods, 1148 and 1131 patients, respectively, received their first transplant. Over the decade, decreases were seen in the adjusted hazards of day-200 NRM (hazard ratio [HR], 0.66 [95% CI, 0.48 to 0.89]), relapse of cancer (HR, 0.76 [CI, 0.61 to 0.94]), relapse-related mortality (HR, 0.69 [CI, 0.54 to 0.87]), and overall mortality (HR, 0.66 [CI, 0.56 to 0.78]). The degree of reduction in overall mortality was similar for patients who received myeloablative versus reduced-intensity conditioning, as well as for patients whose allograft came from a matched sibling versus an unrelated donor. Reductions were also seen in the frequency of jaundice, renal insufficiency, mechanical ventilation, high-level cytomegalovirus viremia, gram-negative bacteremia, invasive mold infection, acute and chronic graft-versus-host disease, and prednisone exposure.

Limitation: Cohort studies cannot determine causality, and current disease severity criteria were not available for patients in the 2003-to-2007 cohort.

Conclusion: Improvement in survival and reduction in complications were substantial after allogeneic transplant. Relapse of cancer remains the largest obstacle to better survival outcomes.

Primary Funding Source: National Institutes of Health.
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http://dx.doi.org/10.7326/M19-2936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847247PMC
February 2020

Refined National Institutes of Health response algorithm for chronic graft-versus-host disease in joints and fascia.

Blood Adv 2020 01;4(1):40-46

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Implementation of the 2014 National Institutes of Health (NIH) response algorithm for joint/fascia graft-versus-host disease (GVHD) has identified real-world limits to its application. To refine the 2014 NIH response algorithm, we analyzed multicenter prospective observational data from the Chronic GVHD Consortium. The training cohort included 209 patients and the replication cohort included 191 patients with joint/fascia involvement during their course of chronic GVHD. Linear mixed models with random patient effect were used to evaluate correlations between response categories and clinician- or patient-perceived changes in joint status as an anchor of response. Analysis of the training cohort showed that a 2-point change in total photographic range of motion (P-ROM) score was clinically meaningful. The results also suggested that a change from 0 to 1 on the NIH joint/fascia score should not be considered as worsening and suggested that both the NIH joint/fascia score and total P-ROM score, but not individual P-ROM scores, should be used for response assessment. On the basis of these results, we developed an evidence-based refined algorithm, the utility of which was examined in an independent replication cohort. Using the refined algorithm, ∼40% of responses were reclassified, largely mitigating most divergent responses among individual joints and changes from 0 to 1 on the NIH joint/fascia score. The refined algorithm showed robust point estimates and tighter 95% confidence intervals associated with clinician- or patient-perceived changes, compared with the 2014 NIH algorithm. The refined algorithm provides a superior, evidence-based method for measuring therapeutic response in joint/fascia chronic GVHD.
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http://dx.doi.org/10.1182/bloodadvances.2019000918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960471PMC
January 2020

Disability Related to Chronic Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2020 04 24;26(4):772-777. Epub 2019 Oct 24.

Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.

Chronic graft-versus-host disease (cGVHD) is a heterogenous syndrome whose symptoms and treatment are often associated with decreases in functional status and quality of life among survivors of transplantation. We explored definitions of cGVHD-related disability and factors associated with disability in cGVHD. We analyzed 371 patients with cGVHD requiring a new systemic therapy with enrollment and 18-month assessments through the Chronic GVHD Consortium, evaluating disability as a composite endpoint including any 1 of 5 impairments previously defined by Fatobene et al [1] (score 2 or 3 keratoconjunctivitis sicca, score 2 or 3 scleroderma, any diagnosis of bronchiolitis obliterans, score 2 or 3 joint/fasciae involvement, or score 3 esophageal stricture requiring dilation). We also evaluated disability, defined as an ≥8-point decline in a human activity profile (HAP) score or a ≥20% decline in Karnofsky Performance Status (KPS) from enrollment to 18 months. At enrollment, 47% of patients had at least 1 of the 5 Flowers disability features, with 50% of this group acquiring additional impairments at 18 months. Of the 197 patients (53%) with no Flowers disability at enrollment, 50% progressed with disability features at 18 months. We found that any progressive Flowers impairment was associated with a decline in HAP/KPS as well as with increased National Institutes of Health severity scores at 18 months. Enrollment mouth scores and patient-reported eye and skin scores were significantly associated with progressive impairment at 18 months. Progressive disability at 18 months did not predict subsequent nonrelapse mortality. Additional studies to define chronic GVHD related-disability and risk factors are needed to develop this important patient-centered outcome.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180104PMC
April 2020

Comparison of characteristics and outcomes of late acute and NIH chronic GVHD between Japanese and white patients.

Blood Adv 2019 09;3(18):2764-2777

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.

Although differences in the incidence of chronic graft-versus-host disease (GVHD) across the races have been suggested, these have not been systematically investigated. This study compared the incidence, sites, severity, and outcomes of late acute GVHD and chronic GVHD according to National Institutes of Health (NIH) consensus criteria between Japanese (n = 413) and white (n = 708) patients after first allogeneic hematopoietic cell transplantation. Analysis was stratified according to bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT). Japanese patients, compared with white patients, had a similar incidence of late acute GVHD (BMT, 19% vs 16%; PBSCT, 19% vs 16%) but experienced more frequent liver late acute GVHD as defined by transaminase elevation (BMT, 79% vs 8%; PBSCT, 92% vs 33%) and less frequent gastrointestinal late acute GVHD (BMT, 11% vs 58%; PBSCT, 20% vs 68%). Japanese patients were more likely to discontinue systemic immunosuppression after late acute GVHD than white patients (hazard ratio, 3.68; 95% confidence interval, 1.96-6.94; < .001). Japanese patients, compared with white patients, had a lower incidence of chronic GVHD (BMT, 15% vs 30% [ = .002]; PBSCT, 37% vs 45% [ < .001]) and experienced more frequent chronic GVHD of the mouth, eyes, and liver and less frequent gastrointestinal chronic GVHD. The duration of immunosuppressive treatment of NIH chronic GVHD was similar between the races. These differences could not be entirely attributed to practice variation between the centers. This study shows that the incidence, affected sites, severity, and clinical outcomes of late acute GVHD and NIH chronic GVHD differ between Japanese and white patients.
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http://dx.doi.org/10.1182/bloodadvances.2019000386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759734PMC
September 2019

In Memoriam: John A. Hansen (1943-2019).

HLA 2019 11 10;94(5):405-406. Epub 2019 Sep 10.

Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA.

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http://dx.doi.org/10.1111/tan.13674DOI Listing
November 2019

A Phase 3 Randomized Study of Remestemcel-L versus Placebo Added to Second-Line Therapy in Patients with Steroid-Refractory Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2020 05 7;26(5):835-844. Epub 2019 Sep 7.

Fred Hutchinson Cancer Research Center, Seattle, Washington.

Uncontrolled studies have suggested that bone marrow-derived mesenchymal stem cells (MSCs) may be effective against acute graft-versus-host disease (aGVHD). We conducted a multicenter, randomized study to assess the efficacy of using ex vivo cultured adult human MSC (remestemcel-L) in addition to second-line therapy to treat steroid-refractory aGVHD (NCT00366145). In total, 260 patients, 6 months to 70 years of age, were enrolled from August 2006 to May 2009 and were randomized 2:1 to receive 8 intravenous infusions of remestemcel-L or placebo, given over 4 weeks, in addition to second-line therapy according to institutional standards. Four additional infusions over 4 weeks were indicated for patients with incomplete response at day 28. Randomization was stratified by aGVHD grade. Efficacy and safety were assessed through 180 days of follow-up, with the primary endpoint being durable complete response (DCR), defined as complete resolution of aGVHD symptoms for any period of at least 28 days after beginning treatment. Remestemcel-L did not meet the primary endpoint of greater DCR in the intent-to-treat population (35% versus 30%; P = 0.42). In post hoc analyses, patients with liver involvement who received at least 1 infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% versus 5%; P = .047). Among high-risk patients (aGVHD grades C and D), remestemcel-L demonstrated significantly higher OR at day 28 than placebo (58% versus 37%; P = 0.03). Furthermore, pediatric patients had a higher OR with MSCs compared with placebo (64% versus 23%; P = .05). Similar rates of adverse events were observed between treatment groups. Remestemcel-L was safe and well tolerated. Results of this study did not demonstrate superior DCR compared with placebo when added to standard of care. The favorable clinical responses seen in some patient subsets may warrant further investigation.
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http://dx.doi.org/10.1016/j.bbmt.2019.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060124PMC
May 2020

The Chronic Graft-versus-Host Disease Failure-Free Survival (cGVHD-FFS) Index.

Biol Blood Marrow Transplant 2019 12 5;25(12):2468-2473. Epub 2019 Aug 5.

Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington. Electronic address:

In clinical trials of chronic graft-versus-host disease (cGVHD), the need to start a new systemic treatment is considered a treatment failure. A composite endpoint called "failure-free survival" (FFS), where events are initiation of a new systemic cGVHD treatment, recurrent malignancy, and death, has been suggested as a possible long-term indicator of success. The goal of the current study was to identify changes in cGVHD manifestations from baseline to 6 months that could accurately predict subsequent longer-term FFS, thereby making it possible to assess outcomes earlier than would otherwise be possible. We used data from 2 prospective, multicenter, observational studies to develop the cGVHD-FFS index. The cGVHD-FFS index was calculated at 6 months, a typical timepoint for assessment of the primary endpoint of phase II cGVHD trials. Subsequent FFS was only 45% within the next 2 years. We found that changes in the scores for the eyes, joint/fascia, and mouth ulcers from baseline to 6 months were associated with subsequent FFS, but the prognostic accuracy of these changes was not adequate for use in trials. Biomarker studies might help to identify criteria that improve prediction of long-term clinical outcomes in patients with cGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900444PMC
December 2019

Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial.

Lancet Haematol 2019 Aug 24;6(8):e409-e418. Epub 2019 Jun 24.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA.

Background: Acute graft-versus-host-disease (GVHD) after non-myeloablative human leucocyte antigen (HLA)-matched, unrelated donor, allogeneic haemopoietic stem cell transplantation (HSCT) is associated with considerable morbidity and mortality. This trial aimed to evaluate the efficacy of adding sirolimus to the standard cyclosporine and mycophenolate mofetil prophylaxis therapy for preventing acute GVHD in this setting.

Methods: This multicentre, randomised, phase 3 trial took place at nine HSCT centres based in the USA, Denmark, and Germany. Eligible patients were diagnosed with advanced haematological malignancies treatable by allogeneic HSCT, had a Karnofsky score greater than or equal to 60, were aged older than 50 years, or if they were aged 50 years or younger, were considered at high risk of regimen-related toxicity associated with a high-dose pre-transplantation conditioning regimen. Patients were randomly allocated by an adaptive randomisation scheme stratified by transplantation centre to receive either the standard GVHD prophylaxis regimen (cyclosporine and mycophenolate mofetil) or the triple-drug combination regimen (cyclosporine, mycophenolate mofetil, and sirolimus). Patients and physicians were not masked to treatment. All patients were prepared for HSCT with fludarabine (30 mg/m per day) 4, 3, and 2 days before receiving 2 or 3 Gy total body irradiation on the day of HSCT (day 0). In both study groups, 5·0 mg/kg of cyclosporine was administered orally twice daily starting 3 days before HSCT, and (in the absence of GVHD) tapered from day 96 through to day 150. In the standard GVHD prophylaxis group, 15 mg/kg of mycophenolate mofetil was given orally three times daily from day 0 until day 30, then twice daily until day 150, and (in the absence of GVHD) tapered off by day 180. In the triple-drug group, mycophenolate mofetil doses were the same as in the standard group, but the drug was discontinued on day 40. Sirolimus was started 3 days before HSCT, taken orally at 2 mg once daily and adjusted to maintain trough concentrations between 3-12 ng/mL through to day 150, and (in the absence of GVHD) tapered off by day 180. The primary endpoint was the cumulative incidence of grade 2-4 acute GVHD at day 100 post-transplantation. Secondary endpoints were non-relapse mortality, overall survival, progression-free survival, cumulative incidence of grade 3-4 acute GVHD, and cumulative incidence of chronic GVHD. Efficacy and safety analyses were per protocol, including all patients who received conditioning treatment and underwent transplantation. Toxic effects were measured according to the Common Terminology Criteria for Adverse Events (CTCAE). The current study was closed prematurely by recommendation of the Data and Safety Monitoring Board on July 27, 2016, after 168 patients received the allocated intervention, based on the results of a prespecified interim analysis for futility. This study is registered with ClinicalTrials.gov, number NCT01231412.

Findings: Participants were recruited between Nov 1, 2010, and July 27, 2016. Of 180 patients enrolled in the study, 167 received the complete study intervention and were included in safety and efficacy analyses: 77 patients in the standard GVHD prophylaxis group and 90 in the triple-drug group. At the time of analysis, median follow-up was 48 months (IQR 31-60). The cumulative incidence of grade 2-4 acute GVHD at day 100 was lower in the triple-drug group compared with the standard GVHD prophylaxis group (26% [95% CI 17-35] in the triple-drug group vs 52% [41-63] in the standard group; HR 0·45 [95% CI 0·28-0·73]; p=0·0013). After 1 and 4 years, non-relapse mortality increased to 4% (95% CI 0-9) and 16% (8-24) in the triple-drug group and 16% (8-24) and 32% (21-43) in the standard group (HR 0·48 [0·26-0·90]; p=0·021). Overall survival at 1 year was 86% (95% CI 78-93) in the triple-drug group and 70% in the standard group (60-80) and at 4 years it was 64% in the triple-drug group (54-75) and 46% in the standard group (34-57%; HR 0·62 [0·40-0·97]; p=0·035). Progression-free survival at 1 year was 77% (95% CI 68-85) in the triple-drug group and 64% (53-74) in the standard drug group, and at 4 years it was 59% in the triple-drug group (49-70) and 41% in the standard group (30-53%; HR 0·64 [0·42-0·99]; p=0·045). We observed no difference in the cumulative incidence of grade 3-4 acute GVHD (2% [0-5] in the triple-drug group vs 8% [2-14] in the standard group; HR 0·55 [0·16-1·96]; p=0·36) and chronic GVHD (49% [39-59] in triple-drug group vs 50% [39-61] in the standard group; HR 0·94 [0·62-1·40]; p=0·74). In both groups the most common CTCAE grade 4 or higher toxic effects were pulmonary.

Interpretation: Adding sirolimus to cyclosporine and mycophenolate mofetil resulted in a significantly lower proportion of patients developing acute GVHD compared with patients treated with cyclosporine and mycophenolate mofetil alone. Based on these results, the combination of cyclosporine, mycophenolate mofetil, and sirolimus has become the new standard GVHD prophylaxis regimen for patients treated with non-myeloablative conditioning and HLA-matched unrelated HSCT at the Fred Hutchinson Cancer Research Center.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S2352-3026(19)30088-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686903PMC
August 2019
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