Publications by authors named "Mary E Flowers"

233 Publications

Long-term survival with mixed chimerism in patients with AML and MDS transplanted after conditioning with targeted busulfan, fludarabine, and thymoglobulin.

Bone Marrow Transplant 2021 Nov 5. Epub 2021 Nov 5.

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

We evaluated long-term outcome in 40 patients with MDS or AML, transplanted from related or unrelated donors following conditioning with targeted busulfan (Bu, over 4 days), fludarabine (Flu, 120 [n = 23] or 250 [n = 17] mg/m) and thymoglobulin (THY). Compared to 95 patients conditioned with Bu/Cyclophosphamide (Cy) without THY, BuFluTHY-conditioned patients had lower rates of chronic graft-vs.-host disease (GVHD). Adjusted hazard ratios (HR) for BuFlu(120)THY and BuFlu(250)THY-conditioned patients were 1.60 (95% confidence interval (CI) 0.66-3.86) and 1.87 (0.68-5.11), respectively, for relapse; 0.77 (0.30-1.99) and 1.32 (0.54-3.23) for non-relapse mortality; 0.81 (0.42-1.57) and 1.38 (0.72-2.57) for overall mortality; and 0.78 (0.30-2.05) and 1.62 (0.63-4.41) for relapse or death (failure for relapse-free survival). At one year, 45% of BuFlu(120 or 250)THY-conditioned patients had mixed CD3+ chimerism compared to 0% with BuCy (p < 0.0001). None of 7 patients with long-term mixed chimerism had chronic GVHD; two relapsed, five remained stable mixed chimeras. THY is effective in reducing chronic GVHD, and long-term mixed T-cell chimerism can be compatible with relapse-free survival. However, Thy may also be associated with an increased risk of relapse and, dose-dependent, with non-relapse mortality.
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http://dx.doi.org/10.1038/s41409-021-01518-0DOI Listing
November 2021

Cancers after HLA-matched related bone marrow transplantation for aplastic anemia.

Bone Marrow Transplant 2021 Oct 16. Epub 2021 Oct 16.

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

We analyzed subsequent cancers in 329 patients with aplastic anemia given HLA-matched related marrow grafts. Median follow-up: 26 (range 1-47) years. Conditioning: cyclophosphamide ± antithymocyte globulin; graft-vs.-host disease (GVHD) prevention: methotrexate ± cyclosporine. The long follow-up and homogeneous treatment allowed definitive analyses of incidence, nature, time of onset, and potential causes of cancers. Fifty-three cancers occurred in 46 patients, 42 had solid tumors and 4 blood cancers. Of the 42, 22 had non-melanoma skin and 7 oropharyngeal cancers. The remainder had a spectrum of other cancers including two liver cancers from pre-transplant hepatitis C. The 26-year cumulative incidence (CI) of cancer was 11% and mortality 5%. Excluding non-melanoma skin cancers, the 26-year CI of cancer was 7%. Cancers were 2.03-fold more than expected from SEER data; that number was 1.89-fold after excluding liver cancers. Nearly all cancers developed between 14 and 34 years. Skin and oropharyngeal cancers showed significant association with chronic GVHD, whereby GVHD had resolved in most patients within 7 years of transplantation. Thus, tumors evolved after a lag time of 7-27 years. Other cancers showed no clear associations with chronic GVHD or drugs used for transplantation. Results reemphasize the importance of preventing chronic GVHD.
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http://dx.doi.org/10.1038/s41409-021-01498-1DOI Listing
October 2021

Initial therapy for chronic graft-versus-host disease: analysis of practice variation and failure-free survival.

Blood Adv 2021 11;5(22):4549-4559

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

Prior clinical trials largely considered prednisone 1 mg/kg per day with or without calcineurin inhibitor as standard initial therapy for chronic graft-versus-host disease (cGVHD), but uncertainty remains regarding the extent of practice variation and whether this affects subsequent outcomes. We assembled a cohort of 745 patients with cGVHD treated with initial systemic immune suppressive (IS) therapy from 3 prior cGVHD Consortium observational studies. Initial therapy was defined as first IS therapy started for cGVHD or prednisone increased to ≥0.4 mg/kg per day from lower doses within 30 days before cGVHD diagnosis to any time afterward. Initial therapies were nonprednisone 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 failure-free survival (FFS; a composite of death, relapse, and new IS therapy), overall survival (OS), or nonrelapse mortality (NRM). Among the prednisone-based approaches, steroid dose was <0.25 (9%), 0.25 to 0.74 (36%), 0.75 to 1.25 (42%), or >1.25 mg/kg per day (13%). Prednisone dose within the patients treated with steroids 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 nonsteroid 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
November 2021

Nonrelapse mortality among patients diagnosed with chronic GVHD: an updated analysis from the Chronic GVHD Consortium.

Blood Adv 2021 10;5(20):4278-4284

Blood and Marrow Transplant Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH.

Chronic graft-versus-host disease (cGVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. To better understand patients at highest risk for nonrelapse mortality (NRM), we analyzed patient-, transplant-, and cGVHD-related variables, risk factors, and causes of nonrelapse deaths in an updated cohort of 937 patients enrolled on 2 prospective, longitudinal observational studies through the Chronic GVHD Consortium. The median follow-up of survivors was 4 years (range, 0.1 months to 12.5 years). Relapse accounted for 25% of the 333 deaths. The cumulative incidence of NRM was 22% at 5 years, and it increased over time at a projected 40% (95% confidence interval, 30%-50%) at 12 years. Centers reported that cGVHD (37.8%) was the most common cause of NRM and was associated with organ failure, infection, or additional causes not otherwise specified. The next most frequent causes without mention of cGVHD were infection (17%) and respiratory failure (10%). In multivariable analysis, an increased risk for NRM was significantly associated with the use of reduced intensity conditioning, higher total bilirubin, National Institutes of Health (NIH) skin score of 2 to 3, NIH lung score of 1 to 3, worse modified Human Activity Profile adjusted activity score, and decreased distance on walk test. To summarize, cGVHD NRM does not plateau but increases over time and is most commonly attributed to GVHD or infection, presumably associated with immunocompromised status. Severe skin and lung cGVHD remain challenging manifestations associated with increased NRM, for which novel therapeutic options that do not predispose patients to infections are needed.
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http://dx.doi.org/10.1182/bloodadvances.2021004941DOI Listing
October 2021

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

Transplant Cell Ther 2021 Nov 29;27(11):951.e1-951.e6. 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
November 2021

Steroid-refractory chronic graft-versus-host disease: treatment options and patient management.

Bone Marrow Transplant 2021 09 3;56(9):2079-2087. Epub 2021 Jul 3.

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

Chronic graft-versus-host disease (cGVHD) is one of the major causes of late mortality after allogenic hematopoietic stem cell transplantation. Moderate-to-severe cGVHD is associated with poor health-related quality of life and substantial disease burden. While corticosteroids with or without calcineurin inhibitors comprise the first-line treatment option, the prognosis for patients with steroid-refractory cGVHD (SR-cGVHD) remains poor. The mechanisms underlying steroid resistance are unclear, and there are no standard second-line treatment guidelines for patients with SR-cGVHD. In this review, we provide an overview on current treatment options of cGVHD and use a series of theoretical case studies to elucidate the rationale of choices of second- and third-line treatment options for patients with SR-cGVHD based on individual patient profiles.
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http://dx.doi.org/10.1038/s41409-021-01389-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410585PMC
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

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

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

Progress in the management of chronic GVHD insights into novel therapies to treat and manage GVHD lasting longer than 12 Months.

Authors:
Mary E D Flowers

Best Pract Res Clin Haematol 2021 03 7;34(1):101253. Epub 2021 Feb 7.

Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, 1100 Fairview Ave N, D5-290, PO Box 19024, Seattle, WA, 98109-1024, USA. Electronic address:

Chronic graft-versus-host disease (cGVHD) is a major cause of poor outcomes after hematopoietic stem cell transplantation (HCT). An increased understanding of the pathobiology of cGVHD has led to the development of novel therapies. This review summarized the underlying pathogenesis of cGVHD and has provided considerations for integrating new agents into practice.
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http://dx.doi.org/10.1016/j.beha.2021.101253DOI Listing
March 2021

Social support as a moderator of healthcare adherence and distress in long-term hematopoietic cell transplantation survivors.

J Cancer Surviv 2021 Dec 9;15(6):866-875. Epub 2021 Jan 9.

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

Background: Treatment with hematopoietic cell transplantation (HCT) has potentially severe effects on physical and psychosocial functioning. Poor social support has been linked with physical morbidity and mortality as well as psychological distress in HCT survivors. This study tested a theory-driven hypothesis that social support buffers adverse effects of health stressors of comorbidities and graft-versus-host disease (cGVHD) on distress and adherence to recommended healthcare among long-term HCT survivors.

Methods: This cross-sectional study analyzed baseline data from a randomized controlled trial in adult survivors 3-18 years post-HCT. Data included medical records and patient-reported outcomes including cancer and treatment distress (CTXD), healthcare adherence (HCA), comorbidity index, cGVHD, ENRICHD Social Support Instrument (ESSI), Social Activity Log, and Health Self-Efficacy. We tested hypothesized models for HCA and CTXD using blocked hierarchical linear regressions.

Results: Among the 781 HCT survivors completing baseline assessment, 38% had > 3 comorbidities, 8% had moderate-severe cGVHD, 30% reported low social support, 30% reported elevated distress, and 49% reported low healthcare adherence. Social support and self-efficacy were directly related to both adherence and distress. Regression models supported the hypothesized moderated relationships for distress but not for healthcare adherence.

Conclusions: The two tested models confirm that the health stressors of comorbidities and cGVHD are moderated by better social support and self-efficacy in their associations with lower distress but without moderating effects for healthcare adherence.

Implications For Cancer Survivors: Social support and self-efficacy confer protective benefits on healthcare adherence and psychological distress. Interventions are needed that focus on maintaining social networks or finding new networks if necessary.

Clinical Trial Registration Number: NCT00799461.
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http://dx.doi.org/10.1007/s11764-020-00979-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267051PMC
December 2021

Blood and marrow transplantation during the emerging COVID-19 pandemic: the Seattle approach.

Bone Marrow Transplant 2021 02 26;56(2):305-313. Epub 2020 Sep 26.

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

On January 20, 2020, the first patient with coronavirus disease 2019 (COVID-19) in the United States of America was diagnosed in Washington state, which subsequently experienced rapidly increasing numbers of COVID-19 cases, hospitalizations, and deaths. This placed the Seattle Blood and Marrow Transplant Program at Fred Hutchinson Cancer Research Center (Fred Hutch) in the national epicenter of this pandemic. Here, we summarize the experience gained during our rapid response to the COVID-19 pandemic. Our efforts were aimed at safely performing urgent and potentially life-saving stem cell transplants in the setting of pandemic-related stresses on healthcare resources and shelter-in-place public health measures. We describe the unique circumstances and challenges encountered, the current state of the program amidst evolving COVID-19 cases in our community, and the guiding principles for recovery. We also estimate the collateral impact of directing clinical resources toward COVID-19-related care on cancer patients in need of stem cell transplantation. Although our experience was influenced by specific regional and institutional factors, it may help inform how transplant programs respond to COVID-19 and future pandemics.
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http://dx.doi.org/10.1038/s41409-020-01068-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519858PMC
February 2021

CMV viral load kinetics as surrogate endpoints after allogeneic transplantation.

J Clin Invest 2021 01;131(1)

Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

BACKGROUNDViral load (VL) surrogate endpoints transformed development of HIV and hepatitis C therapeutics. Surrogate endpoints for CMV-related morbidity and mortality could advance development of antiviral treatments. Although observational data support using CMV VL as a trial endpoint, randomized controlled trials (RCTs) demonstrating direct associations between virological markers and clinical endpoints are lacking.METHODSWe performed CMV DNA PCR on frozen serum samples from the only placebo-controlled RCT of ganciclovir for early treatment of CMV after hematopoietic cell transplantation (HCT). We used established criteria to assess VL kinetics as surrogates for CMV disease or death by weeks 8, 24, and 48 after randomization and quantified antiviral effects captured by each marker. We used ensemble-based machine learning to assess the predictive ability of VL kinetics and performed this analysis on a ganciclovir prophylaxis RCT for validation.RESULTSVL suppression with ganciclovir reduced cumulative incidence of CMV disease and death for 20 years after HCT. Mean VL, peak VL, and change in VL during the first 5 weeks of treatment fulfilled the Prentice definition for surrogacy, capturing more than 95% of ganciclovir's effect, and yielded highly sensitive and specific predictions by week 48. In the prophylaxis trial, the viral shedding rate satisfied the Prentice definition for CMV disease by week 24.CONCLUSIONSOur results support using CMV VL kinetics as surrogates for CMV disease, provide a framework for developing CMV preventative and therapeutic agents, and support reductions in VL as the mechanism through which antivirals reduce CMV disease.FUNDINGMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
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http://dx.doi.org/10.1172/JCI133960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773411PMC
January 2021

Conditioning Intensity, Pre-Transplant Flow Cytometric Measurable Residual Disease, and Outcome in Adults with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation.

Cancers (Basel) 2020 Aug 19;12(9). Epub 2020 Aug 19.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

How conditioning intensity is related to outcomes of AML patients undergoing allografting in morphologic remission is an area of great ongoing interest. We studied 743 patients in morphologic remission and known pre-transplant measurable residual disease (MRD) status determined by multiparameter flow cytometry (MFC) who received a first allograft after myeloablative, reduced intensity, or nonmyeloablative conditioning (MAC, RIC, and NMA). Overall, relapse-free survival (RFS) and overall survival (OS) were longer after MAC than RIC or NMA conditioning, whereas relapse risks were not different. Among MRD patients, 3-year estimates of relapse risks and survival were similar across conditioning intensities. In contrast, among MRD patients, 3-year RFS and OS were longer for MAC (69% and 71%) than RIC (47% and 55%) and NMA conditioning (47% and 52%). Three-year relapse risks were lowest after MAC (18%) and highest after NMA conditioning (30%). Our data indicate an interaction between conditioning intensity, MFC-based pre-transplant MRD status, and outcome, with benefit of intensive conditioning primarily for patients transplanted in MRD remission. Differing from recent findings from other studies that indicated MAC is primarily beneficial for some or all patients with MRD pre-HCT status, our data suggest MAC should still be considered for MRD AML patients if tolerated.
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http://dx.doi.org/10.3390/cancers12092339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565021PMC
August 2020

Challenging and Practical Aspects of Nutrition in Chronic Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2020 11 9;26(11):e265-e270. Epub 2020 Aug 9.

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

There is a paucity of information about nutrition in chronic graft-versus-host disease (GVHD). The role of nutrition is important because malnutrition is strongly associated with severe chronic GVHD manifestations. There is a high prevalence of metabolic syndrome and osteoporosis in this setting. Here we review the literature, describe main aspects of nutrition and discuss macronutrients (ie, vitamins), micronutrients (ie, Mg, Zn, Ca, and K) and supplements (probiotics and omega 3 fatty acids). A search was carried out in March 2020 using PubMed. Databases were screened for searching terms in titles and abstracts referring to chronic GVHD, nutrition intervention, protein, and body composition. Data were extracted for the following outcomes: nutrition, nutrition intervention, chronic GVHD, nutrition deficiencies, diet, vitamin, dry eye, probiotic, protein, and body composition. In this report, we summarize interventional nutrition studies reported in oncology and metabolic syndrome settings and describe our nutritional clinical practice in hematopoietic cell transplantation and chronic GVHD. The impact of nutrition evaluation and intervention on muscle mass loss, dry eye, dysgeusia, metabolic syndrome, osteoporosis, and comorbidities associated with chronic GVHD need to be studied prospectively.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.004DOI Listing
November 2020

Bone Health Management After Hematopoietic Cell Transplantation: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.

Biol Blood Marrow Transplant 2020 10 9;26(10):1784-1802. Epub 2020 Jul 9.

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

Bone health disturbances commonly occur after hematopoietic cell transplantation (HCT) with loss of bone mineral density (BMD) and avascular necrosis (AVN) foremost among them. BMD loss is related to pretransplantation chemotherapy and radiation exposure and immunosuppressive therapy for graft-versus-host-disease (GVHD) and results from deficiencies in growth or gonadal hormones, disturbances in calcium and vitamin D homeostasis, as well as osteoblast and osteoclast dysfunction. Although the pathophysiology of AVN remains unclear, high-dose glucocorticoid exposure is the most frequent association. Various societal treatment guidelines for osteoporosis exist, but the focus is mainly on menopausal-associated osteoporosis. HCT survivors comprise a distinct population with unique comorbidities, making general approaches to bone health management inappropriate in some cases. To address a core set of 16 frequently asked questions (FAQs) relevant to bone health in HCT, the American Society of Transplant and Cellular Therapy Committee on Practice Guidelines convened a panel of experts in HCT, adult and pediatric endocrinology, orthopedics, and oral medicine. Owing to a lack of relevant prospective controlled clinical trials that specifically address bone health in HCT, the answers to the FAQs rely on evidence derived from retrospective HCT studies, results extrapolated from prospective studies in non-HCT settings, relevant societal guidelines, and expert panel opinion. Given the heterogenous comorbidities and needs of individual HCT recipients, answers to FAQs in this article should be considered general recommendations, with good medical practice and judgment ultimately dictating care of individual patients. Readers are referred to the Supplementary Material for answers to additional FAQs that did not make the core set.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.001DOI Listing
October 2020

Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen-mismatched donors.

Blood 2020 09;136(13):1499-1506

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

This trial aimed to evaluate the efficacy of sirolimus in addition to cyclosporine (CSP) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after nonmyeloablative conditioning for HLA class I or II mismatched hematopoietic cell transplantation (HCT). Eligible patients had hematologic malignancies treatable by allogeneic HCT. Conditioning consisted of fludarabine (90 mg/m2) and 2 to 3 Gy total body irradiation. GVHD prophylaxis comprised cyclosporine, mycophenolate mofetil, and sirolimus. The primary objective was to determine whether the cumulative incidence of grade 2 to 4 acute GVHD could be reduced to <70% in HLA class I or II mismatched HCT. The study was closed on December 20, 2018. Seventy-seven participants were recruited between April 14, 2011, and December 12, 2018, of whom 76 completed the study intervention. Median follow-up was 47 months (range, 4-94 months). The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 36% (95% confidence interval [CI], 25-46), meeting the primary end point. The cumulative incidence of nonrelapse morality, relapse/progression, and overall survival was 18% (95% CI, 9-27), 30% (interquartile range, 19-40), and 62% (95% CI, 50-73) after 4 years. In conclusion, the addition of sirolimus to cyclosporine and mycophenolate mofetil resulted in a lower incidence of acute GVHD, thus translating into superior overall survival compared with historical results. This trial was registered at www.clinicaltrials.gov as #NCT01251575.
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http://dx.doi.org/10.1182/blood.2020005338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515688PMC
September 2020

Who Enrolls in an Online Cancer Survivorship Program? Reach of the INSPIRE Randomized Controlled Trial for Hematopoietic Cell Transplantation Survivors.

Biol Blood Marrow Transplant 2020 10 26;26(10):1948-1954. Epub 2020 Jun 26.

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

The internet can be a valuable tool in delivering survivorship care to hematopoietic cell transplantation (HCT) cancer survivors. We describe the reach of INSPIRE, an Internet and social media-based randomized controlled trial, to address healthcare and psychosocial needs of HCT survivors. All survivors 2-10 years after HCT for hematologic malignancy or myelodysplasia from 6 transplantation centers in the US were approached by mail and follow-up calls. Eligible participants had access to the Internet, an email address, and did not have active disease in the past 2 years. We used logistic regression to determine characteristics of eligible survivors who were more or less likely to enroll. Of 2578 eligible HCT survivors, 1065 (41%) enrolled in the study. The mean age of enrollees was 56.3 ± 12.6 years (range, 19 to 89 years), 52% were male, and 94% were white. Survivors less likely to enroll included those who were male, age <40 years, and who received an autologous transplant (all P < .001). Compared with white survivors, African Americans were less likely to enroll (P < .001), whereas Native Americans/Alaska Natives were more likely to join the study (P = .03). The reach of the INSPIRE program was broad, including to survivors who traditionally have less access to resources, such as Native Americans/Alaskan Natives and rural residents. Strategies are still needed to improve the enrollment of online studies of survivorship resources for males, young adults, African American, and autologous HCT survivors because their use may improve outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529848PMC
October 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

Subsequent neoplasms and late mortality in children undergoing allogeneic transplantation for nonmalignant diseases.

Blood Adv 2020 05;4(9):2084-2094

Division of Hematology/Oncology, College of Medicine, University of Florida, Gainesville, FL.

We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, <1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was <1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.
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http://dx.doi.org/10.1182/bloodadvances.2019000839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218429PMC
May 2020

Late infectious complications in hematopoietic cell transplantation survivors: a population-based study.

Blood Adv 2020 04;4(7):1232-1241

Department of Pediatrics, University of Washington, Seattle Children's Hospital, Seattle, WA.

Few studies have compared the incidence of infections occurring ≥2 years after hematopoietic cell transplant (HCT) with other cancer patients and the general population. In this study, ≥2-year HCT survivors who were Washington residents treated from 1992 through 2009 (n = 1792; median age, 46 years; 52% allogeneic; 90% hematologic malignancies) were matched to individuals from the state cancer registry (n = 5455, non-HCT) and driver's license files (n = 16 340; Department of Licensing [DOL]). Based on hospital and death registry codes, incidence rate ratios (IRRs; 95% confidence interval [CI]) of infections by organism type and organ system were estimated using Poisson regression. With 7-year median follow-up, the incidence rate (per 1000 person-years) of all infections was 65.4 for HCT survivors vs 39.6 for the non-HCT group (IRR, 1.6; 95% CI, 1.3-1.9) and 7.2 for DOL (IRR, 10.0; 95% CI, 8.3-12.1). Bacterial and fungal infections were each 70% more common in HCT vs non-HCT cancer survivors (IRR, 1.7; P < .01), whereas the risk for viral infection was lower (IRR, 1.4; P = .07). Among potentially vaccine-preventable organisms, the IRR was 3.0 (95% CI, 2.1-4.3) vs the non-HCT group. Although the incidences of all infections decreased with time, the relative risk in almost all categories remained significantly increased in ≥5-year HCT survivors vs other groups. Risk factors for late infection included history of relapse and for some infections, history of chronic graft-versus-host disease. Providers caring for HCT survivors should maintain vigilance for infections and ensure adherence to antimicrobial prophylaxis and vaccination guidelines.
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http://dx.doi.org/10.1182/bloodadvances.2020001470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160274PMC
April 2020

Age and gender differences in financial distress among hematopoietic cell transplant survivors.

Support Care Cancer 2020 Sep 8;28(9):4361-4371. Epub 2020 Jan 8.

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Purpose: Cancer has long-term financial consequences. Adolescent and young adult (AYA) and middle-aged cancer survivors may experience more financial toxicity than older adults. This study examined age differences in financial distress in hematopoietic cell transplant survivors and whether these differences result from measurement bias, more financial barriers to care, or an overall higher level of distress.

Methods: Hematologic malignancy survivors (n = 1135, 2-10 years post-transplant) completed the Cancer and Treatment Distress Scale (CTXD) and demographics as part of the baseline assessment for a randomized clinical trial. The CTXD has seven subscales, but for this study, we examined the financial distress subscale and the overall score. Item response theory analyses tested for bias by age and gender. Multivariate linear regression tested the association of age and gender with the CTXD scores while controlling for financial barriers to care.

Results: No bias was found on the CTXD. AYA (p < 0.01) and middle-aged adults (p < 0.001) reported more financial and overall distress than older (age 65+) adults. The same association of age and financial distress was observed in women (p < 0.01). However, only middle-aged men (p < 0.01) reported more financial and overall distress than older men; AYA men did not (p > 0.18). Financial barriers to care were not associated with financial or overall distress.

Conclusions: Part of the increase in financial distress with younger age may be due to a higher risk of general distress. Policy initiatives to control cancer costs should consider life stage and the unique financial challenges at different ages for men and women.
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http://dx.doi.org/10.1007/s00520-019-05291-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340568PMC
September 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

Early Post-Transplantation Spirometry Is Associated with the Development of Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2020 05 9;26(5):943-948. Epub 2019 Dec 9.

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

Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (allo-HCT) is often diagnosed at a late stage when lung dysfunction is severe and irreversible. Identifying patients early after transplantation may offer improved strategies for early detection that could avert the morbidity and mortality of BOS. This study aimed to determine whether a decline in lung function before and early after (days +80 to +100) allo-HCT are associated with a risk of BOS beyond 6 months post-transplantation. In a single-center cohort of 2941 allo-HCT recipients, 186 (6%) met National Institutes of Health criteria for BOS. Pretransplantation and post-transplantation day +80 spirometric parameters were analyzed as continuous variables and included in a multivariable model with other factors, including donor source, graft source, conditioning regimen, use of total body irradiation, and immunoglobulin levels. Pre-transplantation forced expiratory flow between 25% and 75% of maximum (FEF), day +80 forced expiratory volume in 1 second (FEV), and day +80 FEF had the strongest associations with increased risk of BOS. Assessment of the multivariable model showed that a decline in day +80 FEF added additional risk to the day +80 FEV model (P = .03), whereas FEV decline at day +80 added no additional risk to the day +80 FEF model (P = .645). Moreover, day +80 FEF conferred additional risk when considered with pretransplantation FEF. These results suggest that day +80 FEF may be more important than FEV in predicting the development of BOS. This study highlights the importance of obtaining early post-transplantation pulmonary function tests for the potential risk stratification of patients at risk for BOS.
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http://dx.doi.org/10.1016/j.bbmt.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255698PMC
May 2020

Azithromycin Use and Increased Cancer Risk among Patients with Bronchiolitis Obliterans after Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2020 02 1;26(2):392-400. Epub 2019 Nov 1.

AP-HP, Université de Paris, Hôpital Saint-Louis, Service de Pneumologie, Paris, France; Université de Paris, ECSTRRA, UMR 1153 CRESS, Biostatistics and Clinical Epidemiology Research Team, Paris, France. Electronic address:

Azithromycin exposure during the early phase of allogeneic hematopoietic cell transplantation (HCT) has been associated with an increased incidence of hematologic relapse. We assessed the impact of azithromycin exposure on the occurrence of relapse or new subsequent neoplasm (SN) in patients with bronchiolitis obliterans syndrome (BOS) after HCT who are commonly treated with azithromycin alone or in combination with other agents. In a retrospective study of patients with BOS from 2 large allograft centers, the effect of azithromycin exposure on the risk of relapse or SN was estimated from a Cox model with a time-dependent variable for treatment initiation. The Cox model was adjusted on time-fixed covariates measured at cohort entry, selected for their potential prognostic value. Similar models were used to assess the exposure effect on the cause-specific hazard of relapse, SN, and death free of those events. Sensitivity analyses were performed using propensity score matching. Among 316 patients, 227 (71.8%) were exposed to azithromycin after BOS diagnosis. The corresponding adjusted hazard ratio (HR) in patients exposed to azithromycin versus unexposed was 1.51 (95% confidence interval [CI], 0.90 to 2.55) for relapse or SN, 0.82 (95% CI, 0.37 to 1.83) for relapse, and 2.00 (95% CI, 1.01 to 3.99) for SN. Patients exposed to azithromycin had a significantly lower cause-specific hazard of death free of neoplasm and relapse (adjusted HR, 0.54; 95% CI, 0.34 to 0.89). In conclusion, exposure to azithromycin after BOS after HCT was associated with an increased risk of SN but not relapse.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430235PMC
February 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

Risk factors for the development of cutaneous melanoma after allogeneic hematopoietic cell transplantation.

J Am Acad Dermatol 2020 Sep 22;83(3):762-772. Epub 2019 Oct 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. Electronic address:

Background: Melanoma risk is increased after allogeneic hematopoietic cell transplantation (HCT), but specific risk factors are unknown.

Objective: Investigate risk factors for melanoma after allogeneic hematopoietic cell transplantation.

Methods: We conducted a nested case-control study of 140 melanoma cases and 557 controls (matched by age at HCT, sex, primary disease, survival time) through the Center for International Blood and Marrow Transplant Research.

Results: Melanoma risk was significantly increased among HCT survivors who received total body irradiation-based myeloablative conditioning (multivariable adjusted odds ratio [OR] = 1.77; 95% confidence interval [CI] = 1.00-3.15) or reduced-intensity conditioning containing melphalan (OR = 2.60; 95% CI = 1.13-6.02) or fludarabine (OR = 2.72; 95% CI = 1.02-7.30) versus busulfan-based myeloablative regimens; were diagnosed with acute graft-versus-host disease (GVHD) with stage 2+ skin involvement (OR = 1.92; 95% CI = 1.19-3.10), chronic GvHD without skin involvement (OR = 1.91; 95% CI = 1.03-3.57), or keratinocytic carcinoma (OR = 2.37; 95% CI = 1.16-4.83); and resided in areas with higher ambient ultraviolet radiation (ORtertile3 = 1.64; 95% CI = 1.01-2.67).

Limitations: Data on individual-level ultraviolet radiation exposure and clinical data on melanoma characteristics were lacking. Additionally, misclassification of melanoma is possible as not all pathology reports were available for review.

Conclusion: These results emphasize the importance of adherence to current surveillance guidelines (routine skin examination, photoprotection recommendations), particularly for HCT survivors at highest risk.
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http://dx.doi.org/10.1016/j.jaad.2019.10.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206613PMC
September 2020
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