Publications by authors named "Stephanie J Lee"

378 Publications

Phase 2 multicenter trial of ofatumumab and prednisone as initial therapy of chronic graft-vs-host disease.

Blood Adv 2021 Oct 14. Epub 2021 Oct 14.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States.

Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal and transient responses in a significant number of patients. Safety and feasibility of anti-CD20 directed B-cell therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n=12). We now report the mature results of the phase II expansion of the trial (n=38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The combined therapy was generally well tolerated, with some anticipated infusion reactions to ofatumumab, and common toxicities of glucocorticoids. Total B-cell depletion following therapy was profound, with marginal recovery within first 12 months from initial therapy. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR=complete + partial response[CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial IS agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial is registered at www.clinicaltrials.gov as NCT01680965.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021005552DOI Listing
October 2021

Chronic Graft-Versus-Host Disease, Non-Relapse Mortality and Disease Relapse in Older versus Younger Adults Undergoing Matched Allogeneic Peripheral Blood Hematopoietic Cell Transplantation: A CIBMTR Analysis.

Transplant Cell Ther 2021 Oct 9. Epub 2021 Oct 9.

CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; Fred Hutchinson Cancer Research Center, Seattle, WA.

Background: The effect of chronic graft-versus-host disease (cGVHD) on the risk of non-relapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (≥60 years).

Methods: We included 4429 adults ≥40 years who received first HLA-matched peripheral blood alloHCT for acute myeloid leukemia or myelodysplastic syndrome between the years 2008-2017. We compared outcomes of 4 groups: older adults (≥60 years) and younger adults (40-59 years) with or without cGVHD to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse and overall survival (OS). We treated cGVHD as a time-dependent covariate. Severity of cGVHD was based on the CIBMTR clinical definitions.

Results: cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher among older versus younger adults. Adults who developed cGVHD as a group had longer OS, compared to age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild and moderate cGVHD were associated with longer OS.

Conclusions: Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse and longer OS. Older adults had a higher risk of NRM but the increased risk of NRM associated with cGVHD did not differ based on age. Development of mild-moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing relapses. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.10.002DOI Listing
October 2021

Distress in a Pandemic: Association of the Coronavirus Disease-2019 Pandemic with Distress and Quality of Life in Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 Sep 15. Epub 2021 Sep 15.

Harvard Medical School, Boston, Massachusetts; Massachusetts General Hospital, Boston, Massachusetts.

The global coronavirus disease 2019 (COVID-19) pandemic has drastically disrupted cancer care, potentially exacerbating patients' distress levels. Patients undergoing hematopoietic stem cell transplantation (HSCT) may be especially vulnerable to this pandemic stress. However, the associations of the COVID-19 pandemic with distress, fatigue, and quality of life (QoL) are not well understood in this population. In a cross-sectional analysis of data from 205 patients undergoing HSCT enrolled in a supportive care trial, we compared baseline pre-HSCT distress symptoms (depression, anxiety, and posttraumatic stress disorder [PTSD]), fatigue, and QoL between enrollees before (ie, March 2019-January 2020) and during (ie, March 2020-January 2021) the COVID-19 pandemic. We used linear regression models adjusting for sociodemographics and cancer diagnosis to examine the associations between enrollment period and patient-reported outcomes. We used semistructured qualitative interviews in 20 allogeneic HSCT recipients who were ≥3-months post-HSCT to understand the impact of the COVID-19 pandemic on their recovery post-HSCT. One hundred twenty-four participants enrolled before COVID-19, and 81 participants enrolled during the pandemic. The 2 cohorts had similar baseline demographics and disease risk factors. In multivariate regression models, enrollment during COVID-19 was not associated with pre-HSCT symptoms of depression, anxiety, PTSD, fatigue, or QoL impairment. COVID-19-era participants reported themes of negative (eg, increased isolation) and positive (eg, engagement with meaningful activities) implications of the pandemic on HSCT recovery. We found no differences in pre-HSCT distress, fatigue, or QoL in patients undergoing HSCT before or during the COVID-19 pandemic; however, patients in early recovery post-HSCT report both negative and positive implications of the COVID-19 pandemic in their lives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442257PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021005286DOI Listing
September 2021

Non-relapse mortality among patients diagnosed with chronic GVHD: An updated analysis from The Chronic GVHD Consortium.

Blood Adv 2021 Sep 14. Epub 2021 Sep 14.

Cleveland Clinic, Cleveland, Ohio, United States.

Chronic graft-versus-host disease (GVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. To better understand patients at highest risk for non-relapse mortality (NRM), we analyzed patient, transplant, and chronic GVHD-related variables, risk factors, and causes of non-relapse deaths in an updated cohort of 937 subjects enrolled on two prospective, longitudinal observational studies through the Chronic GVHD Consortium. The median follow-up of survivors was 4 years (0.1 months - 12.5 years). Relapse accounted for 25% of the 333 deaths. The cumulative incidence of NRM was 22% at 5 years and increased over time with a projected 40% (95%CI, 30-50) at 12 years. Centers reported that chronic GVHD (37.8%) was the commonest cause of NRM and was associated with organ failure, infection, or additional cause not otherwise specified. The next most frequent causes without mention of chronic GVHD were infection (17%) and respiratory failure (10%). In multivariate analysis, an increased risk for NRM was significantly associated with the use of reduced intensity conditioning, higher total bilirubin, NIH skin score 2-3, NIH lung score 1-3, worse modified HAP adjusted activity score, and decreased distance on walk test. In conclusion, chronic GVHD 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 chronic GVHD remain challenging manifestations associated with increased NRM, for which novel therapeutic options are needed that do not predispose patients to infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004941DOI Listing
September 2021

Donor Killer Immunoglobulin Receptor Gene Content and Ligand Matching and Outcomes of Pediatric Patients with Juvenile Myelomonocytic Leukemia Following Unrelated Donor Transplantation.

Transplant Cell Ther 2021 Aug 15. Epub 2021 Aug 15.

Division of Pediatric Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio; Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio.

Natural killer (NK) cell determinants predict relapse-free survival after allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia, and previous studies have shown a beneficial graft-versus-leukemia effect in patients with juvenile myelomonocytic leukemia (JMML). However, whether NK cell determinants predict protection against relapse for JMML patients undergoing HCT is unknown. Therefore, we investigated NK cell-related donor and recipient immunogenetics as determinants of HCT outcomes in patients with JMML. Patients with JMML (age 0 to <19 years) who underwent a first allogeneic HCT from an unrelated donor between 2000 and 2017 and had available donor samples from the Center for International Blood and Marrow Transplant Research Repository were included. Donor killer immunoglobulin receptor (KIR) typing was performed on pre-HCT samples. The primary endpoint was disease-free survival (DFS); secondary endpoints included relapse, grade II-IV acute graft versus-host-disease (aGVHD), chronic GVHD (cGVHD), GVHD-free relapse-free survival, transplantation-related mortality, and overall survival (OS). Donor KIR models tested included KIR genotype (AA versus Bx), B content (0-1 versus ≥2), centromeric and telomeric region score (AA versus AB versus BB), B content score (best, better, or neutral), composite score (2 versus 3 versus 4), activating KIR content, and the presence of KIR2DS4. Ligand-ligand and KIR-ligand mismatch effects on outcomes were analyzed in HLA-mismatched donors (≤7/8; n = 74) only. Univariate analyses were performed for primary and secondary outcomes of interest, with a P value <.05 considered significant. One hundred sixty-five patients (113 males), with a median follow-up of 85 months (range, 6 to 216 months) met the study criteria. Of these, 111 underwent an unrelated donor HCT and 54 underwent a UCB HCT. Almost all (n = 161; 98%) received a myeloablative conditioning regimen. After exclusion of recipients of reduced-intensity/nonmyeloablative conditioning regimens and ex vivo T cell-depleted grafts (n = 8), there were 42 AA donors and 115 Bx donors, respectively. Three-year DFS, OS, relapse, and GRFS for the entire cohort were 58% (95% confidence interval [CI], 50% to 66%), 67% (95% CI, 59% to 74%), 26% (95% CI, 19% to 33%), and 27% (95% CI, 19% to 35%), respectively. The cumulative incidence of grade II-IV aGVHD at 100 days was 36% (95% CI, 27% to 44%), and that of cGVHD at 1 year was 23% (95% CI, 17% to 30%). There were no differences between AA donors and Bx donors for any recipient survival outcomes. The risk of grade II-IV aGVHD was lower in patients with donors with a B content score of ≥2 (hazard ratio [HR], 0.46; 95% CI, 0.26 to 0.83; P = .01), an activating KIR content score of >3 (HR, 0.52; 95% CI, 0.29 to 0.95; P = .032), centromeric A/B score (HR, 0.57; 95% CI, 033 to 0.98; P = .041), and telomeric A/B score (HR, 0.58; 95% CI, 0.34 to 1.00; P = .048). To our knowledge, this is the first study analyzing the association of NK cell determinants and outcomes in JMML HCT recipients. This study identifies potential benefits of donor KIR-B genotypes in reducing aGVHD. Our findings warrant further study of the role of NK cells in enhancing the graft-versus-leukemia effect via recognition of JMML blasts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.08.009DOI Listing
August 2021

Multisite 11-year experience of less-intensive vs intensive therapies in acute myeloid leukemia.

Blood 2021 Aug;138(5):387-400

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

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020008812DOI Listing
August 2021

Reply to A. Heine et al.

J Clin Oncol 2021 Oct 4;39(29):3308-3309. Epub 2021 Aug 4.

Aleksandr Lazaryan, MD, MPH, PhD, Moffitt Cancer Center, Tampa, FL and Stephanie J. Lee, MD, MPH, Fred Hutchinson Cancer Research Center, Seattle, WA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.21.01559DOI Listing
October 2021

Prognostic impact of pre-transplant chromosomal aberrations in peripheral blood of patients undergoing unrelated donor hematopoietic cell transplant for acute myeloid leukemia.

Sci Rep 2021 07 22;11(1):15004. Epub 2021 Jul 22.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA.

To improve risk stratification and treatment decisions for patients with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT). We used SNP-array data from the DISCOVeRY-BMT study to detect chromosomal aberrations in pre-HCT peripheral blood (collected 2-4 weeks before the administration of conditioning regimen) from 1974 AML patients who received HCT between 2000 and 2011. All aberrations detected in ≥ 10 patients were tested for their association with overall survival (OS), separately by remission status, using the Kaplan-Meier estimator. Cox regression models were used for multivariable analyses. Follow-up was through January 2019. We identified 701 unique chromosomal aberrations in 285 patients (7% of 1438 in complete remission (CR) and 36% of 536 not in CR). Copy-neutral loss-of-heterozygosity (CNLOH) in chr17p in CR patients (3-year OS = 20% vs. 50%, with and without chr17p CNLOH, p = 0.0002), and chr13q in patients not in CR (3-year OS = 4% vs. 26%, with and without chr13q CNLOH, p < 0.0001) are risk factors for poor survival. Models adjusted for clinical factors showed approximately three-fold excess risk of post-HCT mortality with chr17p CNLOH in CR patients (hazard ratio, HR = 3.39, 95% confidence interval CI 1.74-6.60, p = 0.0003), or chr13q CNLOH in patients not in CR (HR = 2.68, 95% CI 1.75-4.09, p < 0.0001). The observed mortality was mostly driven by post-HCT relapse (HR = 2.47, 95% CI 1.01-6.02, p = 0.047 for chr17p CNLOH in CR patients, and HR = 2.58, 95% CI 1.63-4.08, p < 0.0001 for chr13q CNLOH in patients not in CR. Pre-transplant CNLOH in chr13q or chr17p predicts risk of poor outcomes after unrelated donor HCT in AML patients. A large prospective study is warranted to validate the results and evaluate novel strategies to improve survival in those patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-94539-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298542PMC
July 2021

Belumosudil for Chronic Graft-versus-Host Disease (cGVHD) After 2 or More Prior Lines of Therapy: The ROCKstar Study.

Blood 2021 Jul 15. Epub 2021 Jul 15.

Kadmon Corporation, West Chicago, Illinois, United States.

Belumosudil, an investigational oral selective inhibitor of rho-associated coiled-coil-containing protein kinase-2 (ROCK2), reduces type 17 and follicular helper T cells via downregulation of signal transducer and activator of transcription 3 (STAT3) and enhances regulatory T cells via upregulation of signal transducer and activator of transcription 5 (STAT5). Belumosudil may effectively treat patients with cGVHD, a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2, randomized, multicenter registration study evaluated belumosudil 200 mg QD (n=66) and 200 mg BID (n=66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR (95% CI) of belumosudil 200 mg QD and 200 mg BID was 74% (62%-84%) and 77% (65%-87%), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg QD and 200 mg BID was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil due to possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. (Funded by Kadmon Corporation, LLC; ClinicalTrials.gov number, NCT03640481.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021012021DOI Listing
July 2021

Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease.

N Engl J Med 2021 07;385(3):228-238

From the Department of Medicine I, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg (R.Z.), and Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden (J.M.M.) - both in Germany; the Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, ASST Spedali Civili di Brescia, University of Brescia, Brescia (N.P.), UOC di Oncoematologia e TMO, Dipartimento Oncologico "la Maddalena," Palermo (M.M.), and Dipartimento di Oncoematologia Pediatrica, IRCCS, Ospedale Pediatrico Bambino Gesu', Sapienza, Università di Roma, Rome (F.L.) - all in Italy; the BMT Unit, Tel Aviv (Sourasky) Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (R.R.); the Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia (S.K.H.); the Department of Medicine, Sheikh Shakhbout Medical City, Mayo Clinic, Abu Dhabi, United Arab Emirates (S.K.H.); UCL Cancer Institute, Institute of Immunity and Transplantation, London (R.C.); the Department of Bone Marrow Transplantation and Onco-Hematology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland (S.G.); Acibadem University Hospital, Hematology Department, Istanbul, Turkey (A.U.); Incyte, Wilmington, DE (P.L.); Novartis Pharma, Basel, Switzerland (N.H., T.S.); Novartis Pharmaceuticals, East Hanover, NJ (M.G.); the Fred Hutchinson Cancer Research Center, Seattle (S.J.L.); and the Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan (T.T.).

Background: Chronic graft-versus-host disease (GVHD), a major complication of allogeneic stem-cell transplantation, becomes glucocorticoid-refractory or glucocorticoid-dependent in approximately 50% of patients. Robust data from phase 3 randomized studies evaluating second-line therapy for chronic GVHD are lacking. In retrospective surveys, ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory or -dependent chronic GVHD.

Methods: This phase 3 open-label, randomized trial evaluated the efficacy and safety of ruxolitinib at a dose of 10 mg twice daily, as compared with the investigator's choice of therapy from a list of 10 commonly used options considered best available care (control), in patients 12 years of age or older with moderate or severe glucocorticoid-refractory or -dependent chronic GVHD. The primary end point was overall response (complete or partial response) at week 24; key secondary end points were failure-free survival and improved score on the modified Lee Symptom Scale at week 24.

Results: A total of 329 patients underwent randomization; 165 patients were assigned to receive ruxolitinib and 164 patients to receive control therapy. Overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; odds ratio, 2.99; P<0.001). Ruxolitinib led to longer median failure-free survival than control (>18.6 months vs. 5.7 months; hazard ratio, 0.37; P<0.001) and higher symptom response (24.2% vs. 11.0%; odds ratio, 2.62; P = 0.001). The most common (occurring in ≥10% patients) adverse events of grade 3 or higher up to week 24 were thrombocytopenia (15.2% in the ruxolitinib group and 10.1% in the control group) and anemia (12.7% and 7.6%, respectively). The incidence of cytomegalovirus infections and reactivations was similar in the two groups.

Conclusions: Among patients with glucocorticoid-refractory or -dependent chronic GVHD, ruxolitinib led to significantly greater overall response, failure-free survival, and symptom response. The incidence of thrombocytopenia and anemia was greater with ruxolitinib. (Funded by Novartis and Incyte; REACH3 ClinicalTrials.gov number, NCT03112603.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2033122DOI Listing
July 2021

Thrombotic Microangiopathy Increases the Risk of Chronic Kidney Disease but Not Overall Mortality in Long-term Transplant Survivors.

Transplant Cell Ther 2021 Oct 1;27(10):864.e1-864.e5. Epub 2021 Jul 1.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Nephrology, Seattle Children's Hospital, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.

Thrombotic microangiopathy (TMA) after allogeneic hematopoietic cell transplant (HCT) is associated with acute kidney injury (AKI) and increased mortality. The impact of TMA on chronic kidney disease (CKD) and long-term mortality among HCT survivors has not been fully examined. To assess the risk of CKD and mortality in HCT survivors with and without history of TMA, we conducted a retrospective cohort study among adult allogeneic HCT recipients who survived to at least 1 year post-transplantation. We examined the association between the history of TMA within 1 year and the onset of CKD longitudinally for 5 years with generalized estimating equation (GEE) while adjusting for other key confounders. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m using the CKD-EPI formula with outpatient creatinine values collected during the annual long-term follow-up unit follow-up visits. Kaplan Meier curves landmarked at 1 year were used for survival analyses. Among 2091 adult patients who underwent allogeneic HCT, we identified 1151 patients who survived at least 1 year and had available long-term follow-up data. Among them, 57 patients developed TMA within 1 year and 1094 did not have TMA. There was no pretransplantation baseline difference in eGFR between groups. After adjusting for confounders, history of TMA was associated with an odds ratio of 2.83 (95% confidence interval 1.33-6.03) for CKD development over 5 years after transplantation. The conditional 5-year survival was 78% in the TMA survivors and 80% in the non-TMA survivors (log rank P = .122). HCT survivors with a history of TMA had increased risk of CKD development. Although TMA was associated with high risk of mortality within 1 year after transplantation, long-term survival was comparable with non-TMA survivors. Future therapeutic interventions should focus on not only short-term mortality outcomes, but also short- and long-term kidney outcomes for HCT patients with TMA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.06.027DOI Listing
October 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478861PMC
October 2021

The disposable bandage soft contact lenses therapy and anterior segment optical coherence tomography for management of ocular graft-versus-host disease.

BMC Ophthalmol 2021 Jul 4;21(1):271. Epub 2021 Jul 4.

Department of Ophthalmology, University of Washington, 1959 NE Pacific St, Washington, Seattle, USA.

Purpose: To identify the ocular surface changes of ocular graft-versus-host disease (GVHD) using anterior segment optical coherence tomography (AS-OCT) and examine the efficacy of disposable bandage soft contact lens (BSCL) treatment in ocular GVHD patients.

Methods: This study is a prospective, Phase II clinical trial. Nineteen patients diagnosed with chronic GVHD based on the NIH criteria and ocular symptoms of NIH eye score 2 or greater were enrolled. Disposable BSCL was applied to the GVHD-affected eyes with topical antibiotic coverage. Ocular exams, eye symptom surveys, and AS-OCT were performed with signed informed consent. Patients were followed for one to three months.

Results: Thirty-eight eyes of 19 patients with ocular GVHD underwent BSCL treatment in this study. AS-OCT scans were done in 14 out of 19 patients. The mean best-corrected visual acuity at enrollment, 2-week, and 4-week visits was 0.180, 0.128, and 0.163 logMAR, respectively. Twenty-four out of 25 eyes (96 %) that initially presented with conjunctival inflammation, twenty-three out of 30 eyes (76.7 %) that initially presented with punctate epithelial erosion, and 8 out of 15 (53.3 %) eyes that initially presented with filamentous keratopathy showed improvement after wearing BSCL for 2 to 4 weeks. AS-OCT revealed corneal epithelial irregularity, abnormal meibomian gland orifice, and conjunctival hyperemia, in patients with ocular GVHD.

Conclusions: BSCL treatment provided significant subjective and objective improvements in ocular GVHD patients. Meanwhile, we found that AS-OCT can be a promising diagnostic tool to characterize the ocular surface changes associated with ocular GVHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12886-021-02031-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254955PMC
July 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403632PMC
September 2021

CMV exposure drives long-term CD57+ CD4 memory T cell inflation following allogeneic stem cell transplant.

Blood 2021 Jun 3. Epub 2021 Jun 3.

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

Donor and recipient cytomegalovirus (CMV) serostatus correlate with transplant related mortality that is associated with reduced survival following allogeneic stem cell transplant (SCT). Prior epidemiologic studies have suggested that CMV seronegative recipients (R-) receiving a CMV seropositive graft (D+) experience inferior outcomes compared to other serostatus combinations, an observation that appears independent of viral reactivation. We therefore investigated the hypothesis that prior donor CMV exposure irreversibly modifies immunologic function after SCT. We identified a CD4+/CD57+/CD27- T cell subset that was differentially expressed between D+ and D- transplants and validated results with 120 patient samples. This T cell subset represents an average of 2.9% (D-/R-), 18% (D-/R+), 12% (D+/R-), and 19.6% (D+/R+) (p<0.0001) of the total CD4+ T cell compartment and stably persists for at least several years post-SCT. Even in the absence of CMV reactivation post-SCT, D+/R- transplants displayed a significant enrichment of these cells compared to D-/R- transplants (p=0.0078). These are effector memory cells (CCR7-/ CD45RA+/-) that express T-bet, EOMES, granzyme B, secrete Th1 cytokines, and are enriched in CMV-specific T cells. These cells are associated with decreased T cell receptor diversity (p<0.0001) and reduced proportions of major histocompatibility class II expressing classical monocytes (p<0.0001), myeloid (p=0.024), and plasmacytoid dendritic cells (p=0.0014). These data describe a highly expanded CD4+ T cell population and putative mechanisms by which prior donor or recipient CMV exposure may create a lasting immunologic imprint following SCT, providing a rationale for using D- grafts for R- transplant recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020009492DOI Listing
June 2021

Impact of anticoagulation on recurrent thrombosis and bleeding after hematopoietic cell transplantation.

Am J Hematol 2021 09 24;96(9):1137-1146. Epub 2021 Jun 24.

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

History of venous thromboembolism (VTE) is prevalent among patients undergoing hematopoietic cell transplantation (HCT). Management of anticoagulation is particularly challenging as most patients will have chemotherapy-induced thrombocytopenia while awaiting engraftment post-HCT. We conducted a retrospective study of autologous and allogeneic HCT recipients with prior VTE from 2006-2015 to 1) compare anticoagulant strategies on short-term VTE recurrence and bleeding and 2) assess predictors for VTE recurrence beyond 30 days. Patients with VTE were allocated to two cohorts based on anticoagulant strategy at thrombocytopenia onset and underwent inverse probability weighting to assess primary outcomes of VTE recurrence and bleeding within 30 days post-HCT. Subsequently, multivariable logistic regression model was used to assess the association of 100-day VTE recurrence by the HIGH-2-LOW VTE risk assessment score and whether patients resumed anticoagulation at platelet recovery. Thirteen percent of recipients had VTE prior to HCT; of those meeting inclusion criteria, 227 continued anticoagulation and 113 temporarily discontinued it. Anticoagulant strategy was not significantly associated with decreased risk of VTE recurrence within 30 days (3% vs 4%, p = 0.61); however, risk of overall bleeding was non-significantly higher in those who continued vs discontinued anticoagulation (41% vs 31%, p = 0.08). In a subgroup of 250 allogeneic HCT patients, every one-point increase of HIGH-2-LOW score was significantly associated with VTE recurrence at 100 days (OR 1.57 [95% CI 1.10-2.23]), while anticoagulation resumption upon platelet engraftment was associated with lower recurrent risk (OR 0.48 [0.20-1.14]). Temporarily withholding anticoagulation during thrombocytopenia may optimize risk-benefit tradeoffs, though additional strategies are essential to prevent VTE recurrence after hematopoietic recovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.26268DOI Listing
September 2021

Long-term neurocognitive and quality of life outcomes in survivors of pediatric hematopoietic cell transplant.

J Cancer Surviv 2021 Jun 4. Epub 2021 Jun 4.

Department of Pediatrics, Division of Hematology/Oncology, University of Washington, Seattle Children's Hospital, 4600 Sand Point Way NE, Seattle, WA, 98105, USA.

Purpose: Pediatric patients who undergo hematopoietic cell transplant (HCT) are at risk for neurocognitive impairments, which can impact quality of life. Given limited long-term studies, we aimed to characterize the late neurocognitive outcomes in a cohort of pediatric HCT survivors.

Methods: Eligible survivors (HCT at age < 21 year and ≥ 1 year post-HCT) completed a 60-question survey of neurocognitive function and quality of life, which included the Childhood Cancer Survivor Study Neurocognitive Questionnaire (CCSS-NCQ) and the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL). Analyses of risk factors included univariate comparisons and multivariable logistic regression.

Results: Participants (n = 199, 50.3% female, 53.3% acute leukemia, 87.9% allogeneic transplants) were surveyed at median age of 37.8 years (interquartile range [IQR] 28.5-48.8) at survey and median 27.6 years (IQR 17.0-34.0) from transplant. On the CCSS-NCQ, 18.9-32.5% of survivors reported impairments (Z score > 1.28) in task efficiency, memory, emotional regulation, or organization, compared with expected 10% in the general population (all p < 0.01). In contrast, survivors reported average Neuro-QoL (T score 49.6±0.7) compared with population normative value of 50 (p = 0.52). In multivariable regression, impaired Neuro-QoL (T score < 40) was independently associated with hearing issues (OR 4.97, 95% CI 1.96-12.6), history of stroke or seizure (OR 4.46, 95% CI 1.44-13.8), and sleep disturbances (OR 6.95, 95% CI 2.53-19.1).

Conclusions: Although long-term survivors of pediatric HCT reported higher rates of impairment in specific neurocognitive domains, cognitive quality of life was perceived as similar to the general population. Subsets of survivors with certain co-morbidities had substantially worse neurocognitive outcomes.

Implications For Cancer Survivors: While the long-term impact of pediatric HCT can include neurocognitive deficits, survivors report average cognitive quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11764-021-01063-1DOI Listing
June 2021

Sclerotic chronic GVHD: you may WANT to block WNT.

Authors:
Stephanie J Lee

Blood 2021 Apr;137(17):2284

Fred Hutchinson Cancer Research Center.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021010953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085478PMC
April 2021

Multi-Site 11-Year Experience of Less-Intensive versus Intensive Therapies in Acute Myeloid Leukemia.

Blood 2021 04 28. Epub 2021 Apr 28.

University of Washington School of Medicine, United States.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia, assuming they are better than intensive induction. Using an AML-composite model (AML-CM) that assigns higher scores to older age, increased comorbidity-burdens and adverse cytogenetic-risks, we defined three distinct prognostic groups, and within each, compared outcomes after less-intensive versus intensive induction therapies in a multicenter retrospective cohort (n=1292) treated at six institutions from 2008-2012 and a prospective cohort (n=695) treated at thirteen institutions from 2013-2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physicians' perceptions of cure. In the retrospective cohort, recipients of less-intensive therapies were older, had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks for mortality in AML-CM scores of 4-6, 7-9, and ≥10. Results were independent from receipt of allogeneic transplants and similar in those aged 70-79 years old. In the Prospective cohort, the two groups were similar in baseline QOL, geriatric assessment, and patients' outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS and chances of cure, mortality risks and QOL were similar. Less-intensive recipients had lessened length of hospitalization (LOH). Our studies question the survival or QOL, except LOH, benefits from less-intensive therapies in patients with AML, including those aged 70-79 years or with high comorbidity-burden. A randomized trial in older/medically infirm patients is needed to better assess the value of less-intensive, intensive, or a combination of both therapies. ClinicalTrials.gov #NCT01929408.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020008812DOI Listing
April 2021

A positive psychology intervention to promote health outcomes in hematopoietic stem cell transplantation: the PATH proof-of-concept trial.

Bone Marrow Transplant 2021 09 20;56(9):2276-2279. Epub 2021 Apr 20.

Harvard Medical School, Boston, MA, USA.

Allogeneic hematopoietic stem cell transplantation (HSCT) recipients often experience deficits in positive psychological well-being (PPWB) due to intensive treatment and follow-up care. Positive psychology interventions (PPIs) that promote PPWB via deliberate and systematic exercises (e.g., writing a gratitude letter) have consistently improved PPWB in medical populations, yet have never been studied in early HSCT recovery. In this single-arm, proof-of-concept study, we assessed the feasibility and acceptability of a novel eight-session, telephone-delivered PPI in early HSCT recovery. A priori, we defined feasibility as >50% of eligible patients enrolling in the study and >50% of participants completing 5/8 sessions, and acceptability as mean ease and utility scores of weekly participant ratings of PP exercises as 7/10. Of 45 eligible patients, 25 (55.6%) enrolled, 20 (80%) completed baseline assessments, 15 (75%) started the intervention, and 12 (60%) completed the intervention and follow-up assessments. The intervention was feasible (55.6% of eligible participants enrolled; 60% of baseline assessment completers finished 5/8 sessions) and led to very small-to-medium effect-size improvements in patient-reported outcomes. A novel, eight-week, telephone-delivered PPI was feasible and acceptable in allogeneic HSCT recipients. Larger, randomized studies are needed to examine the efficacy of PPIs for improving outcomes in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-021-01296-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416696PMC
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217141PMC
June 2021

ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease.

J Clin Oncol 2021 06 20;39(17):1888-1898. Epub 2021 Apr 20.

Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: The rho-associated coiled-coil-containing protein kinase-2 (ROCK2) signaling pathway regulates the Th17/regulatory T cells balance and controls profibrotic pathways. Selective ROCK2 inhibition with belumosudil (KD025) may offer a novel approach to the management of chronic graft-versus-host disease (cGVHD).

Patients And Methods: A phase IIa, open-label, dose-finding study of belumosudil enrolled 54 patients with cGVHD who had received one to three prior lines of therapy (LOTs). The primary end point was overall response rate (ORR).

Results: The median time from cGVHD diagnosis to enrollment was 20 months. Seventy-eight percent of patients had severe cGVHD, 50% had ≥ 4 organs involved, 73% had cGVHD refractory to their last LOT, and 50% had received ≥ 3 prior LOTs. With an overall median follow-up of 29 months, the ORR (95% CI) with belumosudil 200 mg once daily, 200 mg twice daily, and 400 mg once daily was 65% (38% to 86%), 69% (41% to 89%), and 62% (38% to 82%), respectively. Responses were clinically meaningful, with a median duration of response of 35 weeks, and were associated with quality-of-life improvements and corticosteroid (CS) dose reductions. CS treatment was discontinued in 19% of patients. The failure-free survival rate was 76% (62% to 85%) and 47% (33% to 60%) at 6 and 12 months, respectively. The 2-year overall survival rate was 82% (69% to 90%). Belumosudil was well-tolerated, with low rates of cytopenia. There were no unexpected adverse events and no apparent increased risk of infection, including cytomegalovirus infection and reactivation.

Conclusion: Belumosudil treatment resulted in a high ORR and overall survival rate and demonstrated quality-of-life improvements, CS dose reductions, and limited toxicity. Data from the study indicated that belumosudil may prove to be an effective therapy for patients with treatment-refractory cGVHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.02754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189612PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.03.033DOI Listing
July 2021

Epigenetic Aging and Hematopoietic Cell Transplantation in Patients With Severe Aplastic Anemia.

Transplant Cell Ther 2021 04 16;27(4):313.e1-313.e8. Epub 2021 Jan 16.

Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Cellular aging in hematopoietic cell transplantation (HCT) is important in the context of immune reconstitution and age-related complications. Recently, several DNA-methylation (DNAm)-based biomarkers of aging known as "epigenetic clocks" have been introduced as novel tools to predict cellular age. Here, we used Cox proportional hazards models to assess the possible associations of donor pre-HCT DNAm age, and its post-HCT changes, using the recently published lifespan-associated epigenetic clock known as "DNAm-GrimAge," with outcomes among patients with severe aplastic anemia (SAA). The study included 732 SAA patients from the Transplant Outcomes in Aplastic Anemia project, who underwent unrelated donor HCT and for whom a donor pre-HCT blood DNA sample was available; 41 also had a post-HCT sample collected at day 100. In multivariable analyses, we found similar associations for donor chronological age and pre-HCT DNAm-GrimAge with post-HCT survival (hazard ratio [HR] per decade = 1.13; 95% confidence interval [CI], 0.99-1.28; P = .07 and HR = 1.14; 95% CI, 0.99-1.28; P = .06, respectively). In donors with 10+ years of GrimAge acceleration (ie, deviation from expected DNAm age for chronological age), elevated risks of chronic graft versus host disease (HR = 2.4; 95% CI, 1.21-4.65; P = .01) and possibly post-HCT mortality (HR = 1.79; 95% CI, 0.96-3.33; P = .07) were observed. In the subset with post-HCT samples, we observed a significant increase in DNAm-GrimAge in the first 100 days after HCT (median change 12.5 years, range 1.4 to 26.4). Higher DNAm-GrimAge after HCT was associated with inferior survival (HR per year = 1.11; 95% CI, 1.02-1.21; P = .01), predominantly within the first year after HCT. This study highlights the possible role cellular aging may play in HCT outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036238PMC
April 2021

Prognostic Biomarkers for Thrombotic Microangiopathy after Acute Graft-versus-Host Disease: A Nested Case-Control Study.

Transplant Cell Ther 2021 04 16;27(4):308.e1-308.e8. Epub 2020 Dec 16.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Nephrology, Seattle Children's Hospital, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a complication of allogeneic hematopoietic cell transplantation (HCT) that often occurs following the development of acute graft-versus-host disease (aGVHD). In this study, we aimed to identify early TMA biomarkers among patients with aGVHD. We performed a nested-case-control study from a prospective cohort of allogeneic HCT recipients, matching on the timing and severity of antecedent aGVHD. We identified 13 TMA cases and 25 non-TMA controls from 208 patients in the cohort. Using multivariable conditional logistic regression, the odds ratio for TMA compared with non-TMA was 2.65 (95% confidence interval [CI], 1.00 to 7.04) for every 100 ng/mL increase in terminal complement complex sC5b9 and 2.62 (95% CI, 1.56 to 4.38) for every 1000 pg/mL increase in angiopoietin-2 (ANG2) at the onset of aGVHD. ADAMTS13 and von Willebrand factor (VWF) antigens were not appreciably associated with TMA. Using a Cox regression model incorporating sC5b9 >300 ng/mL and ANG2 >3000 pg/mL at the onset of aGVHD, the adjusted hazard ratio for mortality was 5.33 (95% CI, 1.57 to 18.03) for the high-risk group (both elevated) and 4.40 (95% CI, 1.60 to 12.07) for the intermediate-risk group (one elevated) compared with the low-risk group (neither elevated). In conclusion, we found that elevated sC5b9 and ANG2 levels at the onset of aGVHD were associated with the development of TMA and possibly mortality after accounting for the timing and severity of aGVHD. The results suggest important roles of complement activation and endothelial dysfunction in the pathogenesis of TMA. Measurement of these biomarkers at the onset of aGVHD may inform prognostic enrichment for preventive trials and improve clinical care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2020.12.010DOI Listing
April 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.03.029DOI Listing
August 2021

Impact of Previously Unrecognized HLA Mismatches Using Ultrahigh Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation.

J Clin Oncol 2021 Jul 9;39(21):2397-2409. Epub 2021 Apr 9.

Anthony Nolan Research Institute, Royal Free Hospital, London, UK.

Purpose: Ultrahigh resolution (UHR) HLA matching is reported to result in better outcomes following unrelated donor hematopoietic cell transplantation, improving survival and reducing post-transplant complications. However, most studies included relatively small numbers of patients. Here we report the findings from a large, multicenter validation study.

Methods: UHR HLA typing was available on 5,140 conventionally 10 out of 10 HLA-matched patients with malignant disease transplanted between 2008 and 2017.

Results: After UHR HLA typing, 82% of pairs remained 10 out of 10 UHR-matched; 12.3% of patients were 12 out of 12 UHR HLA-matched. Compared with 12 out of 12 UHR-matched patients, probabilities of grade 2-4 acute graft-versus-host disease (aGVHD) were significantly increased with UHR mismatches (overall = .0019) and in those patients who were HLA-DPB1 T-cell epitope permissively mismatched or nonpermissively mismatched (overall = .0011). In the T-cell-depleted subset, the degree of UHR HLA mismatch was only associated with increased transplant-related mortality (TRM) (overall = .0068). In the T-cell-replete subset, UHR HLA matching was associated with a lower probability of aGVHD (overall = .0020); 12 out of 12 UHR matching was associated with reduced TRM risk when compared with HLA-DPB1 T-cell epitope permissively mismatched patients, whereas nonpermissive mismatching resulted in a greater risk (overall = .0003).

Conclusion: This study did not confirm that UHR 12 out of 12 HLA matching increases the probability of overall survival but does demonstrate that aGVHD risk, and in certain settings TRM, is lowest in UHR HLA-matched pairs and thus warrants consideration when multiple 10 out of 10 HLA-matched donors of equivalent age are available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.03643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280068PMC
July 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.

View Article and Find Full Text PDF

Download full-text PDF

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