ABSTRACT
Chronic graft-vs.-host disease (GVHD) is associated with morbidity, mortality, impaired quality of life, prolonged immunosuppressive (IS) therapy, and infection risk after allogeneic hematopoietic cell transplantation (HCT). Major strides have occurred in the understanding of chronic GVHD biology, NIH Consensus meetings have refined rigorous approaches to diagnosis, staging and response criteria, major interventional trials have established standard benchmarks for treatment outcome, and three agents to date have been FDA-approved for treating steroid-refractory chronic GVHD. Promising results from several recent trials have led some but not others to conclude that the risk of developing chronic GVHD is sufficiently low to by-and-large be considered a major post-HCT complication of the past. We propose that it is time to critically examine the results of contemporary GVHD prophylaxis regimens and discuss the state-of-the-science and associated controversies in spectrum of conclusions reached as to the risk of chronic GVHD. With these data, the current chronic GVHD incidence can be most precisely determined, and the present and future burden of chronic GVHD-affected patients be accurately modeled. Through review of existing evidence, we highlight unresolved needs and opportunities to refine best GVHD prophylaxis or preemptive therapy approaches, optimize established chronic GVHD therapy, and make the argument that support of preclinical and clinical research is critical in improving patient outcomes.
ABSTRACT
Our phase I graft-versus-host disease (GVHD) prevention trial of JAK2 inhibitor, pacritinib, (recommended phase II dose: 100mg po BID day 0 to +70) plus sirolimus and tacrolimus (PAC/SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits IL-6 receptor activity and pathogenic Th1/Th17 differentiation in preclinical models and the phase I trial. Herein we report on our completed phase II trial of PAC/SIR/TAC after 8/8-HLA matched alloHCT. This single-arm phase II trial (NCT02891603) was powered to determine if PAC/SIR/TAC suppressed %pSTAT3+ CD4+ T cells at day +21 (primary endpoint: %pSTAT3+ CD4+ T cells ≤ 35%) and estimated grade II-IV acute GVHD by day +100. The impact of PAC/SIR/TAC on T cell subsets, CD28 (pS6 and pH3ser10), and IL-2 receptor (pSTAT5) signal transduction was also evaluated. Eligible patients (n=28) received alloHCT for hematologic malignancies or myeloproliferative neoplasms. Reduced or myeloablative intensity conditioning was permitted. PAC/SIR/TAC met the primary endpoint, reducing %pSTAT3+ CD4+ T cells to 9.62% at day +21. Th1/Th17 cells were decreased at day +21, increasing the ratio of Tregs to Th1 and Th17 cells with PAC/SIR/TAC at RP2D PAC compared to dose level 1 PAC. The cumulative incidence of grade II-IV acute GVHD by day +100 with PAC/SIR/TAC was similar to historic SIR/TAC values (46 v 43%). While PAC/SIR/TAC suppressed pSTAT3 and Th1/Th17 cells, the regimen did not improve acute GVHD prevention.
ABSTRACT
Chronic graft-versus-host disease (cGvHD) is a common complication after allogeneic haematopoietic stem cell transplantation, characterised by a broad disease spectrum that can affect virtually any organ. Although pulmonary cGvHD is a less common manifestation, it is of great concern due to its severity and poor prognosis. Optimal management of patients with pulmonary cGvHD is complicated and no standardised approach is available. The purpose of this joint European Respiratory Society (ERS) and European Society for Blood and Marrow Transplantation task force was to develop evidence-based recommendations regarding the treatment of pulmonary cGvHD phenotype bronchiolitis obliterans syndrome in adults. A multidisciplinary group representing specialists in haematology, respiratory medicine and methodology, as well as patient advocates, formulated eight PICO (patient, intervention, comparison, outcome) and two narrative questions. Following the ERS standardised methodology, we conducted systematic reviews to address these questions and used the Grading of Recommendations Assessment, Development and Evaluation approach to develop recommendations. The resulting guideline addresses common therapeutic options (inhalation therapy, fluticasone-azithromycin-montelukast, imatinib, ibrutinib, ruxolitinib, belumosudil, extracorporeal photopheresis and lung transplantation), as well as other aspects of general management, such as lung functional and radiological follow-up and pulmonary rehabilitation, for adults with pulmonary cGvHD phenotype bronchiolitis obliterans syndrome. These recommendations include important advancements that could be incorporated in the management of adults with pulmonary cGvHD, primarily aimed at improving and standardising treatment and improving outcomes.
Subject(s)
Bronchiolitis Obliterans Syndrome , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Lung Transplantation , Adult , Humans , Graft vs Host Disease/therapy , Graft vs Host Disease/etiology , Lung , Hematopoietic Stem Cell Transplantation/adverse effects , Lung Transplantation/adverse effects , Chronic DiseaseABSTRACT
Hematopoietic cell transplantation (HCT) is the only potentially curative treatment option for many patients with hematologic malignancies. While HCT outcomes have improved drastically over the years, patients and clinicians continue to face numerous survivorship challenges, such as relapse, graft-versushost disease, and secondary malignancies. Recent literature suggests that clonal hematopoiesis (CH), the presence of a recurrent somatic mutation in hematopoietic cells, in HCT patients or donors may be associated with outcomes in autologous and allogeneic HCT. Herein, we perform a review of the literature and summarize reported associations between CH and clinical outcomes in HCT. For commonly reported outcomes, we used meta-analysis methods to provide estimates of effect sizes when combining results. A total of 32 articles with relevant and independent contributions were included, covering both autologous (n = 19) and allogeneic (n = 13) HCT. The articles report variable risk for developing outcomes according to CH characteristics, patient disease status, and method of HCT. Using meta-analysis of available results, HCT outcomes with statistically significant effects by CH status include therapy-related myeloid neoplasms (OR 3.65, 95%CI 2.18-6.10) and overall survival (HR 1.38, 95%CI 1.20-1.58) in autologous HCT and relapse (HR 0.80, 95%CI 0.68-0.94) in allogeneic HCT. However, heterogeneity, biases, and limitations in the literature provide challenges for informing the translation of CH to clinical decision-making. We conclude with a call to action and discussion of next steps to build upon the current literature and provide granularity to the true clinical impact of CH in the setting of HCT.
ABSTRACT
Chronic graft-versus-host disease (GvHD) treatment response is assessed using National Institutes of Health (NIH) Consensus Criteria in clinical trials, and by clinician assessment in routine practice. Patient-reported treatment response is central to the experience of chronic GvHD manifestations as well as treatment benefit and toxicity, but how they correlate with clinician- or NIH-responses has not been well-studied. We aimed to characterize 6-month patientreported response, determine associated chronic GvHD baseline organ features and changes, and evaluate which patientreported quality of life and chronic GvHD symptom burden measures correlated with patient-reported response. From two nationally representative Chronic GVHD Consortium prospective observational studies, 382 subjects were included in this analysis. Patient and clinician responses were categorized as improved (completely gone, very much better, moderately better, a little better) versus not improved (about the same, a little worse, moderately worse, very much worse). At six months, 270 (71%) patients perceived chronic GvHD improvement, while 112 (29%) perceived no improvement. Patient-reported response had limited correlation with either clinician-reported (kappa 0.37) or NIH chronic GvHD response criteria (kappa 0.18). Notably, patient-reported response at six months was significantly associated with subsequent failure-free survival. In multivariate analysis, NIH responses in eye, mouth, and lung had significant association with 6-month patient-reported response, as well as a change in Short Form 36 general health and role physical domains and Lee Symptom Score skin and eye changes. Based on these findings, patient-reported responses should be considered as an important complementary endpoint in chronic GvHD clinical trials and drug development.
Subject(s)
Bronchiolitis Obliterans Syndrome , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Humans , Quality of Life , Hematopoietic Stem Cell Transplantation/adverse effects , Graft vs Host Disease/diagnosis , Graft vs Host Disease/etiology , Graft vs Host Disease/therapy , Chronic Disease , Patient Reported Outcome MeasuresABSTRACT
OBJECTIVE: Depression and fatigue are common among cancer patients and are associated with germline genetic variation. The goal of this pilot study was to examine genetic associations with depression and fatigue in the year after allogeneic hematopoietic cell transplant (HCT). METHODS: Blood was collected from patients and their donors before HCT. Patients completed self-report measures of depression and fatigue before HCT (T1), 90 days post-HCT (T2), and 1 year post-HCT (T3). Of the 384 genetic variants genotyped on a custom Illumina BeadChip microarray, 267 were retained for analysis based on quality control. Main effects of patient and donor variants as well as their interaction were examined using regression analyses. Significant variants were defined as those with a false discovery rate-adjusted p value of <.05. RESULTS: The sample consisted of 59 patient-donor pairs. Mean levels of depression and fatigue did not change significantly over time ( p values of > .41). Increases in depression from T1 to T2 were associated with patient-donor interactions at rs1928040 ( p = 3.0 × 10 -4 ) and rs6311 ( p = 2.0 × 10 -4 ) in HTR2A . Increases in fatigue from T1 to T2 were associated with patient rs689021 in SORL1 ( p = 6.0 × 10 -5 ) and a patient-donor interaction at rs1885884 in HTR2A ( p < 1.0 × 10 -4 ). CONCLUSIONS: Data suggest that variants in genes regulating the serotonergic system ( HTR2A ) and lipid metabolism ( SORL1 ) are associated with changes in depression and fatigue in allogeneic HCT patients, implicating patients' own genetic inheritance as well as that of donors. Additional studies are warranted to confirm these findings.
Subject(s)
Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Depression/genetics , Pilot Projects , Transplantation, Homologous , Hematologic Neoplasms/complications , Hematologic Neoplasms/genetics , Hematologic Neoplasms/therapy , Fatigue/genetics , Germ Cells , LDL-Receptor Related Proteins , Membrane Transport ProteinsABSTRACT
Successful treatment of chronic graft-versus-host disease (GvHD) often requires long-term systemic therapy (ST). Durable discontinuation of ST reflects the resolution of active chronic GvHD. We evaluated the factors associated with durable ST discontinuation, defined as cessation of all ST for ≥12 months, using data from two prospectively followed cohorts from the Chronic GvHD Consortium (n=684). Transplant sources were peripheral blood (89%), bone marrow (6.6%), and cord blood (4.4%) from HLA matched related (37.6%), HLA matched unrelated (45%), and other donor types (18%). Half of the patients received non-myeloablative conditioning. The median time from transplantation to chronic GvHD diagnosis was 7.7 months (range, 1.0-141.3) and the median time from chronic GvHD onset to enrollment into the cohorts was 0.9 months (range, 0.0-12.0). The cumulative incidence estimate of durable ST discontinuation was 32% (95% confidence interval: 28%-37%) at 10 years after enrollment into the cohort. Among patients who discontinued ST, the median time from chronic GvHD diagnosis to durable ST discontinuation was 3.6 years (range, 1.2-10.5). In multivariate analysis, patients who received myeloablative conditioning, had chronic GvHD manifested as moderate/severe lower gastrointestinal involvement, and had a higher (worse) Lee symptom overall score were less likely to attain durable ST discontinuation. In contrast, mild lower gastrointestinal involvement and cord blood (vs. peripheral blood) as the graft source were associated with a greater likelihood of ST discontinuation. Although a minority of patients can discontinue ST permanently, most patients require prolonged ST. Viewing chronic GvHD in this way has implications for management approaches.
Subject(s)
Bronchiolitis Obliterans Syndrome , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Humans , Graft vs Host Disease/diagnosis , Graft vs Host Disease/drug therapy , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Transplantation, Homologous/adverse effects , Tissue Donors , Transplantation Conditioning/adverse effectsABSTRACT
Prevention of allograft rejection often requires lifelong immune suppression, risking broad impairment of host immunity. Nonselective inhibition of host T cell function increases recipient risk of opportunistic infections and secondary malignancies. Here we demonstrate that AJI-100, a dual inhibitor of JAK2 and Aurora kinase A, ameliorates skin graft rejection by human T cells and provides durable allo-inactivation. AJI-100 significantly reduces the frequency of skin-homing CLA+ donor T cells, limiting allograft invasion and tissue destruction by T effectors. AJI-100 also suppresses pathogenic Th1 and Th17 cells in the spleen yet spares beneficial regulatory T cells. We show dual JAK2/Aurora kinase A blockade enhances human type 2 innate lymphoid cell (ILC2) responses, which are capable of tissue repair. ILC2 differentiation mediated by GATA3 requires STAT5 phosphorylation (pSTAT5) but is opposed by STAT3. Further, we demonstrate that Aurora kinase A activation correlates with low pSTAT5 in ILC2s. Importantly, AJI-100 maintains pSTAT5 levels in ILC2s by blocking Aurora kinase A and reduces interference by STAT3. Therefore, combined JAK2/Aurora kinase A inhibition is an innovative strategy to merge immune suppression with tissue repair after transplantation.
Subject(s)
Aurora Kinase A , Immunity, Innate , Animals , Aurora Kinase A/metabolism , Graft Rejection/etiology , Graft Rejection/prevention & control , Humans , Janus Kinase 2 , Mice , Mice, Inbred C57BL , Th17 Cells , Transplantation, HomologousABSTRACT
Clinical- and biomarker-based tools may identify a lower-risk acute graft-versus-host disease (GVHD) population amenable to novel, reduced-intensity treatments. Previous data suggest sirolimus may rival standard of care prednisone. We conducted a National Heart, Lung, and Blood Institute/National Cancer Institute-funded Blood and Marrow Transplant Clinical Trials Network multicenter, open-label, randomized phase 2 trial to estimate the difference in day 28 complete response (CR)/partial response (PR) rates for sirolimus vs prednisone as initial treatment of patients with standard risk (SR) acute GVHD as defined by the Minnesota (MN) GVHD Risk Score and Ann Arbor (AA1/2) biomarker status. A total of 127 MN-SR patients were randomized (1:1), and 122 were AA1/2 (sirolimus, n = 58; prednisone, n = 64). Others were AA3 (n = 4), or AA status missing (n = 1). The day 28 CR/PR rates were similar for sirolimus 64.8% (90% confidence interval [CI], 54.1%-75.5%) vs 73% (90% CI, 63.8%-82.2%) for prednisone. The day 28 rate of CR/PR with prednisone ≤0.25 mg/kg/day was significantly higher for sirolimus than prednisone (66.7% vs 31.7%; P < .001). No differences were detected in steroid-refractory acute GVHD, disease-free survival, relapse, nonrelapse mortality, or overall survival. Sirolimus was associated with reduced steroid exposure and hyperglycemia, reduced grade 2 to 3 infections, improvement in immune suppression discontinuation and patient-reported quality of life, and increased risk for thrombotic microangiopathy. For patients with clinical- and biomarker-based SR acute GVHD, sirolimus demonstrates similar overall initial treatment efficacy as prednisone. In addition, sirolimus therapy spares steroid exposure and allied toxicity, does not compromise long-term survival outcomes, and is associated with improved patient-reported quality of life. This trial was registered at www.clinicaltrials.gov as #NCT02806947.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Graft vs Host Disease/drug therapy , Prednisone/therapeutic use , Sirolimus/therapeutic use , Acute Disease , Adolescent , Adult , Aged , Antineoplastic Agents, Hormonal , Bone Marrow Transplantation/adverse effects , Child , Child, Preschool , Female , Follow-Up Studies , Graft vs Host Disease/pathology , Humans , Infant , Male , Middle Aged , Prognosis , Survival Rate , Young AdultABSTRACT
Ruxolitinib for steroid-refractory acute graft-versus-host disease (SR-aGVHD) results in resistance or intolerance in 1/5 of patients. Outcomes of such patients are undefined. We identified these patients in a multicentre review and reported outcomes. Ruxolitinib-resistant aGVHD was identified in 48/307 patients. Among patients receiving additional therapy, the overall response rate to next therapy was 36%. Median survival was 21 days. Ruxolitinib intolerance led to treatment discontinuation in 16/307 patients. Ten intolerant patients received additional therapy with 50% experiencing continued improvement of aGVHD. Median survival was 50 days in these patients. These data serve as a baseline for future SR-aGVHD studies.
Subject(s)
Graft vs Host Disease/drug therapy , Nitriles/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Acute Disease , Adult , Aged , Allografts , Bone Marrow Transplantation/adverse effects , Cord Blood Stem Cell Transplantation/adverse effects , Drug Resistance , Female , Graft vs Host Disease/mortality , Graft vs Host Disease/prevention & control , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Nitriles/adverse effects , Nitriles/therapeutic use , Peripheral Blood Stem Cell Transplantation/adverse effects , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Retrospective Studies , Salvage Therapy , Young AdultABSTRACT
Allogeneic hematopoietic cell transplantation involves consideration of both donor and recipient characteristics to guide the selection of a suitable graft. Sufficient high-resolution donor-recipient HLA match is of primary importance in transplantation with adult unrelated donors, using conventional graft-versus-host disease prophylaxis. In cord blood transplantation, optimal unit selection requires consideration of unit quality, cell dose and HLA-match. In this summary, the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow Transplant Research, jointly with the NMDP Histocompatibility Advisory Group, provide evidence-based guidelines for optimal selection of unrelated donors and cord blood units.
Subject(s)
Cord Blood Stem Cell Transplantation/standards , Donor Selection/standards , Fetal Blood , Hematopoietic Stem Cell Transplantation/standards , Unrelated Donors , Adult , Cord Blood Stem Cell Transplantation/methods , Donor Selection/methods , Fetal Blood/immunology , Graft vs Host Disease/immunology , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/methods , Histocompatibility Testing/methods , Histocompatibility Testing/standards , Humans , Infant, Newborn , Registries , Unrelated Donors/supply & distributionABSTRACT
Janus kinase 2 (JAK2) signal transduction is a critical mediator of the immune response. JAK2 is implicated in the onset of graft-versus-host disease (GVHD), which is a significant cause of transplant-related mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Transfer of JAK2-/- donor T cells to allogeneic recipients leads to attenuated GVHD yet maintains graft-versus-leukemia. Th1 differentiation among JAK2-/- T cells is significantly decreased compared with wild-type controls. Conversely, iTreg and Th2 polarization is significantly increased among JAK2-/- T cells. Pacritinib is a multikinase inhibitor with potent activity against JAK2. Pacritinib significantly reduces GVHD and xenogeneic skin graft rejection in distinct rodent models and maintains donor antitumor immunity. Moreover, pacritinib spares iTregs and polarizes Th2 responses as observed among JAK2-/- T cells. Collectively, these data clearly identify JAK2 as a therapeutic target to control donor alloreactivity and promote iTreg responses after allo-HCT or solid organ transplantation. As such, a phase I/II acute GVHD prevention trial combining pacritinib with standard immune suppression after allo-HCT is actively being investigated (https://clinicaltrials.gov/ct2/show/NCT02891603).
Subject(s)
Cell Differentiation , Graft vs Host Disease/immunology , Graft vs Leukemia Effect/immunology , Janus Kinase 2/physiology , Primary Myelofibrosis/immunology , T-Lymphocytes/immunology , Th2 Cells/immunology , Animals , Female , Graft vs Host Disease/genetics , Graft vs Host Disease/prevention & control , Graft vs Leukemia Effect/genetics , Lymphocyte Activation , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Primary Myelofibrosis/genetics , Primary Myelofibrosis/prevention & control , Skin Transplantation , Xenograft Model Antitumor AssaysABSTRACT
Previously reported experimental and clinical data suggest that proteasome inhibition may have immunomodulatory activity relevant to graft-versus-host disease (GVHD). To explore the safety and activity of carfilzomib in advanced chronic GVHD, we conducted a multicenter pilot phase II trial through the Chronic GVHD Consortium. Carfilzomib was administered at 20 mg/m2 on day 1, then 36 mg/m2 on days 8 and 15 of a 28-day treatment cycle (cycle 1), and then 36 mg/m2 on days 1, 8, and 15 of a 28-day treatment cycle (cycles 2 to 6). The primary endpoint was 6-month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic immunosuppressive therapy. A total of 20 subjects were enrolled at 4 institutions. The median time from chronic GVHD onset to enrollment was 1.5 years (interquartile range, 0.5 to 3.7 years). Chronic GVHD was National Institutes of Health category moderate (30%) or severe (70%), predominantly classic (90% versus overlap 10%), and involved multiple diverse organ sites. The number of previous lines of systemic therapy for chronic GVHD was ≤2 in 6 patients (30%) and ≥3 in the other 14 (70%). Doses were held primarily for infection (50% of total held doses); only 3 patients (15%) completed all planned doses of the 6 cycles of carfilzomib. Serious adverse effects occurred in 40% of the patients, and 7 patients died, between .3 and 9 months after the last carfilzomib dose, but no deaths were attributed to carfilzomib. The 6-month treatment failure rate was not significantly improved versus the historical benchmark rate (40% versus 44%; Pâ¯=â¯.36). Overall survival was 80% at 6 months and 65% at 12 months. Failure-free survival at 12 months was 32%. These pilot phase II data suggest that carfilzomib therapy in this advanced chronic GVHD population did not improve over the expected 6-month treatment failure rates achieved under conventional practices and is not recommended for further study for this indication.
Subject(s)
Graft vs Host Disease , Chronic Disease , Graft vs Host Disease/drug therapy , Humans , Oligopeptides/therapeutic use , RecurrenceABSTRACT
New interventions are needed in advanced chronic graft-versus-host disease (GVHD). In a phase II, single-arm, multicenter trial, we examined the efficacy of ixazomib in patients with chronic GVHD who had progressed after at least 1 previous line of systemic immunosuppressive (IS) therapy. Ixazomib was given as a 4 mg oral dose weekly on days 1, 8, and 15 of a 28-day cycle for up to 6 total cycles. The primary endpoint was 6-month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic IS therapy. A total of 50 subjects were enrolled at 6 institutions. The median time from the onset of chronic GVHD to enrollment was 2.8 years (interquartile range, 1.5 to 4.3 years). The degree of chronic GVHD at enrollment was National Institutes of Health (NIH)-defined moderate (16%) or severe (84%), predominantly classic (80% versus 20% overlap), with 52% of patients having involvement of 4 or more organs. The patients were heavily pretreated, with 39 (78%) receiving 3 or more previous lines of systemic therapy for chronic GVHD. Of the 50 patients treated, 26 completed 6 months of planned therapy. The 6-month treatment failure rate was significantly lower than the historical benchmark (28% versus 44%; Pâ¯=â¯.01) previously established in second-line therapy for chronic GVHD. No patient, transplantation, or chronic GVHD variables were significantly associated with 6-month treatment failure. NIH-defined overall response rate was 40% at 6 months. Overall survival was 92% at 6 months and 90% at 12 months. Ixazomib met the primary endpoint of low treatment failure at 6 months in the setting of advanced chronic GVHD. At 6 months, the NIH-defined rate of complete/partial response was 40%, and 52% of patients remained on ixazomib therapy, suggesting that the low treatment failure rate was due in part due to prevention of progressive disease that would have required additional treatment.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Boron Compounds/therapeutic use , Chronic Disease , Glycine/analogs & derivatives , Glycine/therapeutic use , Graft vs Host Disease/drug therapy , HumansABSTRACT
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.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Chronic Disease , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Karnofsky Performance Status , Quality of LifeABSTRACT
Systemic glucocorticoids remain the standard treatment for gastrointestinal (GI) acute graft-versus-host disease (aGVHD) despite their toxicity and incomplete efficacy. Controlled trials have tested poorly absorbable steroids as adjuncts with systemic glucocorticoids, but only small case series have reported treatment with poorly absorbed beclomethasone dipropionate (BDP) and budesonide (BUD) alone. Our team has adopted the practice of administering BDP or BDP+BUD without systemic glucocorticoids as first-line therapy for isolated upper GI (UGI) aGVHD. We report results in 76 patients treated with BDP alone and in 81 patients treated with BDP+BUD, with allocation by physician choice. Almost all patients received peripheral blood stem cells (92%) from a fully HLA-matched related or unrelated donor (80%) after myeloablative conditioning (76%) for acute leukemia (49%), myelodysplastic syndrome (17%), non-Hodgkin lymphoma (14%), or another hematopoietic disorders (20%). After 28 days of treatment with BDP, 46% of the patients had a complete response (CR) and 10% had a partial response (PR); after 200 days, 61 (80%) patients were alive, 34% maintained a CR, and 3% maintained a PR, whereas 53% required additional immunosuppression (IS). After 28 days of treatment with BDP+BUD, 67% had a CR and 10% a PR; after 200 days, 74 (91%) patients were alive, 46% maintained a CR, and 2% maintained a PR, whereas 43% required additional IS. Among the entire cohort of 157 patients, 66 (42%) were treated successfully without systemic glucocorticoids. This study reports the efficacy of poorly absorbable steroids alone for patients with isolated UGI aGVHD. Prospective trials should test for the potential advantages of BDP and BUD use over systemic glucocorticoids.
Subject(s)
Anti-Inflammatory Agents , Beclomethasone , Budesonide , Graft vs Host Disease , Adult , Aged , Anti-Inflammatory Agents/therapeutic use , Beclomethasone/therapeutic use , Budesonide/therapeutic use , Female , Graft vs Host Disease/drug therapy , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Adult , Cyclophosphamide/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Risk Factors , Transplantation ConditioningABSTRACT
Despite high levels of stress, there are few empirically supported stress management interventions for caregivers of allogeneic hematopoietic stem cell transplant (HCT) cancer patients. This study examined the feasibility, acceptability, and various stress-related outcomes from pre- to post-treatment of a pilot, single-arm trial of a 6-week mindfulness-based intervention (FOCUS) for stress management. Caregivers (N = 21; 76% female; mean age = 57.43) were enrolled prior to patient transplant and received FOCUS during the first 90 days post-transplant. Findings indicated that FOCUS was highly feasible and acceptable (e.g., 71% attended at least four of six sessions; 100% reported using the skills learned at follow-up; high treatment engagement). Significant increases in mindfulness, post-traumatic growth, and general mental health were observed, along with significant decreases in negative affect (all ps < .05).
Subject(s)
Caregivers/psychology , Hematopoietic Stem Cell Transplantation/psychology , Mindfulness/methods , Neoplasms/psychology , Stress, Psychological/therapy , Adult , Caregivers/education , Feasibility Studies , Female , Hematopoietic Stem Cell Transplantation/nursing , Humans , Male , Middle Aged , Neoplasms/nursing , Pilot Projects , Resilience, Psychological , Stress, Psychological/etiology , Treatment OutcomeABSTRACT
To characterize donor search and selection practices, the National Marrow Donor Program (NMDP) Histocompatibility Advisory Group developed a survey of allogeneic hematopoietic cell transplant (HCT) physicians and search coordinators. The objectives were to describe search practices, understand practices surrounding urgent time to HCT, and characterize strategies used when identifying a matched unrelated donor is unlikely. Participants included US physician members of the American Society for Transplantation and Cellular Therapy and donor search coordinators within the NMDP network. The web-based survey was conducted from February to May 2018. Three hundred seventeen of 858 physicians (37%) and 225 of 327 coordinators (69%) responded, of which 263 and 194, respectively, were eligible and included in the analysis. Most centers, 142 (95%), were represented; 108 (72%) had at least 1 physician and 128 (85%) had at least 1 coordinator respondent. Most (68% physicians, 61% coordinators) indicated donor selection decisions were made by individual physicians. Urgent time to HCT was most commonly (90% and 87% of physicians and coordinators, respectively) defined as HCT within 4 to 6 weeks of search initiation. Higher HCT urgency was associated with a higher disease risk index. For urgent cases with low probability of an 8/8 matched unrelated donor , 75% and 80% of physicians and coordinators endorsed a short (1 to 2 weeks) unrelated donor search before proceeding to an alternative donor source. NMDP-provided solutions to expedite donor identification were strongly endorsed. This survey clarified current donor selection practices in the United States and defined urgent time to HCT. These data provide insight to NMDP on potential solutions to support the path to transplant, such as highlighting futile searches and providing alternative donor options at the time of search initiation.