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

Purpose: High-dose chemotherapy with autologous stem-cell rescue (SCR) is a key component of high-risk neuroblastoma (HRNB) therapy. Carboplatin, etoposide, and melphalan (CEM) or busulfan and melphalan (Bu/Mel) are the most evaluated, effective high-dose chemotherapy for HRNB on the basis of results from major cooperative group studies. Toxicity profiles vary between these regimens, and practice variation exists regarding the preferred high-dose therapy (HDT). We sought to evaluate the safety of HDT and autologous SCR for HRNB in a resource-limited country (Egypt) compared with the resource-rich United States. Patients and Methods: We performed a retrospective comparative review of single CEM-based HDT/SCR outcomes through day 100 for HRNB at the Fred Hutchinson Cancer Research Center (FH) in the United States (2005 to 2015) versus Bu/Mel-based HDT at El-Sheikh Zayed Specialized Hospital (SZ) in Egypt (2009 to 2015). Results: Forty-four patients at FH and 77 patients at SZ were reviewed. Pretransplant hepatic comorbidities were significantly higher at SZ (29 of 77 v nine of 44; P = .05), with 19 of 77 patients at SZ having hepatitis infection. Engraftment was delayed after SZ-Bu/Mel therapy compared with FH-CEM therapy for neutrophils (median 12 days v 10 days, respectively; P < .001) and platelets (median 20 days v 18 days, respectively; P < .001). Sinusoidal obstruction syndrome occurred later, after SZ-Bu/Mel therapy (median 19 days v 7 days; P = .033), and four of eight cases were fatal (six of eight patients had underlying hepatitis infection), whereas three of three cases after FH-CEM therapy were moderately severe. Resource utilization associated with the number of days with fever, antibiotic use, and the number of transfusions administered was significantly higher after FH-CEM therapy than after SZ-Bu/Mel therapy. Conclusion: Use of autologous stem-cell transplantation is feasible in the context of a resource-limited country.

We determined the incidence of disability related to chronic graft-versus-host disease (bronchiolitis obliterans, grade ≥2 keratoconjunctivitis sicca, sclerotic features or esophageal stricture) for three categories of alternative donor: cord blood, haplorelated marrow or peripheral blood with post-transplant cyclophosphamide, and unrelated single HLA-allele mismatched peripheral blood. Among 396 consecutive hematopoietic cell transplant recipients, 129 developed chronic graft-versus-host disease with 3-year cumulative incidences of 8% for cord blood, 24% for haplorelated grafts, and 55% for unrelated single HLA-allele mismatched peripheral blood. Disability rates were significantly lower for cord blood [hazard ratio (HR) 0.13; 95% confidence interval (CI): 0.1-0.4] and for the haplorelated group (HR 0.31; 95% CI: 0.1-0.7) compared to the rate in the group transplanted with unrelated single HLA-allele mismatched peripheral blood. Cord blood recipients were also >2-fold more likely to return to work/school within 3 years from the onset of chronic graft-versus-host disease (HR 2.54; 95% CI: 1.1-5.7, P=0.02), and the haplorelated group trended similarly (HR 2.38; 95% CI: 1.0-5.9, P=0.06). Cord blood recipients were more likely to discontinue immunosuppression than were recipients of unrelated single HLA-allele mismatched peripheral blood (HR 3.96; 95% CI: 1.9-8.4, P=0.0003), similarly to the haplorelated group (HR 4.93; 95% CI: 2.2-11.1, P=0.0001). Progression-free survival and non-relapse mortality did not differ between groups grafted from different types of donors. Our observations that, compared to recipients of unrelated single HLA-allele mismatched peripheral blood, recipients of cord blood and haplorelated grafts less often developed disability related to chronic graft-versus-host disease, and were more likely to resume work/school, should help better counseling of pre-hematopoietic cell transplant candidates.

Initial therapy of chronic graft-versus-host disease is prednisone ± a calcineurin-inhibitor, but most patients respond inadequately. In a randomized, adaptive, phase II/III, multicenter trial we studied whether prednisone/sirolimus or prednisone/sirolimus/photopheresis was more effective than prednisone/sirolimus/calcineurin-inhibitor for treating chronic graft-versus-host disease in treatment-naïve or early inadequate responders. Primary endpoints of this study were proportions of subjects alive without relapse or secondary therapy with 6-month complete or partial response in phase II, or with 2-year complete response in phase III. The prednisone/sirolimus/photopheresis arm closed prematurely because of slow accrual and the remaining two-drug versus three-drug study ended in phase II due to statistical futility with 138 evaluable subjects. The two-drug and three-drug arms did not differ in rates of 6-month complete or partial response (48.6% versus 50.0%, P=0.87), or 2-year complete response (14.7% versus 15.5%, P=0.90). Serum creatinine values >1.5 times baseline were less frequent in the calcineurin-inhibitor-free arm at 2 months (1.5% versus 11.7%, P=0.025) and 6 months (7.8% versus 24.0%, P=0.016). Higher adjusted Short Form-36 Physical Component Summary and Physical Functioning scores were seen in the two-drug arm at both 2 months (P=0.02 and P=0.04, respectively) and 6 months (P=0.007 and P=0.001, respectively). Failure-free survival and overall survival rates at 2 years were similar for patients in the the two-drug and three-drug arms (48.6% versus 46.2%, P=0.78; 81.5% versus 74%, P=0.28). Based on similar long-term outcomes, prednisone/sirolimus is a therapeutic alternative to prednisone/sirolimus/calcineurin-inhibitor for chronic graft-versus-host disease, being easier to administer and better tolerated. Clinicaltrials.gov identifier: NCT01106833.

We conducted a phase III study to test the hypothesis that initial therapy with “lower dose” prednisone is effective and safe for patients with newly diagnosed acute graft-versus-host disease. We hypothesized that a 50% decrease in the initial dose of prednisone for treatment of acute graft-versus-host disease would suffice to control graft-versus-host disease without increasing the incidence of secondary treatment. Patients with grade IIa manifestations (upper gastrointestinal symptoms, stool volumes

We evaluated short-term response endpoints for acute graft-versus-host disease treatment trials. We postulated that response endpoints should correlate with reduced symptom burden and decreased subsequent treatment failure, defined as non-relapse mortality, recurrent malignancy, or additional systemic treatment. The cohort included 303 consecutive patients who received initial systemic steroid treatment for acute graft-versus-host disease. Response was evaluated at day 28 after initial treatment, which in all cases preceded the onset of chronic graft-versus-host disease. At day 28, 36% of patients had a complete response, 26% had a very good partial response, 10% had another degree of partial response (other partial response) and 28% had no response. As expected, the symptom burden was lower in patients with very good partial response compared to those with other partial response. The frequencies of subsequent treatment failure were similar in patients with complete and very good partial responses, but lower than in patients with other partial response or no response at day 28. The frequency of second-line treatment was lower in patients with very good partial response than in those with other partial response. Risk factors associated with a lower probability of complete or very good partial response at day 28 were unrelated or human leukocyte antigen-mismatched related donor grafts and liver or gastrointestinal involvement at onset of initial treatment. Taken together, these results suggest that endpoints in acute graft-versus-host disease treatment trials should distinguish between very good partial response and other partial response. Our results support the use of complete or very good partial response at day 28 as an appropriate short-term primary endpoint.