Background Dysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD. Methods In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×106, 1×106, or 3×106 IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period. Results A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×106 IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (P<0.001 for both comparisons with baseline values), then declined when the patients were not receiving interleukin-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received interleukin-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60% (range, 25 to 100). Conclusions Daily low-dose interleukin-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients. (Funded by a Dana–Farber Dunkin' Donuts Rising Star award and others; ClinicalTrials.gov number, NCT00529035.)

Key Points The DRI successfully stratified patients in a very large allogeneic transplantation registry cohort. The DRI was refined by using this cohort to build a more inclusive and conditioning intensity–independent index.

Purpose Recurrently mutated genes in myelodysplastic syndrome (MDS) are pathogenic drivers and powerfully associated with clinical phenotype and prognosis. Whether these types of mutations predict outcome after allogeneic hematopoietic stem-cell transplantation (HSCT) in patients with MDS is not known. Patients and Methods We used massively parallel sequencing to examine tumor samples collected from 87 patients with MDS before HSCT for coding mutations in 40 recurrently mutated MDS genes. Results Mutations were identified in 92% of patients, most frequently in the ASXL1 (29%), TP53 (21%), DNMT3A (18%), and RUNX1 (16%) genes. In univariable analyses, only TP53 mutations were associated with shorter overall (OS; hazard ratio [HR], 3.74; P < .001) and progression-free survival (HR, 3.97; P < .001). After adjustment for clinical variables associated with these end points, mutations in TP53 (HR, 2.30; P = .027), TET2 (HR, 2.40; P = .033), and DNMT3A (HR, 2.08; P = .049) were associated with decreased OS. In multivariable analysis including clinical variables, complex karyotype status, and candidate genes, mutations in TP53 (HR, 4.22; P ≤ .001) and TET2 (HR, 1.68; P = .037) were each independently associated with shorter OS. Nearly one half of patients (46%) carried a mutation in TP53, DNMT3A, or TET2 and accounted for 64% of deaths. Three-year OS in patients without these mutations was 59% (95% CI, 43% to 72%), versus 19% (95% CI, 9% to 33%) in patients with these mutations. Conclusion Mutations in TP53, TET2, or DNMT3A identify patients with MDS with shorter OS after HSCT.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org.

Iron overload could be a significant contributor to treatment-related mortality (TRM) for patients with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT). We studied 590 patients who underwent myeloablative allogeneic HSCT at our institution, and on whom a pretransplantation serum ferritin was available. An elevated pretransplantation serum ferritin level was strongly associated with lower overall and disease-free survival. Subgroup multivariable analyses demonstrated that this association was restricted to patients with acute leukemia or myelodysplastic syndrome (MDS); in the latter group, the inferior survival was attributable to a significant increase in TRM. There was also a trend toward an increased risk of venoocclusive disease in patients with high ferritin. Our results argue that iron overload plays an important role in transplantation outcome for patients with acute leukemia or MDS, as it does in thalassemia. They also suggest future prospective trials to examine the potential benefit of chelation therapy in this setting. (Blood. 2007;109: [4586][4587][4588]