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Cryoprevention (CP) using ice (IC) is an effective strategy to prevent chemotherapy-induced oral mucositis (OM). However, the use of IC may cause adverse reactions and requires water of safe quality to minimize risk of serious infections. This randomized, blinded, parallel group, phase 3 trial was conducted in five Scandinavian centers. Eligible patients were diagnosed with multiple myeloma or lymphoma, scheduled to receive conditioning with high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (ASCT). Patients were assigned to cooling with IC or a novel intraoral cooling device (ICD). The primary outcome was the highest OM score during the study period, expressed as peak value on the Oral Mucositis Assessment Scale (OMAS–total). When the entire study population (n= 172) was analyzed for peak OMAS–total, the two cooling methods were equally effective. However, when the lymphoma group was analyzed separately, the ICD significantly reduced the peak OMAS–total score to a greater extent compared to IC (x̄± SD; 1.77 ± 1.59 vs. 3.08 ± 1.50; p= 0.047). Combined with existing evidence, the results of the present trial confirm that CP is an effective method to prevent OM. ClinicalTrials.gov. NCT03203733.

Steroid‐refractory chronic graft‐vs‐host disease (cGvHD) contributes to morbidity after allogeneic hematopoietic stem cell transplantation. Here, we report on 11 patients with severe, refractory cGvHD treated with repeated infusions of allogeneic bone marrow‐derived mesenchymal stromal cells (MSC) over a 6‐ to 12‐month period. Six patients responded to MSC treatment following National Institutes of Health response criteria, accompanied by improvement in GvHD‐related symptoms and quality of life. This response was durable, with systemic immunosuppressive therapy withdrawn from two responders, and a further two free from steroids and tapering calcineurin inhibitors. All responders displayed a distinct immune phenotype characterized by higher levels of naïve T cells and B cells before treatment compared with the nonresponders, and a significantly higher fraction of CD31+ naïve CD4+ T cells. MSC treatment was associated with significant increases in naïve T cells, B cells, and Tregs 7 days after each infusion. Skin biopsies showed resolution of epidermal pathology. CXCL9 and CXCL10 showed differential responses in responder and nonresponder patients. Our data support the use of MSC infusions as treatment for steroid‐refractory cGvHD with durable responses. We propose CXCL9 and CXCL10 as early biomarkers for responsiveness to MSC treatment. Our results highlight the importance of the MSC recipient immune phenotype in promoting treatment response. This trial was registered at www.ClinicalTrials.govas #NCT01522716. A, In this clinical phase II study, 11 patients with severe, refractory chronic graft‐vs‐host disease (cGvHD) were treated with repeated monthly infusions of mesenchymal stromal cell (MSC). B, Six patients responded with a reduction in disease severity as measured by the National Institutes of Health score. Immunological analysis revealed that response was associated with an immune profile with increased naïve CD4+ T‐cell and Treg numbers. In addition, a better thymic function in the responders was suggested based on increased ratio of recent thymic emigrants among naïve CD4+ T cells. Short‐term after each infusion we observed an increase in CD4+ T‐cell and Treg numbers in the responders. Skin histology improved in both groups with reduced epidermal inflammation. Our results support the use of MSC infusions for refractory cGvHD and suggest the recipient immune system phenotype as a predictor of responsiveness. R, responder; NR, nonresponder.

Allogeneic hematopoietic stem cell transplantation (HSCT) is widely used to treat hematopoietic cell disorders but is often complicated by graft-versus-host disease (GVHD), which causes severe epithelial damage. Here we have investigated longitudinally the effects of induction chemotherapy, conditioning radiochemotherapy, and allogeneic HSCT on composition, phenotype, and recovery of circulating innate lymphoid cells (ILCs) in 51 acute leukemia patients. We found that reconstitution of ILC1, ILC2, and NCR−ILC3 was slow compared with that of neutrophils and monocytes. NCR+ ILC3 cells, which are not present in the circulation of healthy persons, appeared both after induction chemotherapy and after allogeneic HSCT. Circulating patient ILCs before transplantation, as well as donor ILCs after transplantation, expressed activation (CD69), proliferation (Ki-67), and tissue homing markers for gut (α4β7, CCR6) and skin (CCR10 and CLA). The proportion of ILCs expressing these markers was associated with a decreased susceptibility to therapy-induced mucositis and acute GVHD. Taken together, these data suggest that ILC recovery and treatment-related tissue damage are interrelated and affect the development of GVHD.

Allogeneic hematopoietic stem cell transplantation (HSCT) is widely used to treat hematopoietic cell disorders but is often complicated by graft-versus-host disease (GVHD), which causes severe epithelial damage. Here we have investigated longitudinally the effects of induction chemotherapy, conditioning radiochemotherapy, and allogeneic HSCT on composition, phenotype, and recovery of circulating innate lymphoid cells (ILCs) in 51 acute leukemia patients. We found that reconstitution of ILC1, ILC2, and NCR−ILC3 was slow compared with that of neutrophils and monocytes. NCR+ILC3 cells, which are not present in the circulation of healthy persons, appeared both after induction chemotherapy and after allogeneic HSCT. Circulating patient ILCs before transplantation, as well as donor ILCs after transplantation, expressed activation (CD69), proliferation (Ki-67), and tissue homing markers for gut (α4β7, CCR6) and skin (CCR10 and CLA). The proportion of ILCs expressing these markers was associated with a decreased susceptibility to therapy-induced mucositis and acute GVHD. Taken together, these data suggest that ILC recovery and treatment-related tissue damage are interrelated and affect the development of GVHD.

There is no established treatment for patients unresponsive to first line therapy for chronic graft versus host disease (cGVHD). Infusion of mesenchymal stromal cells (MSCs) is a promising alternative in this situation, but the treatment efficacy and mechanism of action have not yet been established. Furthermore, there is great need for biomarkers for selecting patients that are more likely to respond to MSC therapy.

No relevant conflicts of interest to declare.

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