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• Nonmalignant blood diseases are curable by allogeneic bone marrow transplantation (BMT). • Too few patients are offered BMT due to perceived risks. • The Blood and Marrow Transplant Clinical Trials Network has prioritized diseases for clinical trial development. • Bone marrow failure is the top priority, followed by thalassemia. Nonmalignant blood diseases such as bone marrow failure disorders, immune dysregulation disorders, and hemoglobinopathies often lead to shortened life spans and poor quality of life. Many of these diseases can be cured with allogeneic hematopoietic cell transplantation, but patients are often not offered the procedure because of perceived insufficient efficacy and/or excess toxicity. In 2018, the Blood and Marrow Transplant Clinical Trials Network convened a task force to identify the most urgently needed yet feasible clinical trials with potential to improve the outcomes for patients with nonmalignant diseases. This report summarizes the task force discussions and specifies the network plans for clinical trial development for nonmalignant blood diseases. [ABSTRACT FROM AUTHOR]

Corticosteroids are the accepted primary therapy for acute graft-versus-host disease (GVHD), but durable responses are seen in only about half of the patients. Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0802, a phase 3 multicenter randomized double-blinded trial, was designed to test whether mycophenolate mofetil (MMF) plus corticosteroids was superior to corticosteroids alone as initial therapy for acute GVHD. Patients with newly diagnosed acute GVHD were eligible if they required systemic therapy. Patients were randomized to receive prednisone with either MMF or placebo. The primary end point was acute or chronic GVHD-free survival at day 56 after initiation of therapy. A futility rule for GVHD-free survival at day 56 was met at a planned interim analysis after 235 patients (of 372) were enrolled: 116 MMF, 119 placebo. Baseline characteristics were well balanced between treatment groups including grade and organ distribution of GVHD. GVHD-free survival at day 56, cumulative incidence of chronic GVHD at 12 months, overall survival, Epstein-Barr virus reactivation, severe, life-threatening infections, relapse at 12 months, and quality of life were similar. The addition of MMF to corticosteroids as initial therapy for acute GVHD does not improve GVHD-free survival compared with corticosteroids alone. [ABSTRACT FROM AUTHOR]

The introduction of reduced-intensity conditioning (RIC) regimens made it possible to offer allogeneic hematopoietic cell transplantation (alloHCT) to older patients with myelodysplastic syndromes (MDS). However, the relative risks and benefits of alloHCT compared with novel nontransplant therapies continue to be the source of considerable uncertainty. We will perform a prospective biologic assignment trial to compare RIC alloHCT with nontransplant therapies based on donor availability. Primary outcome is 3-year overall survival. Secondary outcomes include leukemia-free survival, quality of life, and cost-effectiveness. Four hundred patients will be enrolled over roughly 3 years. Planned subgroup analyses will evaluate key biologic questions, such as the impact of age and response to hypomethylating agents on treatment effects. Findings from this study potentially may set a new standard of care for older MDS patients who are considered candidates for alloHCT. [ABSTRACT FROM AUTHOR]

Chronic GVHD remains as the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are the first line of therapy, but outcomes are poor in steroid refractory (SR) patients. Previous reports show that in SR patients, IL-2 therapy results in partial response (PR) associated with increase in regulatory T cells (Tregs). ECP has been used for cGVHD with skin response rates of 40-100%. Based on non-overlapping toxicities and, we prospectively studied a combination of low dose IL-2 + ECP to treat SR-cGVHD. Patients with SR-cGVHD, were treated with low dose IL-2 (1 × 106 U/m2, daily) + ECP for 12 weeks. IL-2 was provided by Prometheus Laboratories. ECP was administered 2 times/week for 4 weeks followed by 2 treatments every 2 weeks for the next 8 weeks. The NIH consensus criteria was used to assess cGVHD severity. PBMC and plasma samples were banked at baseline and on 3-week intervals to assess regulatory T cell (Tregs) and reactive oxygen species (ROS). Of the 12 consented patients, 9 completed the study (2 were not treated due to rapid disease progression before enrollment and 1 died from sepsis at week 11). All enrolled patients (n=10) had scleroderma as the predominant cGVHD manifestation. Median age was 45.6 years (range: 23-66). Median prior lines of therapy were 4.2(range 3-6), 5 patients had prior exposure to ruxolitinib and 4 were on ECP at the enrollment. Donors were fully matched unrelated (n=8), matched sibling (n=1) or mismatched unrelated (n=1). Conditioning regimen was myeloablative (n=5) or reduced intensity (n=4). GVHD prophylaxis was tacrolimus/Sirolimus (tac/sir) (n=6), tac/methotrexate (MTX) (n=2), or Tac/sir/MTX (n=1). Of the 10 enrolled patients, 9 responded to IL-2 + ECP combination (all classified as PR). A 37% dose reduction in steroid dose was noted among 7 patients. The remaining 3 patients were on stable steroid dose at end of study. Only 1 patient had progressive cGVHD in form of scleroderma. ECP+IL-2 therapy was well tolerated with no drug related serious adverse events (SAE). Grade 3-4 AEs included grade 3 metabolic and nutrition (n=8), grade 3 anemia (n=3), and grade 4 atrial flutter (n=1). Infectious complications were noted in 3 patients (one grade 4 [sepsis]). There was a robust increase in Tregs from the baseline mean of 0.755% (range 0.08-1.88) to end of treatment 6.999% (range 0.78-17.13) [p=0.02] Fig 1. Increment in Tregs was seen in patients who were on ECP therapy prior to enrollment (n=4) and in one patient who progressed while on therapy. No correlation was found between the treatment response and ROS levels. In conclusion, the combination of ECP +IL-2 is well tolerated in patients with SR-cGVHD with no apparent increase in infectious complications or other toxicities. Clinical response correlates with a robust increase in Tregs, but no correlation was found with ROS levels. [ABSTRACT FROM AUTHOR]

Accurate and reproducible methods to diagnose, grade and report acute graft vs. host disease (GVHD) are critical for evaluation of new treatments and biomarkers. BMTCTN 1202 created a biorepository and clinical data bank for the study of GVHD biomarkers and other transplant outcomes. To create a representative study population any pt >10 kg undergoing alloHCT was eligible (Table 1). Symptoms suggestive of GVHD, biopsy results, immunosuppressive medications, and possible etiologies were reported weekly until day 100. An end-point review committee (ERC) performed a near real time adjudication of reported symptoms at their onset and assigned a confidence level (Confirmed, Probable, Possible or Negative) for each organ according to Harris, BBMT, 2016. The final repository included 41,468 annotated biospecimens from 1709 alloHCT patients (pts) transplanted at U.S. centers from 2012-2016. Although 90% of pts developed symptoms at least once, physicians suspected GVHD in only 23% of cases and GVHD was considered the only etiology in 12%. Biopsies (bx) were performed in 40% of pts, most often for upper or lower GI symptoms. Bx results were equivocal in 11% although the range among centers was broad (0-45%). Equivocal results were most likely for skin bx and during the 2nd week after transplant. Systemic steroids were administered to 70% of pts at least once, often for non-GVHD reasons (41% of steroid courses). When GVHD was in the differential diagnosis, systemic steroids were started 81% of the time. The ERC adjudicated 2,008 cases with symptoms suggestive of GVHD onset. In 12.3% of cases the ERC modified either the center reported diagnosis of GVHD (4.6%) or the automated generated severity grade (7.7%). GVHD was diagnosed in 1025 pts and categorized as confirmed (31%), probable (50%), or possible (19%). The proportion of definitive diagnoses (Confirmed or Negative) increased with longer time post-transplant (Fig 1). ERC adjudication substantially lowered the incidence of GVHD grade 2-4 from 30% as reported by centers to 23% (confirmed or probable) by ERC. An adjudicated diagnosis of GVHD strongly associated with 6 month NRM, adjusted for patient age, gender and HLA matching (HR = 2.0, p < 0.001). Adjudicated GVHD grade was also strongly associated with 6 month NRM (Grade 2, HR = 2.1, p < 0.001; Grade 3-4, HR = 7.1, p < 0.001). In summary, the largest prospective observational study of GVHD outcomes demonstrated that symptoms in GVHD target organs are almost universal after transplant, their differential diagnosis is broad, tissue biopsies are infrequently done and their results are often equivocal, and steroids are often prescribed for reasons other than acute GVHD. These limitations undermine the current methods of diagnosis and reporting of acute GVHD on clinical trials. A robust reporting and adjudication system has significant value and may improve the chances of success of prospective clinical trials. [ABSTRACT FROM AUTHOR]