Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and High-Dose Rituximab for Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma: A Phase Two Multicenter Trial from the Blood and Marrow Transplant Clinical Trials Network

Allogeneic hematopoietic cell transplantation (alloHCT) can induce long term remissions in chemosensitive relapsed follicular lymphoma (FL). The BMT CTN conducted a multicenter phase 2 trial to examine the efficacy of alloHCT using reduced intensity conditioning (RIC) with rituximab (RTX) in multiply relapsed, chemosensitive FL. The primary endpoint was 2 year progression-free survival (PFS). The conditioning regimen consisted of fludarabine, cyclophosphamide and high-dose RTX (FCR) in which 3 of the 4 doses of RTX were administered at a dose of 1 gm/m2. Graft vs host disease (GvHD) prophylaxis was with tacrolimus and methotrexate. Sixty five patients were enrolled and 62 were evaluable. Median age was 55 years (range, 29-74). This group was heavily pre-treated: 77% had received ≥ 3 prior regimens, 32% had received ≥ 5 prior regimens and 11% had received prior autologous HCT. Donors were HLA-matched siblings (n=33) or HLA-matched unrelated adults (n=29). No graft failures occurred. The overall response rate after HCT was 94% with 90% in complete remission (CR), including 24 patients not in CR before alloHCT. With a median follow-up of 47 months (range, 30-73), 3 year PFS and overall survival rates were 71% (95% confidence interval: 58%-81%) and 82% (70%-90%) respectively. Three year cumulative incidences of relapse/progression and non-relapse mortality were 13% and 16%, respectively. Two year cumulative incidences of grade 2-4 and grade 3-4 acute GvHD were 27% and 10%, respectively and extensive chronic GvHD incidence was 55%. Serum RTX concentrations peaked at day +28 and remained detectable as late as 1 year in 59% of patients with available data. In conclusion, alloHCT with FCR conditioning confers high CR rates, a low incidence of relapse/progression and excellent survival probabilities in heavily pretreated FL patients

Health-Related Quality of Life among Older Related Hematopoietic Stem Cell Donors (>60 Years) Is Equivalent to That of Younger Related Donors (18 to 60 Years): A Related Donor Safety Study

The increasing number of older adults with blood-related disorders and the introduction of reduced intensity conditioning regimens has led to increases in hematopoietic stem cell (HSC) transplantation among older adults and a corresponding increase in the age of siblings who donate HSCs to these patients. Data regarding the donation-related experiences of older donors is lacking. The Related Donor Safety Study (RDSafe) aimed to examine/compare health-related quality of life (HRQoL) of older versus younger HSC donors. 60 peripheral blood stem cell (PBSC) donors ages 18–60 and 104 PBSC donors age >60 completed validated questionnaires at pre-donation, 4 weeks and 1 year post-donation. Prior to donation, older donors had poorer general physical health (t=−3.27; p=.001) but better mental health (t=2.11; p<.05). There were no age differences in multiple other donation-related factors. At 4 weeks post-donation, there were no group differences in general physical/mental health, but older donors were less likely to report donation-related pain (t=−2.26; p<.05) and concerns (t=−3.38; p=.001). At both 4 weeks and 1 year post-donation, there were no significant differences in the percentage of each age group feeling physically back to normal or in the number of days it took donors to feel completely well. There was no evidence that increasing age within the older donor group was associated with poorer donation-related HRQoL. Taken together, these data support the current practice of HSC donation by sibling donors above age 60, providing no evidence of worsening HRQoL up to one year after donation in individuals up to age 76

Burden and Outcomes of Mucosal Barrier Injury-Laboratory Confirmed Bloodstream Infections (MBI-LCBI) in the First 100 Days after Allogeneic Stem Cell Transplant: A CIBMTR Analysis

Abstract Background: Patients undergoing stem cell transplant (SCT) are at risk of bloodstream infections (BSI). BSI led to prolonged hospitalization, intensive care admissions, prolonged antibiotic treatment and increased mortality. Recently, the Centers for Disease Control and Prevention developed a modification of the Central line associated bloodstream infection (CLABSI) definition, termed "mucosal barrier injury laboratory-confirmed bloodstream infection" (MBI-LCBI) to differentiate BSI likely related to mucosal barrier injury. BSI are identified as an MBI-LCBI if: (1) it resulted from 1 or more of a group of selected organisms known to be commensals of the oral cavity or gastrointestinal tract and (2) occurred in a patient with signs or symptoms compatible with the presence of mucosal barrier injury such as gastrointestinal graft-versus-host disease and/or neutropenia. We utilized the CIBMTR database to determine the incidence and timing of MBI-LCBI, risk factors for development of MBI-LCBI, and compare transplant outcomes by 1 year after SCT. Methods: We identified 16,875 pediatric and adult patients receiving first allogeneic transplant from 2009-2016. Patients were classified into 4 categories based on the occurrence of BSI in first 100 days: MBI-LCBI (n=1434; 8.5%), MBI-LCBI +other BSI (n=700; 4.1%), BSI only (n=3016; 17.8%), and control (n=11725; 69.5%) (Figure 1). Demographics and outcomes, including overall survival (OS), chronic GVHD, and transplant-related mortality (TRM, for malignant disease patients only), were compared between groups. Results: The cumulative incidence of MBI-LCBI was 13% (99% CI: 12-13%) by day 100 whereas the probability for another BSI not meeting MBI-LCBI criteria was 22% (99% CI: 21-23%) by day 100. The median time from transplant to first MBI-LCBI was 8 days (<1-98), MBI-LCBI + other BSI 10 days (<1-99), and other BSI was 38 days (<1-100). Karnofsky/Lansky performance status <90 [RR 1.21 (99% CI: 1.06 - 1.38)], myeloablative conditioning [RR 1.45 (99% CI: 1.27-1.69)], post-transplant cyclophosphamide as GVHD prophylaxis [RR 1.83 (99% CI: 1.40 - 2.39)], and receipt of cord blood [RR 2.89 (99% CI: 2.06 - 4.06)] were associated with a significant increase in the risk of MBI-LCBI (Table 1). The 1 year OS was inferior for patients with MBI-LCBI only [59% (99% CI: 56 - 61%); RR 1.86 (99% CI: 1.65 - 2.09)], Other BSI only [60% (99% CI: 58 - 63%); RR 1.86 (99% CI: 1.70 - 2.04)], and MBI-LCBI + Other BSI [46% (99% CI: 41 - 50%); RR 2.79 (99% CI: 2.42 - 3.23)] compared to controls [72% (71 - 73); p <0.0001] (Table 2). There was no impact of MBI-LCBI only, Other BSI only, or MBI-LCBI + Other BSI compared to controls on development of chronic GVHD. As expected 1 year TRM in patients with malignant disease was increased with any BSI but was similar for patients with MBI-LCBI only [30% (99% CI: 27 - 34%); RR 2.41 (99% CI: 2.05-2.82] or Other BSI [25% (99% CI: 23 - 27%); RR 2.20 (1.94 - 2.51)] and further worsened for patients with both MBI-LCBI + Other BSI [45% (99% CI: 39 - 50%); RR 4.23 (3.53 - 5.07)] compared to controls [16% (99% CI:15 - 17%)]. Finally, infection as a cause of mortality was higher in patients with MBI-LCBI (19%), BSI only (17%), and MBI-LCBI + BSI (21%) then controls (12%). Discussion: Our data demonstrate approximately 13% of all patients develop at least one MBI-LCBI and an additional 22% of patients develop another BSI in the first 100 days post SCT. Multivariable analysis revealed increased risk of MBI-LCBI with poor performance status, cord blood grafts, myeloablative conditioning, and post-transplant cyclophosphamide GVHD prophylaxis. BSI, whether or not MBI-LCBI, significantly decreases overall survival, primarily related to an increased TRM. The combination of MBI-LCBI and other BSI worsens both TRM and OS, but the respective impact of MBI-LCBI only was similar to Other BSI only. BSI, both MBI-LCBIs and other BSI, lead to significant morbidity and mortality and healthcare resource utilization. Reduction in frequency of BSI should be a major public health and scientific priority. Disclosures Perales: Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Abbvie: Other: Personal fees; Takeda: Other: Personal fees; Merck: Other: Personal fees

A phase II, prospective, randomized, open-label study of defibrotide added to standard-of-care prophylaxis for the prevention of acute graft-versus-host disease after allogeneic hematopoietic cell transplantation

Acute graft-versus-host disease (aGvHD) is a life-threatening complication typically occurring within 100 days after allogeneic hematopoietic cell transplantation (allo-HCT). This hypothesis-generating, phase II, prospective, open-label, randomized study (clinicaltrials gov. Identifier: NCT03339297) compared defibrotide added to standard-of-care (SOC) GvHD prophylaxis (defibrotide prophylaxis arm) versus SOC alone (SOC arm) to prevent aGvHD post-transplant. This study estimated incidences of aGvHD and was not statistically powered to assess differences among treatment arms. Patients were randomized 1:1 to defibrotide prophylaxis arm (n=79; median age 57 years; range, 2-69 years) or SOC arm (n=73; median age 56 years; range, 2-72 years). Patient demographics in the two arms were similar except for conditioning regimen type (myeloablative: defibrotide, 76% vs. SOC, 61%) and stem cell source for allo-HCT (bone marrow: defibrotide, 34% vs. SOC, 26%). In the intent-to-treat primary endpoint analysis, the cumulative incidence of grade B-D aGvHD at day 100 post-transplant was 38.4% in the defibrotide prophylaxis arm versus 47.1% in the SOC arm (difference: -8.8%, 90% confidence interval [CI]: -22.5 to 4.9). The difference noted at day 100 became more pronounced in a subgroup analysis of patients who received antithymocyte globulin (defibrotide: 30.4%, SOC: 47.6%; difference: -17.2%; 90% CI: -41.8 to 7.5). Overall survival rates at day 180 post-transplant were similar between arms, as were the rates of serious treatment-emergent adverse events (defibrotide: 42%, SOC: 44%). While the observed differences in endpoints between the two arms were not substantial, these results suggest defibrotide prophylaxis may add a benefit to currently available SOC to prevent aGvHD following allo-HCT without adding significant toxicities.The study was funded by Jazz Pharmaceuticals, Inc. (Palo Alto, CA, USA).Peer reviewe