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

Prolonged sirolimus administration after allogeneic hematopoietic cell transplantation is associated with decreased risk for moderate-severe chronic graft-versus-host disease

Effective pharmacological strategies employed in allogeneic hematopoietic cell transplantation should prevent serious chronic graft-versus-host disease and facilitate donor-recipient immune tolerance. Based on demonstrated pro-tolerogenic activity, sirolimus (rapamycin) is an agent with promise to achieve these goals. In a long-term follow-up analysis of a randomized phase II trial comparing sirolimus/tacrolimus versus methotrexate/tacrolimus for graft-versus-host disease prevention in matched sibling or unrelated donor transplant, we examined the impact of prolonged sirolimus administration (≥ 1 year post-transplant). Median follow-up time for surviving patients at time of this analysis was 41 months (range 27–60) for sirolimus/tacrolimus and 49 months (range 29–63) for methotrexate/tacrolimus. Sirolimus/tacrolimus patients had significantly lower National Institutes of Health Consensus moderate-severe chronic graft-versus-host disease (34% vs. 65%; P=0.004) and late acute graft-versus-host disease (20% vs. 43%; P=0.04). While sirolimus/tacrolimus patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to tacrolimus discontinuation 368 days vs. 821 days; P=0.002), there was no significant difference in complete immune suppression discontinuation (60-month estimate: 43% vs. 31%; P=0.78). Prolonged sirolimus administration represents a viable approach to mitigate risk for moderate-severe chronic and late acute graft-versus-host disease. Further study of determinants of successful immune suppression discontinuation is needed

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

IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation

Graft-versus-host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16th April 2014 and 19th December 2015, 20 patients received IL-2 (200,000 IU/m2 thrice weekly, days 0 to +90) with SIR (5–14 ng/mL) and tacrolimus (TAC) (3–7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8% vs. 16.0%, P=0.0016; 0.052 k/uL vs. 0.037 k/uL, P=0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7% vs. 50%, P=0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3+ CD4+ T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. (clinicaltrials.gov identifier: 01927120)

In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation

T-helper 1 and T-helper 17 lymphocytes mediate acute graft-versus-host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo-controlled trial, we examined the biological impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. Thirty patients received peripheral blood mobilized hematopoietic cell transplantation (HCT) from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as GvHD prophylaxis, and were randomized to ustekinumab versus placebo with 1:1 allocation after stratification by donor type. The primary end point of the trial was the mean percentage (%) T-regulatory (Treg) cells on day 30 post HCT. Ustekinumab was delivered by subcutaneous injection on day −1 and day +20 after transplantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at days 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-α production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and National Institute of Health moderate/severe chronic GvHD-free, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic GvHD, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL-23p40 neutralization can polarize donor anti-host alloresponse in vivo and provide initial clinical efficacy evidence to be tested in subsequent trials. (Trial registered at clinicaltrials.gov identifier: 01713400.

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