Nicotinamide enhances natural killer cell function and yields remissions in patients with non-Hodgkin lymphoma.

Allogeneic natural killer (NK) cell adoptive transfer has shown the potential to induce remissions in relapsed or refractory leukemias and lymphomas, but strategies to enhance NK cell survival and function are needed to improve clinical efficacy. Here, we demonstrated that NK cells cultured ex vivo with interleukin-15 (IL-15) and nicotinamide (NAM) exhibited stable induction of l-selectin (CD62L), a lymphocyte adhesion molecule important for lymph node homing. High frequencies of CD62L were associated with elevated transcription factor forkhead box O1 (FOXO1), and NAM promoted the stability of FOXO1 by preventing proteasomal degradation. NK cells cultured with NAM exhibited metabolic changes associated with elevated glucose flux and protection against oxidative stress. NK cells incubated with NAM also displayed enhanced cytotoxicity and inflammatory cytokine production and preferentially persisted in xenogeneic adoptive transfer experiments. We also conducted a first-in-human phase 1 clinical trial testing adoptive transfer of NK cells expanded ex vivo with IL-15 and NAM (GDA-201) combined with monoclonal antibodies in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) (NCT03019666). Cellular therapy with GDA-201 and rituximab was well tolerated and yielded an overall response rate of 74% in 19 patients with advanced NHL. Thirteen patients had a complete response, and 1 patient had a partial response. GDA-201 cells were detected for up to 14 days in blood, bone marrow, and tumor tissues and maintained a favorable metabolic profile. The safety and efficacy of GDA-201 in this study support further development as a cancer therapy.

Harvest Quality, Nucleated Cell Dose and Clinical Outcomes in Bone Marrow Transplantation: A Retrospective Study.

Higher doses of infused nucleated cells (NCs) are associated with improved clinical outcomes in bone marrow transplantation (BMT) recipients. Most clinicians recommend infusing at least 2.0 × 108 NCs/kg. BMT clinicians request a target NC dose, but the harvested NC dose may be below the requested NC dose even before cell processing. We conducted this retrospective study to investigate the quality of bone marrow (BM) harvest and factors that influence infused NC doses at our institution. We also correlated infused NC doses with clinical outcomes. The study population included 347 BMT recipients (median age, 11 years; range, <1 to 75 years) at the University of Minnesota between 2009 and 2019. Underlying diagnoses mainly included 39% malignant and 61% nonmalignant diagnoses. Requested, harvested, and infused NC doses, as well as cell processing data, were obtained from the Cell Therapy Laboratory; clinical outcomes data were obtained from the University of Minnesota BMT Database. BM harvests were facilitated either by our institution (61%) or by the National Marrow Donor Program (39%). Associations of infused doses with baseline characteristics were assessed using the general Wilcoxon test/Pearson's correlation coefficient. The association of infused dose with neutrophil engraftment (absolute neutrophil count >500) by day 42, platelet engraftment (>20,000) by 6 months, acute graft-versus-host disease grade II-IV, and overall survival (OS) at 5 years were evaluated using regression and Kaplan-Meier curves. The median requested NC dose was 3.0 × 108/kg (range, 2 to 8 × 108/kg), and the median harvested and infused NC doses were 4.0 × 108/kg and 3.6 × 108/kg, respectively. Only 7% of donors had a harvested dose below the minimum requested dose. Moreover, the correlation between requested doses and harvested doses was adequate, with a harvested/requested dose ratio <.5 observed in only 5% of harvests. Additionally, the harvest volume and cell processing method were significantly correlated with the infused dose. Harvest volume exceeding the median of 948 mL was related to a significantly lower infused dose (P < .01). Moreover, hydroxyethyl starch (HES)/buffy coat processing (used to reduce RBCs with major ABO incompatibility) led to a significantly lower infused dose (P < .01). Donor age (median, 19 years; range, <1 to-70 years) and sex did not significantly influence the infused dose. Finally, the infused dose was significantly correlated with neutrophil and platelet engraftment (P < .05) but not with 5-year OS (P = .87) or aGVHD (P = .33). In our program's experience, BM harvesting is efficient and meets the requested minimum dose for 93% of recipients. Harvest volume and cell process play significant roles in determining the final infused dose. Minimizing harvest volume and cell processing could lead to increased infused dose and thus improved outcomes. Moreover, a higher infused dose leads to a better rate of neutrophil and platelet engraftment but not to improved OS, which may be linked to the sample size of our study.

A Multicenter Phase 2 Clinical Trial of 10-Day Decitabine, Dose-Escalated Donor Lymphocyte Infusion, and Ruxolitinib for Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Cell Transplantation.

Post-transplantation relapse of acute myeloid leukemia and myelodysplastic syndromes has a poor prognosis. Donor lymphocyte infusion (DLI) is one treatment approach. However, efficacy is limited, and toxicity, mostly in the form of acute graft-versus-host disease (GVHD), is frequent. We tested a novel approach using 10-day decitabine, dose-escalated DLI, and ruxolitinib in a multicenter phase 2 trial aimed at increasing the efficacy of DLI and reducing its toxicity. Up to four 28-day cycles were administered. The primary endpoint was 6-month overall survival (OS). Of the 14 patients who started cycle 1, 13 received 1 DLI, 6 received 2 DLIs, and 1 received 3 4 DLIs. A preplanned interim analysis after enrolling 14 patients suggested futility, and the trial was closed to accrual. The final analysis showed a 6-month OS of 36% (95% confidence interval [CI], 18 to 72), a 1-year progression-free survival of 7% (95% CI, 1% to 47%), a 6-month cumulative incidence of grade II-IV acute GVHD of 57% (95% CI, 26% to 80%), and a 1-year nonrelapse mortality of 14% (95% CI, 2% to 38%). The combined modality treatment studied in this trial was ineffective and did not reduce DLI toxicity.

Impact of CDC warning on co-prescribing of opioids and benzodiazepines in older allogeneic hematopoietic cell transplant recipients.

The use of opioids and/or benzodiazepines in older adults (65 y+) who received an allogeneic hematopoietic cell transplant (HCT) is not known. In March 2016, the CDC released its strongest guidelines against prescription of opioids and co-prescription of opioids + benzodiazepines. We evaluated the use of opioids and/or benzodiazepines in older (65 y + , n = 114) vs. younger (40-64 y, n = 240) allogeneic-HCT recipients before and after the CDC guidelines. The proportion of patients with >10-days of use of opioids and/or benzodiazepines peri-HCT (day-14 to +28) was compared. Opioids: the older (65 + y) group had similar odds of receiving opioids as the younger group (40-64 y) [O.R. 0.7 (95%CI:0.4-1.2)]. Those transplanted after the CDC guideline had 0.4 (95%CI:0.2-0.7) times the odds of receiving opioids. Benzodiazepines: The older (65 + y) group was 0.6 times (95%CI:0.3-0.9) as likely to receive benzodiazepines. There was no significant change in benzodiazepines use after the CDC guideline. Opioids + Benzodiazepines: The older group (65 + y) was 0.5 (95%CI:0.3-0.9) times as likely to receive both opioids+benzodiazepines. There was no significant change in opioids+benzodiazepines use after the CDC guideline. Though we observed a significant decrease in use of opioids after the CDC guideline, the use of benzodiazepines and combined opioids+benzodiazepines remained constant. Older recipients (65 + y) received less opioids, benzodiazepines, and combined opioids+benzodiazepines.

Prediction of outcomes after second-line treatment for acute graft-versus-host disease.

Acute graft-versus-host disease (GVHD) requiring second-line treatment represents a highly morbid complication of allogenic hematopoietic cell transplantation (HCT). Recent studies have defined short-term outcomes after second-line treatment for acute GVHD, but longer-term outcomes have not been well defined. We examined overall survival (OS) and failure-free-survival (FFS) of 216 patient who had HCT who received second-line treatment for acute GVHD. Failure time for FFS was defined as the earliest of death, relapse, or implementation of third-line treatment. Multivariable Cox regression was used to identify risk factors for mortality and failure, and predictive models were derived for 6- and 12-month mortality. Point estimates of OS at 6 and 12 months were 59% (95% confidence interval [CI], 52-65) and 52% (95% CI, 45-68), respectively. Point estimates of FFS at 6 and 12 months were 42% (95% CI, 35-48) and 37% (95% CI, 31-43), respectively. Predictive models for both end points included serum albumin and total bilirubin concentrations at the onset of second-line treatment, patient age at onset of second-line therapy, and a combination of abdominal pain/stage 4 gut involvement. Optimism-corrected areas under the receiver-operator characteristic curve and Brier scores were 77.4 and 0.169 for 6-month mortality, respectively, and 80.0 and 0.169 for 12-month mortality. We identify risk factors associated with mortality and failure after second-line treatment of acute GVHD, provide historical benchmarks for assessment of FFS and OS in other studies, and propose predictive models for 6- and 12-month mortality that could be used to generate population-specific benchmarks.

Predictors and outcomes of flares in chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) requires prolonged immunosuppressive therapy (IST), often requiring slow tapering with patients experiencing cGVHD flares and treatment failure. In 145 adult recipients developing cGVHD after matched sibling or umbilical cord blood donor HCT from 2010 to 2018, 2-year cumulative incidence of flares after cGVHD diagnosis was estimated at 60% (95% CI, 51-70%), with median time-to-first flare of 188 days (range, 16-751). Of 88 patients experiencing a flare, 32 (36%) had multiple flares (range, 2-4). First flare treatment consisted of an increase in prednisone dose in 77 patients (88%), plus topical therapy in 8 (9%) or another systemic IST in 43 patients (49%). Higher flare risk was associated with quiescent type of cGVHD at onset (HR 1.8; 95% CI: 1.1-2.7; p = 0.04). Patients without a flare required a shorter duration of IST and were more likely to achieve a durable discontinuation of systemic IST (86% vs. 31% for ≥6 consecutive months). Flares were associated with protective effect on relapse (HR 0.2, 95% CI: 0.1-0.3), however not with worsened 2-year NRM or OS. Flares of cGVHD identify a group needing better approaches to limit the duration of IST and thus the morbidity of cGVHD.

Engraftment of Double Cord Blood Transplantation after Nonmyeloablative Conditioning with Escalated Total Body Irradiation Dosing to Facilitate Engraftment in Immunocompetent Patients.

To improve accrual to a randomized clinical trial of double unrelated cord blood (dUCB) versus HLA-haploidentical bone marrow (haplo-BM) transplantation, patients with less previous therapy and potentially greater immunocompetence were enrolled. To reduce the risk of graft rejection, patients randomized to receive dUCB received a higher dose of total body irradiation (TBI) (300 cGy versus 200 cGy). In this study, we investigated whether the inclusion of recipients of 300 cGy TBI influenced the trial outcomes. This was a secondary analysis of dUCB recipients, 161 who received TBI 200 cGy and 18 who received TBI 300 cGy. Fine and Gray regression was used to evaluate the effect of TBI dose on relapse and nonrelapse mortality (NRM). Cox regression was used for evaluation of neutrophil engraftment and overall survival. Patient characteristics were similar in the 2 TBI dose subgroups. The probability of neutrophil engraftment was 100% for patients who received TBI 300 cGy versus 91% (95% confidence interval, 86% to 95%) for those who received TBI 200 cGy (P = .64), which was similar after regression analysis adjusting for age, total infused nucleated cell dose, HLA matching to the patient, and comorbidity score. We also investigated whether the lower survival probability and higher cumulative incidence of NRM observed in the dUCB arm of BMT CTN 1101 could be influenced by the TBI 300 cGy patient subset. There was no significant difference in the 1-year incidences of NRM and relapse or in 1-year survival, even after adjustment in multivariate analysis. Patients in BMT CTN 1101 who received TBI 300 cGy and 200 cGy had similar engraftment and early mortality. We conclude that inclusion of a modified regimen for dUCB transplantation had no demonstrable influence on this large randomized trial.

Late-Onset Acute and Chronic Graft-versus-Host Disease in Children: Clinical Features and Response to Therapy.

Although acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) are known causes of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT), the syndrome of late aGVHD is less well understood, particularly in children. We aimed to characterize the clinical features and response to therapy of late aGVHD and cGVHD by retrospectively reviewing 573 consecutive patients age <18 years who underwent their first allogeneic HCT at the University of Minnesota. We included patients with de novo late aGVHD (ie, first occurrence of aGVHD after day +100 post-HCT) and cGVHD. We retrospectively scored cGVHD cases based on the 2014 National Institutes of Health guidelines. At 3 years, 9 patients (2%) had developed late aGVHD, 16 (3%) had overlap cGVHD, and 7 had (1%) classic cGVHD. No cases of joint or genital cGVHD were observed. The overall response to therapy at 6 months was 78% (95% confidence interval [CI], 40% to 97%) after late aGVHD and 43% (95% CI, 23% to 66%) after cGVHD. Higher nonrelapse mortality from day +100 was seen in patients with cGVHD but not in those with late aGVHD compared with patients without GVHD (hazard ratio, 3.6 [95% CI, 1.3 to 10.0] and 1.6 [95% CI, 0.2 to 11.7], respectively). We found variable organ involvement and treatment responses between patients with late aGVHD and those with cGVHD in a single-center pediatric cohort. Further research is needed to investigate the risks and clinical features of late aGVHD and cGVHD in larger cohorts to better understand how to tailor even more effective GVHD preventive and therapeutic approaches in children.

Infusion reactions in natural killer cell immunotherapy: a retrospective review.

BACKGROUND AIMS: The use of natural killer (NK) cells as a cellular immunotherapy has increased over the past decade, specifically in patients with hematologic malignancies. NK cells have been used at the authors' institution for over 15 years. Most patients have a reaction to NK cell infusion. The authors retrospectively analyzed the reactions associated with NK cell infusions to characterize the types of reactions and investigate why some patients have higher-grade reactions than others. METHODS: A retrospective chart review of NK cell infusions was performed at the authors' institution under nine clinical protocols from 2008 to 2016. An infusion reaction was defined as any symptom from the time of NK cell infusion up to 4 h after infusion completion. The severity of infusion reactions was graded based on Common Terminology Criteria for Adverse Events, version 4. Two major endpoints of interest were (i) infusion reaction with any symptom and (ii) grade ≥3 infusion reaction. Multivariable logistic regression models were used to investigate the association between variables of interest and outcomes. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained for each variable. RESULTS: A total of 130 patients were receiving NK cell infusions at the authors' institution. The most common reported symptom was chills (n = 110, 85%), which were mostly grade 1 and 2, with only half of patients requiring intervention. There were 118 (91%) patients with infusion reactions, and only 36 (28%) were grade 3. There was one life-threatening grade 4 reaction, and no death was reported due to infusion reaction. Among grade ≥3 reactions, cardiovascular reactions (mainly hypertension) were the most common, and less than half of those with hypertension required intervention. NK cell dose was not associated with any of the grade 3 infusion reactions, whereas monocyte dose was associated with headache (grade ≤3, OR, 2.17, 95% CI, 1.19-3.97) and cardiovascular reaction (grade ≥3, OR, 2.13, 95% CI, 1.13-3.99). Cardiovascular reaction (grade ≥3) was also associated with in vitro IL-2 incubation and storage time. Additionally, there was no association between grade ≥3 infusion reactions and overall response rate (OR, 0.75, 95% CI, 0.29-1.95). CONCLUSIONS: The majority of patients who receive NK cell therapy experience grade 1 or 2 infusion reactions. Some patients experience grade 3 reactions, which are mainly cardiovascular, suggesting that close monitoring within the first 4 h is beneficial. The association of monocytes with NK cell infusion reaction relates to toxicities seen in adoptive T-cell therapy and needs further exploration.

High incidence of thromboembolism in patients with chronic GVHD: association with severity of GVHD and donor-recipient ABO blood group.

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with systemic inflammation and endothelial dysfunction, increasing risk for thromboembolic events (TEE). In 145 adult recipients who developed cGVHD after a matched sibling or umbilical cord blood donor HCT from 2010 to 2018, 32(22%) developed at least 1 TEE event, and 14(10%) developed 2 TEE events. The 5-year cumulative incidence of TEE was 22% (95% CI, 15-29%) with a median time from cGVHD to TEE of 234 days (range, 12-2050). Median time to the development of LE DVT or PE was 107 (range, 12-1925) compared to 450 days (range, 158-1300) for UE DVT. Cumulative incidence of TEE was 9% (95% CI, 0-20%), 17% (95% CI, 9-25%), and 38% (95% CI, 22-55%) in those with mild, moderate, and severe GVHD, respectively. Higher risk for TEE was associated with cGVHD severity (hazard ratio [HR] 4.9, [95% CI, 1.1-22.0]; p = 0.03), non-O-donor to recipient ABO match compared to O-donor to O-recipient match (HR 2.7, [95% CI, 1.0-7.5]; p = 0.053), and personal history of coronary artery disease (HR 2.4, [95% CI, 1.1-5.3]; p = 0.03). TEE was not associated with 2-year non-relapse mortality or 5-year overall survival.

Steroid-dependent acute GVHD after allogeneic hematopoietic cell transplantation: risk factors and clinical outcomes.

Acute graft-versus-host disease (aGVHD) has various risk factors and outcomes. We defined distinct aGVHD treatment response groups based on response to first-line corticosteroids: steroid sensitive (SS), steroid resistant (SR), and the rarely studied steroid dependent (SD) aGVHD. In 1143 consecutive adult and pediatric allogeneic hematopoietic cell transplant recipients, 385 (34%) developed aGVHD, with 10% having SS aGVHD, 9% SD aGVHD, and 14% SR aGVHD. The only factor significantly associated with SD in comparison with SS was older age (odds ratio [OR], 3.9; 95% confidence interval [CI], 1.4-11.3, when comparing 18- to 60-year-olds with <18-year-olds). Factors significantly associated with SR in comparison with SS were unrelated donor (OR, 3.0; 95% CI, 1.2-7.4) and Minnesota high-risk aGVHD (OR, 2.4; 95% CI, 1.3-4.6). SR aGVHD was independently associated with higher risk for 2-year overall mortality (hazards ratio [HR], 1.8; 95% CI, 1.2-2.8) and nonrelapse mortality (NRM; HR, 2.1; 95% CI, 1.2-3.9). SS and SD GVHD groups had similar overall survival and NRM. The cumulative incidence of chronic GVHD was highest in the SD group, followed by the SR and SS groups (46%, 41%, and 29%, respectively). SD and SS GVHD had similar prognoses, both markedly better than those of the SR groups.

Phase I Dose-Finding, Safety, and Tolerability Trial of Romiplostim to Improve Platelet Recovery After UCB Transplantation.

Platelet recovery is delayed after umbilical cord blood transplant (UCBT). Romiplostim is a thrombopoietin receptor agonist that has the potential to improve platelet engraftment after UCBT. The purpose of this study was to determine the safety profile and maximum tolerated dose (MTD) of romiplostim and to investigate whether romiplostim accelerates platelet recovery post-UCBT. It was a single-center, dose-finding, safety and tolerability phase I trial of weekly romiplostim in 20 adult patients who failed to achieve an un-transfused platelet count of 20 × 109/L by day +28 post-UCBT. Romiplostim was administered at the assigned dose as 6 weekly injections beginning by day +42 post-UCBT. Four dose levels (4, 6, 8, and 10 µg/kg per dose) were evaluated. The MTD of romiplostim was determined by the continual reassessment method, with a goal to identify a dose level with desired toxicity rate of ≤20%. Median age of the patients was 59.5 years, and 60% were female. Eleven patients received nonmyeloablative (NMA) double UCBT, seven patients received myeloablative single UCBT, and two patients received NMA single UCBT. Two patients received 4 µg/kg per dose, two received 6 µg/kg per dose, four received 8 µg/kg per dose, and the remaining 12 received 10 µg/kg per dose. Only five patients completed the full six doses of treatment. Of the 15 patients who received fewer than six doses, 12 were due to a platelet count of >100 × 109/L, two were due to platelet count of >400 × 109/L, and one was due to right upper extremity edema without thrombosis. All romiplostim-treated patients achieved platelet engraftment to 20 × 109/L at a median of 45 days post-UCBT compared to 90% of controls at a median of 45 days (P = .08). Similarly, 90% of romiplostim-treated patients achieved platelet engraftment to 50 × 109/L at a median of 48 days compared to 75% of controls at a median of 52 days (P = .09). All dose levels were effective with low toxicity; therefore, the MTD of romiplostim was 10 µg/kg per dose, and romiplostim is a safe and potentially effective therapy to counter delayed platelet recovery post-UCBT.

First-in-human phase 1 trial of induced regulatory T cells for graft-versus-host disease prophylaxis in HLA-matched siblings.

Human CD4+25- T cells cultured in interleukin 2 (IL-2), rapamycin, and transforming growth factor ß (TGFß) along with anti-CD3 monoclonal antibody-loaded artificial antigen-presenting cells generate FoxP3+ induced regulatory T cells (iTregs) with potent suppressive function. We performed a phase 1, single-center, dose-escalation study to determine the safety profile of iTregs in adults with high-risk malignancy treated with reduced-intensity conditioning and mobilized peripheral blood stem cells (PBSCs) from HLA-identical sibling donors. Sixteen patients were enrolled and 14 were treated (2 productions failed to meet desired doses). One patient each received 3.0 × 106/kg, 3.0 × 107/kg, and 3.0 × 108/kg iTregs with corresponding T-conventional-to-iTreg ratios of 86:1, 8:1, and 1:2. After 3 patients received 3.0 × 108/kg in the presence of cyclosporine (CSA) and mycophenolate mofetil (MMF) with no dose-limiting toxicities, subsequent patients were to receive iTregs in the presence of sirolimus/MMF that favors Foxp3 stability based on preclinical modeling. However, 2 of 2 developed grade 3 acute graft-versus-host disease (GVHD), resulting in suspension of the sirolimus/MMF. An additional 7 patients received 3.0 × 108/kg iTregs with CSA/MMF. In the 14 patients treated with iTregs and CSA/MMF, there were no severe infusional toxicities with all achieving neutrophil recovery (median, day 13). Of 10 patients who received 3.0 × 108/kg iTregs and CSA/MMF, 7 had no aGVHD, 2 had grade 2, and 1 had grade 3. Circulating Foxp3+ iTregs were detectable through day 14. In summary, iTregs in the context of CSA/MMF can be delivered safely at doses as high as 3 × 108/kg. This trial was registered at www.clinicaltrials.gov as #NCT01634217.

Comparison of continuous versus intermittent infusion cyclosporine and impact on transplant related outcomes in allogeneic transplant recipients.

INTRODUCTION: Continuous infusion (CIVI) cyclosporine (CsA) is an alternative for allograft recipients intolerant of twice daily infusions (TDI). The importance of achieving therapeutic levels of CsA early after allogeneic HCT has been demonstrated in previous studies. Our study evaluated the incidence of acute graft versus host disease (GVHD) and survival among patients receiving CIVI vs. TDI CsA during their first allogeneic HCT. METHODS: A retrospective study of adult patients undergoing first allogeneic HCT at the University of Minnesota Medical Center between 2011 and 2017. Patients were grouped according to the administration method. The primary outcome was the occurrence of acute grade II-IV GVHD by day +180. Secondary outcomes included the 1-year incidence of chronic GVHD, relapse, and overall survival. RESULTS: 42 patients intolerant of TDI CsA received CsA via CIVI for >48 hours for a median of 9 days (range, 3-32 days). CsA concentrations were similar between groups. We found no difference between the rates of grade II-IV acute (45% vs 53%, p = 0.59) or chronic (17% vs 30%, p = 0.20) GVHD or overall survival (57% vs 67%, p = 0.10). Subgroup analysis of patients that received myeloablative conditioning or umbilical cord blood did not reveal significant differences in GVHD or overall survival. Cumulative incidence of relapse was higher among the continuous infusion group (39% vs. 23%, p < 0.01). CONCLUSION: Due to the finding of increased risk of relapse, cyclosporine should be administered as traditional twice daily infusion unless necessary. A prospective clinical trial is needed to confirm these results.

Use of Potentially Inappropriate Medications in Older Allogeneic Hematopoietic Cell Transplantation Recipients.

The use of potentially inappropriate medications (PIMs) using Beers criteria and its impact on older allogeneic hematopoietic cell transplantation (HCT) recipients is not known. Here the use of any PIMs and their therapeutic classes in reduced-intensity conditioning allogeneic HCT recipients were compared between older (≥65 years; n = 114) and younger (40 to 64 years; n = 240) patients during their initial HCT admission, defined as the number of days that a patient received 1 or more PIMs between day -14 and day +28. Poisson regression was used to determine rate ratios (RRs) in the 2 groups. In the ≥65 years group, we evaluated the impact of PIMs on Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 toxicities within 100 days and on overall mortality within 1 year post-HCT. The rate of any PIM use was similar in the older and younger groups (RR, .98; 95% confidence interval [CI], .90 to 1.06; P = .65). In terms of PIM classes, the older group had a 48% higher rate of gastrointestinal (GI) medication use (RR, 1.48; 95% CI, 1.32 to 1.65; P < .01) and a 25% higher rate of genitourinary (GU) medication use (RR, 1.25; 95% CI, 1.02 to 1.53; P = .03). Compared with males, females had a 19% higher rate of central nervous system (CNS) medication use (RR, 1.19; 95% CI, 1.03 to 1.37; P = .02) and a 30% higher rate of benzodiazepine use (RR, 1.30; 95% CI. 1.09 to 1.54; P < .01). A high-risk HCT-CI was associated with a higher rate of use of any PIMs (RR, 1.13; 95% CI, 1.01 to 1.26; P = .02), CNS medications (RR, 1.26; 95% CI, 1.04 to 1.53; P = .02) and GU medications (RR, 1.46; 95% CI, 1.09 to 1.94; P = .01). Compared with matched sibling donor HCT recipients, umbilical cord blood transplantation recipients had higher rates of GI medication use (RR, 1.32; 95% CI, 1.14 to 1.53; P < .01) and anticholinergic medication use (RR, 1.30; 95% CI, 1.06 to 1.61; P = .01). In the ≥65 years group, increasing duration of narcotic use was associated with a 1.3-fold (95% CI, 1.0 to 1.7; P = .05) higher risk of overall mortality and a 1.6-fold (95% CI, 1.02 to 2.69) greater odds of CTCAE grade 3-4 toxicities (P = .04). Our data show that older recipients (≥65 years) were as likely as their younger counterparts to receive PIMs. Among older recipients, the use of PIMs, particularly narcotics, was associated with higher mortality and higher incidence of grade 3-4 toxicities. Identifying and reducing the use of PIMs in older HCT recipients may help decrease the burden of adverse events and associated health care costs.

Tissue mast cell counts may be associated with decreased severity of gastrointestinal acute GVHD and nonrelapse mortality.

The functions of mast cells in human graft-versus-host disease (GVHD) are unknown. We studied 56 patients who had an allogeneic hematopoietic cell transplantation (alloHCT) with a biopsy for diagnosis of gastrointestinal tract (GIT) GVHD before any treatment (including steroids): 35 with GIT GVHD, 21 HCT recipients whose biopsies did not confirm GVHD, and 9 with a new diagnosis of inflammatory bowel disease (IBD) as a comparison. The median number of mast cells (mean of CD117+ cells, counted in 3 selected spots under 40× magnification) was similar between patients with GVHD (59 cells) and those without GVHD (60 cells). However, the median number of mast cells was significantly associated with maximum clinical stage of GIT GVHD; the lowest counts of mast cells were observed in the highest clinical stage of GIT GVHD (stage 1, 80; stage 2, 69; stage 3, 54; stage 4, 26; P = .01). Moreover, every decrease by 10 mast cells was associated with increased nonrelapse mortality through 1 year (hazard ratio, 0.77; 95% confidence interval, 0.59-1.00; P = .05). AlloHCT recipients all had significantly fewer mast cells, even those without GVHD compared with those with IBD (median, 59 vs 119; P < .01). The median number of GIT mast cells was also significantly lower in patients who received myeloablative conditioning (61.5 cells) than in those who received reduced intensity conditioning (78 cells) in the entire study population (P = .02). We conclude that GIT mast cells are depleted in all alloHCT patients, more prominently in those receiving myeloablative conditioning and those with severe GIT GVHD. Our novel findings warrant further investigation into the biological effects of mast cells in GIT GVHD.

Validation of Minnesota acute graft-versus-host disease Risk Score.

Using multicenter data, we developed a novel acute graft-versus-host disease Risk Score which more accurately predicts response to steroid treatment, survival and transplant related mortality than other published risk scores based upon clinical grading criteria.1 To validate this Risk Score in a contemporary cohort, we examined 355 recent University of Minnesota patients (2007-2016) diagnosed with acute graft-versus-host disease and treated with prednisone 60 mg/m2/day for 14 days, followed by an 8-week taper. Overall response [complete response + partial response] was higher in the 276 standard risk versus 79 high risk graft-versus-host disease patients at day 14 (71% versus 56%, P<0.01), day 28 (74% versus 59%, P=0.02) and day 56 (68% versus 49%, P<0.01) after steroid initiation. Day 28 response did not differ by the initial graft-versus-host disease grade. In multiple regression analysis, patients with high risk graft-versus-host disease were less likely to respond at day 28 (odds ratio 0.5, 95% CI 0.3-0.9, P<0.01) and had higher risks of 2 year transplant related mortality (Hazard Ratio 1.8, 95% CI, 1.0-2.1, P=0.03) and overall mortality (Hazard Ratio 1.7, 95% CI, 1.2-2.4, P<0.01) than patients with a standard risk graft-versus-host disease. This analysis confirms the Minnesota graft-versus-host disease Risk Score as a valuable bedside tool to define risk in patients with acute graft-versus-host disease. A tailored approach to upfront acute graft-versus-host disease therapy based upon the Minnesota Risk Score may improve outcomes and facilitate testing of novel treatments in these patients.

Pediatric acute GVHD: clinical phenotype and response to upfront steroids.

To better understand the clinical phenotype of acute graft-versus-host disease (GVHD) in children, we examined the GVHD clinical stage, grade, and response to prednisone 60 mg/m2/day PO in a diverse group of 370 pediatric patients with acute GVHD treated from 1990 to 2016 at a single institution. Overall response [complete response (CR) + partial response (PR)] at day 28 occurred in 65%, (CR 52%; PR 13%). Initial GVHD grade did not predict day 28 response. However, the Minnesota GVHD Risk Score predicted response with 68% standard risk (SR)-GVHD patients achieving CR/PR at day 28 versus 48% high risk (HR)-GVHD patients (p < 0.01). Multivariable analysis confirmed that response rates were lower in patients with HR-GVHD [odds ratio (OR), 0.4, p < 0.01] and in recipients of HLA mismatched URD (OR 0.4, p = 0.03). Transplant-related mortality (TRM) at 2 years was greater in HR-GVHD patients, recipients of HLA-partially matched or mismatched unrelated donor (URD) grafts, but not umbilical cord blood (UCB). These data highlight the importance of including children in novel acute GVHD treatment trials. Compared with initial GVHD grade, the Minnesota GVHD Risk Score better demarcates risk of steroid failure and TRM in children and could be used for risk stratification in pediatric acute GVHD studies.

A phase I dose finding study of intravenous voriconazole in pediatric patients undergoing hematopoietic cell transplantation.

To optimize voriconazole dosing in pediatric hematopoietic cell transplantation (HCT), we conducted a phase I study with a modified 3 + 3 dose-escalation followed by an expansion cohort at the maximum tolerated, minimum efficacious dose (MTD/MED). Patients ≤21 years who required voriconazole for prevention or treatment of an invasive fungal infection were assigned to three age groups. Of the 59 evaluable patients, 13 were <2 years, 23 were 2-11, and 23 were 12-21. Therapeutic serum voriconazole troughs (1.5-5 µg/mL) drawn at 7 days after initiation determined efficacy. The MTD/MED was 12 mg/kg/dose q12 h × 2 loading doses, then 10 mg/kg/dose q12 h in patients <2, and was 10 mg/kg/dose q12 h in patients 2-11. The 12-21 age group had no dose-limiting toxicity at 8 mg/kg/dose q12 h; however, the MED was not reached. Drug-related AEs ≥grade 3 included increased bilirubin, transaminases, and creatinine, all occurring in <10%. There was no significant association between supra-therapeutic troughs and AEs. Five of 17 patients who had supra-therapeutic troughs (29%) had an AE, compared to 8 of 42 who did not (19%, p = 0.38). Observational population pharmacokinetic analysis demonstrated that inter-individual variability on voriconazole clearance was >100% CV, and clearance increased with age.

Follistatin and Soluble Endoglin Predict 1-Year Nonrelapse Mortality after Allogeneic Hematopoietic Cell Transplantation.

Damage-associated angiogenic factors (AFs), including follistatin (FS) and soluble endoglin (sEng), are elevated in circulation at the onset of acute graft-versus-host disease (GVHD). We hypothesized that regimen-related tissue injury also might be associated with aberrant AF levels and sought to determine the relevance of these AF on nonrelapse mortality (NRM) in patients with acute GVHD and those without acute GVHD. To test our hypothesis, we analyzed circulating levels of FS, sEng, angiopoietin-2 (Ang2), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) A and B, placental growth factor (PlGF), and soluble VEGF receptor (sVEGFR)-1 and -2, in plasma samples from patients enrolled on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402 (n = 221), which tested GVHD prophylaxis after myeloablative hematopoietic stem cell transplantation (HCT). We found that the interaction between FS and sEng had an additive effect in their association with 1-year NRM. In multivariate analysis, patients with the highest levels of day +28 FS and sEng had a 14.9-fold greater hazard ratio (HR) of NRM (95% confidence interval, 3.2 to 69.4; P < .01) when compared with low levels of FS and sEng. We validated these findings using an external cohort of patients (n = 106). Pre-HCT measurements of FS and sEng were not associated with NRM, suggesting that elevations in these factors early post-HCT may be consequences of early regimen-related toxicity. Determining the mechanisms responsible for patient-specific vulnerability to treatment toxicities and endothelial damage associated with specific AF elevation may guide interventions to reduce NRM post-HCT.