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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 with10-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.

Genetic variants may influence the pharmacokinetics and pharmacodynamics (PKPD) of cyclophosphamide (CY). CY plays a critical role in conditioning chemotherapy for hematopoietic cell transplantation (HCT), but its use is limited by toxicity. We explored the effect of genetic variants, potentially affecting PKPD of CY, and outcomes after HCT.This observational pharmacogenomic study included 85 adults with hematologic malignancies who received reduced intensity conditioning with CY, fludarabine, and total body irradiation. We collected recipient DNA prior to HCT and evaluated 97 candidate variants in 66 genes and 3 metabolism phenotypes potentially involved in PKPD pathways of CY. In multivariable analysis we investigated the association between the genotypes and four clinical outcomes: Day 180 non-relapse mortality (NRM) and day 180 overall survival (OS), acute graft-versus-host-disease (aGVHD) grades 2-4, and engraftment. p values were not adjusted for multiple testing.The median recipient age was 63 years (range 21-75). Acute myeloid leukemia was the most common diagnosis (34%; n = 29). In multivariable analysis adjusted for exposure to phosphoramide mustard, the final active metabolite of CY, we identified 6 variants in 6 genes associated with at least one of the clinical outcomes. An ABCC4 variant (rs9561778) was associated with poor Day 180 NRM (p 0.01), MUTYH variant (rs3219484) with higher Day 180 NRM and aGVHD (both p 0.01), and SYNE1 variant (rs4331993) with better Day 180 OS and engraftment (both p ≤ 0.01).The present study suggests that genetic variants influencing the PKPD of CY may help identify patients at risk for inferior outcomes after HCT using CY-based reduced-intensity conditioning.

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 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.

Background: Limited studies report a wide range of venous thromboembolism (VTE) incidence among allogeneic hematopoietic cell transplant (alloHCT) recipients. Chronic GVHD (cGVHD) is an immune mediated complication after alloHCT associated with vascular endothelial damage and prolonged systemic inflammation. We hypothesized that patients developing cGVHD are a subgroup at particularly high risk for VTE. Aims: To assess VTE incidence, sites of involvement, and risk factors in patients with cGVHD and to examine the impact of VTE on clinical outcomes after alloHCT. Methods: We performed a retrospective cohort study of all 145 patients who developed cGVHD after a matched sibling (MSD) and umbilical cord blood (UCB) donor alloHCT from 2010 to 2018. VTE was defined as a new confirmed event by imaging at any time after cGVHD diagnosis. VTE sites were categorized as upper extremity (UE), lower extremity (LE) deep vein thrombosis (DVT) or pulmonary embolus (PE). We assessed the cumulative incidence of VTE treating non-VTE mortality as a competing risk. Multivariate regression was used to evaluate the independent association of risk factors with the incidence of VTE using predefined factors in our model including gender, age, DRI, cGVHD severity, days to cGVHD from transplant and platelet level. We accounted for multiple events of VTE using PWP regression. Cox and Fine and Gray regressions were used to evaluate the independent association of time-dependent VTE on overall survival (OS) and non-relapse mortality (NRM), respectively using propensity scoring to control for confounding.. Results: Median age at time of cGVHD diagnosis was 52 years (range 19-74). 104 (72%) patients received MSD and 41 (28%) UCB alloHCT. Of the 145 patients with cGVHD, 32 (22%) developed either 1 or 2 VTE events and 14 (10%) developed 2 VTE events. The first VTE events were PE (n=6, 19%), and DVT (n=26, 81%; n=17 LE, n= 8 UE and n=5 catheter related UE DVT); one patient developed an IVC thrombus. The second VTE events were PE (n=2, 14%), and DVT (n=12, 86%; n=5 LE, n= 7 UE and n=4 catheter related UE DVT). Most patients were on corticosteroids at the first (n=28, 88%) and second (n=10, 71%) VTE with a median dose of (0.3 and 0.2 mg/kg/day, respectively) ± additional immunosuppression therapies. The cumulative incidence of VTE through 5 years post cGVHD diagnosis was estimated at 22% (95% CI: 15-29%) with median time from cGVHD diagnosis to VTE of 234 days (IQR 85-599). Median time to the development of LE DVT or PE was shorter than UE DVT (107 vs 450 days, respectively). Incidence was higher in males (24% vs 18%), and was not significantly different by age (< or ≥50), BMI (< or ≥30), HCT- comorbidity index, donor type, conditioning regimen and GVHD prophylaxis. Cumulative incidence was higher (50%) in patients with high/very high risk DRI compared to 19% in those with low and intermediate risk DRI. VTE incidence was highest in patients with de novo cGVHD (25%) compared to quiescent (20%) and progressive type (17%). Cumulative incidence was 9%, 17% and 38% in those with mild, moderate and severe GVHD respectively. Patients with lung, gastrointestinal, genitourinary and liver cGVHD had a higher incidence of VTE. Patients developing cGVHD >6 months from HCT had a higher incidence of VTE (24% vs 19%). In multivariate analysis, high/very high risk DRI was associated with higher risk of VTE (HR 2.5; 95% CI; 1.2-5.3) (Figure 2). VTE was not associated with a significantly higher 2-year NRM (HR 1.2; 95% CI; 0.4-3.6) or 5 year OS (HR 1.4; 95% CI; 0.7-3.0). Conclusion: Patients who develop cGVHD after alloHCT have a high incidence VTE. Identifying a subgroup at a particularly high risk for VTE could inform thromboprophylaxis and other supportive care strategies for prevention of such events. Disclosures Bachanova: Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; FATE: Research Funding; BMS: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. Blazar:Tmunity: Other: Co-founder; Magenta Therapeutics: Consultancy; KidsFirst Fund: Research Funding; Fate Therapeutics Inc.: Research Funding; Childrens' Cancer Research Fund: Research Funding; BlueRock Therapeuetic: Consultancy; BlueRock Therapeutics: Research Funding. Brunstein:Astex: Research Funding; AlloVir: Other: Advisory board; Magenta: Research Funding; Gamida: Research Funding. Holtan:CSL Behring: Other: Clinical trial data adjudication; BMS: Consultancy; Generon: Consultancy; Incyte: Consultancy. Janakiram:Takeda, Fate, Nektar: Research Funding. Gangaraju:Sanofi Genzyme, Consultant for Cold Agglutinin Disease: Consultancy. MacMillan:Talaris Therapeutics, Inc: Consultancy; Angiocrine Biosciences, Inc.: Consultancy; Equillium, Inc.: Consultancy; Fate Therapeutics, Inc.: Consultancy; Mesoblast: Consultancy. Rashidi:Synthetic Biologics: Other: DSMC member (1 trial) and related honorarium. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy. Arora:Pharmacyclics: Research Funding; Fate Therapeutics: Consultancy; Kadmon: Research Funding; Syndax: Research Funding.

Data are limited on whether to adjust high-dose chemotherapy before autologous hematopoietic cell transplant (autoHCT) in obese patients. This study explores the effects of dose adjustment on the outcomes of obese patients, defined as body mass index (BMI) >= 30 kg/m(2). Dose adjustment was defined as a reduction in standard dosing >= 20%, based on ideal, reported dosing and actual weights. We included 2 groups of US patients who had received autoHCT between 2008 and 2014. Specifically, we included patients with multiple myeloma (MM, n = 1696) treated with high-dose melphalan and patients with Hodgkin or non-Hodgkin lymphomas (n = 781) who received carmustine, etoposide, cytarabine, and melphalan conditioning. Chemotherapy dose was adjusted in 1324 patients (78%) with MM and 608 patients (78%) with lymphoma. Age, sex, BMI, race, performance score, comorbidity index, and disease features (stage at diagnosis, disease status, and time to transplant) were similar between dose groups. In multivariate analyses for MM, adjusting for melphalan dose and for center effect had no impact on overall survival (P = .894) and treatment-related mortality (TRM) (P = .62), progression (P = .12), and progression-free survival (PFS; P= .178). In multivariate analyses for lymphoma, adjusting chemotherapy doses did not affect survival (P = .176), TRM (P = .802), relapse (P = .633), or PFS (P = .812). No center effect was observed in lymphoma. This study demonstrates that adjusting chemotherapy dose before autoHCT in obese patients with MM and lymphoma does not influence mortality. These results do not support adjusting chemotherapy dose in this population. (C) 2018 American Society for Blood and Marrow Transplantation.

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., Key points Patients with chronic GVHD after allogeneic hematopoietic cell transplantation are at high risk for thromboembolic events occurring years after diagnosis. More severe chronic GVHD, non-O donor-recipient ABO compared to O-O match and personal history of coronary artery disease are associated with higher risk of thromboembolic events.

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.

OBJECTIVES Higher MMF dose can reduce acute GVHD risk after allogeneic hematopoietic cell transplantation (HCT). We examined the effect of MMF dose, relative to patient actual body weight (mg/kg/day), on outcomes of 680 adults after HCT. METHODS MMF was combined with cyclosporine (n = 599) or sirolimus (n = 81). We divided MMF dose/kg/day in quartiles. RESULTS The median time to grade II-IV acute GVHD was 32 days. The incidence of grade II-IV acute GVHD at day 30 was 30% in 1st (

CD33 is a transmembrane protein that is found on cells of myeloid lineage. It is also intensely expressed on acute myeloid leukemia (AML) progenitor cells but not on normal stem cells. It internalizes on binding and dimerization, making it a specific and ideal target for AML therapeutics and drug delivery. Several targeted therapies have been tested and many are still currently in development. Gemtuzumab ozogamicin was the first and only CD33-directed antibody-drug conjugate to be US Food and Drug Administration approved for AML. Other targeted agents have not achieved such success. Promising new strategies include cellular therapy mechanisms and linker molecules. This is an exciting target that requires a considerable amount of precision to yield clinical benefit.

Catheter-related thrombosis (CRT) occurs frequently during autologous hematopoietic cell transplantation (AHCT) and data regarding the incidence, risk factors, and management are understudied. We evaluated 789 consecutive patients with lymphoma and myeloma that underwent AHCT over 10 years (2006 to 2016) and detected the incidence of CRT was 6.3%; only 32% of CRT were symptomatic. The majority occurred within 100 days of AHCT (86%) and median time from tunneled line placement to CRT was 44 days (range, 11 to 89 days). Outcomes of these 50 patients with CRT were compared with age- and disease-matched AHCT control subjects to identify risk factors. History of prior venous thromboembolism (VTE) (20.9% versus 7.0%, P = .02) was the only significant risk factor. Treatment with low-molecular-weight heparin was tolerated with rare minor bleeding (4%), although CRT recurrence or extension (10%) and subsequent VTE (12%) were common. CRT did not impact on nonrelapse mortality or risk of relapse; 2-year progression-free survival was 55% in CRT cases versus 54% in control subjects (P = .42). CRT appears to be common in patients with lymphoma and myeloma undergoing AHCT and significantly contributes to morbidity. Further study to determine mitigating strategies and modify risk factors for CRT is warranted.

Reduced-intensity conditioning regimens using fludarabine (Flu) and cyclophosphamide (Cy) have been widely used in hematopoietic cell transplantation (HCT) recipients. The optimal exposure of these agents remains to be determined. We aimed to delineate the exposure-outcome associations of Flu and Cy separately and then both combined on HCT outcomes. This is a single-center, observational, pharmacokinetic (PK)-pharmacodynamic (PD) study of Flu and Cy in HCT recipients age ≥18 years who received Cy (50 mg/kg in a single dose), Flu (150 to 200 mg/m(2) given as 5 daily doses), and total body irradiation (TBI; 200 cGy). We measured trough concentrations of 9-β-D-arabinosyl-2-fluorade-nine (F-ara-A), an active metabolite of Flu, on days −5 and −4 (F-ara-A(Day-5) and F-ara-A(Day-4), respectively), and measured phosphoramide mustard (PM), the final active metabolite of Cy, and estimated the area under the curve (AUC). The 89 enrolled patients had a nonrelapse mortality (NRM) of 9% (95% confidence interval [CI], 3% to 15%) at day +100 and 15% (95% CI, 7% to 22%) at day +180, and an overall survival (OS) of 73% (95% CI, 63% to 81%) at day +180. In multivariate analysis, higher PM area under the curve (AUC) for 0 to 8 hours (PM AUC(0–8 hr)) was an independent predictor of worse NRM (P < .01 at both day +100 and day +180) and worse day +180 OS (P < .01), but no associations were identified for F-ara-A trough levels. We observed lower day +100 NRM in those with both high F-ara-A(Day-4) trough levels (≥40 ng/mL; >25th percentile) and low PM AUC(0–8 hr) (16-fold higher NRM. These results warrant further investigation to optimize reduced-intensity regimens based on better PK-PD understanding and possible adaptation to predictable factors influencing drug clearance.

Background The American Geriatric Society has established criteria (Beers criteria) for Potentially Inappropriate Medications (PIMs) in older (65+y) adults (J Am Geriatr Soc. 2019 Apr;67(4):674-694). The use of PIMs in allogeneic hematopoietic cell transplant (allo-HCT) and its impact on outcomes is unknown. Methods The use of PIMs, in defined categories [anticholinergics, central nervous system (CNS), benzodiazepines, gastrointestinal (GI), genitourinary (GU), and narcotics] in older (≥ 65y) allo-HCT recipients were compared to younger recipients [(40-64y undergoing reduced intensity conditioning (RIC)] during initial HCT admission (day-14 to +28 post HCT). Use of PIMs was defined as the number of days a patient received 1 or more PIMs between d-14 to +28. Medications were retrieved from medical records and categorized by Beers criteria for 354 allo-HCT recipients ≥ 40y in 2 groups (40-64y RIC, n=240; and 65+y RIC, n=114). Poisson regression determined the log use of PIMs in the 2 groups. In 65+y group, we evaluated the impact of PIMs on the incidence of CTCAE grade 3 and 4 toxicities; and non-relapse mortality (NRM). All analyses were adjusted or length of hospital stay. Results All PIMs: The median (range) days of all PIMs in 65+y RIC recipients [94 (24-279)] was similar to 40-64y RIC recipients [101 (8-441), p=0.48, confirmed in Poisson regression (Figure 1) [65+y RIC vs 40-64y RIC log change 0.0, p=1.0). Patients with a high (vs. low) HCT-CI score received more days of all PIMs (p=0.02). PIM Categories (Figure 1) were compared and 65+y recipients received fewer days of benzodiazepines (log change -0.18, p=0.04) or narcotics (-0.21, p=0.04), but more days of anticholinergics (0.22, p=0.03) and GI PIMs (0.16, p 65+y group: In adjusted regression analysis, increasing days of narcotics was associated with a 1.6 fold (95% CI 1.1-2.6, p=0.03) higher risk of NRM. Increasing days of narcotics was also associated with a 1.66 fold (95% CI 1.02-2.69) greater odds of grade 3-4 toxicities, p=0.04 (Figure 2). More days of all PIMs was associated with a 5 times greater odds of discharge to rehab or a nursing facility (95% CI 1.43-10.0, p Conclusions Older recipients (65+y) receive PIMs as frequently as younger recipients (40-64y). Females, those with a high HCT-CI and UCB recipients receive PIMs more frequently. Amongst older recipients, use of PIMs, particularly narcotics, was associated with a higher NRM and higher risks of grade 3-4 toxicities. Identifying and reducing use of PIMs in older HCT recipients may help lower the burden of adverse events and associated health care costs.

Regimen-related toxicities with high-dose therapy followed by hematopoietic cell rescue leads to considerable patient distress, morbidity, and high readmission rates. Palifermin is a recombinant keratinocyte growth factor that is Food and Drug Administration-approved to decrease severe oral mucositis (OM) associated with autologous hematopoietic cell transplantation (ASCT) for hematologic malignancies. We added palifermin as a supportive care measure for patients with lymphoma undergoing ASCT with BEAM conditioning. We compared patients receiving palifermin (n = 35) with historical controls (n = 38) for toxicity and readmission outcomes. The cumulative incidence of OM of any grade was 23% in the palifermin-treated patients and 42% in the control group. Patients receiving palifermin were less likely to be readmitted (57% versus 82%; P = .04), had fewer hospital readmission days (median, 4 days versus 7 days; P.01), and had fewer total days in the hospital through day +30 after ASCT (median, 12 days versus 15 days; P = .05). Fewer patients in the palifermin group had20 days in the hospital through day +30 (9% in the palifermin group versus 23% of controls). Adverse events associated with palifermin were mild and transient. The addition of palifermin limits severe regimen-related toxicities and decreases readmissions and duration of hospital stay. This and other measures are needed to identify comprehensive and cost-effective approaches, possibly including palifermin, to prevent severe regimen-related toxicities and decrease health care resource utilization.

The use of calcineurin inhibitors (CNIs) to reduce the risk of graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) requires intensive post-transplantation toxicity monitoring. Sirolimus-based GVHD prophylaxis is associated with a favorable toxicity profile and requires less intensive monitoring. However, the efficacy of sirolimus-based regimen compared with CNI-based regimen has not been evaluated in the setting of reduced-intensity conditioning (RIC) double umbilical cord blood (UCB) HCT. We compared outcomes of patients receiving sirolimus/mycophenolate mofetil (MMF) (n = 37) or cyclosporine (CSA)/MMF (n = 123) in an ongoing phase II study of RIC UCB transplantation. In multiple regression analysis, sirolimus/MMF did not influence the risk of grades II to IV or grades III and IV acute GVHD. In addition, there was no association between type of GVHD prophylaxis and hematopoietic engraftment. Infection density analysis found a significantly lower risk of infections with sirolimus/MMF between days +46 and +180 after HCT compared with CSA/MMF (3.4 versus 6.3 per 1000 patient-days, P = .03); however, no difference was observed before day +45. Sirolimus/MMF use resulted in no thrombotic microangiopathy, fewer instances of elevated serum creatinine >2 mg/dL (14% versus 45%; P

No clear dosing guidelines exist for cyclophosphamide (Cy) dose adjustments in obese patients treated with high-dose chemoradiotherapy followed by autologous hematopoietic cell transplantation (HCT). We prospectively compared the outcomes of high-dose Cy/total body irradiation (TBI) conditioning in 147 non-Hodgkin lymphoma (NHL) patients in 3 weight groups: nonobese (

The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell transplantation (HCT), remains a major challenge. To potentially address this problem, we evaluated the effect of prophylactic foscarnet administered twice daily beginning on day +7 and continuing through engraftment in 25 patients. To determine the impact of foscarnet on HHV-6, engraftment, and other transplantation outcomes, we compared results in 61 identically treated patients with hematologic malignancies. Treatment and control groups underwent reduced-intensity conditioning UCB HCT with a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation 200 cGy with or without antithymocyte globulin (ATG), using sirolimus plus mycophenolate mofetil immune suppression. The treatment and control groups were similar in terms of age, disease risk, use of ATG, Hematopoietic Cell Transplantation Comorbidity Index, and graft CD34 cell dose; however, foscarnet-treated patients were less likely to receive a double UCB graft and to be treated more recently (2016 to 2018). The cumulative incidence of HHV-6 reactivation by day +100 was 63% for all patients (95% confidence interval [CI], 51% to 75%) and was not significantly different between the 2 groups. HHV-6 reactivation occurred at a median of 34 days in the foscarnet group and 25.5 days in the control group. The incidence of neutrophil engraftment at day 42 was higher in the foscarnet group compared with the control group (96%; [95% CI, 83% to 100%] versus 75% [95% CI, 64% to 85%]; P< .01). The cumulative incidence of platelet engraftment by 6 months was 92% (95% CI, 69% to 100%) for the foscarnet group versus 75% (95% CI, 60% to 90%) for the control group (P= .08), and multivariate analysis identified the use of foscarnet as an independent predictor of better platelet engraftment. No patients died as a result of graft failure in recipients of foscarnet, whereas 5 patients died from graft failure in the control group. Six-month overall survival (OS) and nonrelapse mortality (NRM) were better in the foscarnet group (96% versus 72% [P= .02] and 4% versus 18% [P= .07], respectively). Even though foscarnet prophylaxis did not prevent HHV-6 viremia, we observed a delay in time to HHV-6 reactivation, a trend toward differences in engraftment, NRM, and OS compared with historical controls.

Introduction Continuous infusion (CIVI) cyclosporine (CSA) is an alternative for allograft recipients intolerant of twice daily infusions (TDI). Trough concentrations are an accepted surrogate for monitoring therapy, however total exposure may be dependent on peak concentrations not obtained when given via CIVI. Therefore, maintaining the same trough goals for both routes of administration may lead to decreased CSA exposure and subsequent increased rates of graft versus host disease (GVHD). The purpose of this study was to evaluate the incidence of acute GVHD and overall survival among patients receiving CIVI vs. TDI CSA. Methods We performed a retrospective study of adult patients undergoing first allogeneic HCT at the University of Minnesota Medical Center between 2011 and 2017 that received > 48 hours of CSA. All patients initially received CSA via TDI per institutional standard and targeted whole blood trough concentrations of 200-400 ng/mL via HPLC. Any change to CIVI was made at the discretion of the treating physician. All patients were changed to oral CSA when able. Patients were grouped according to administration method; those that received cyclosporine via CIVI for > 48 hours at any time during initial transplant admission were classified as CIVI and those that received CSA exclusively as TDI were classified as TDI. Results 308 patients met inclusion criteria (CIVI 42, TDI 266). Donor type, GVHD prophylaxis, underlying diagnosis, and conditioning intensity were similar between groups. The majority of subjects received HLA-matched sibling or cord blood allografts. There were an equal proportion of myeloablative and reduced intensity conditioning regimens, and nearly all GVHD prophylaxis therapy consisted of cyclosporine combined with either mycophenolate or methotrexate. Forty two patients received CSA via CIVI for > 48 hours for a median of 9 days (range, 3-32 days). The average time of change from TDI to CIVI was 3 days after transplant. The TDI group received only TDI for a median 17 days (range 4-62 days) prior to conversion to oral CSA. CSA concentrations at day -1 and weeks 1, 2, and 3 were similar between the groups (Figure 1). 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) between groups. Subgroup analysis of patients that received myeloablative conditioning did not reveal significant differences in GVHD or overall survival. Conclusion In contrast to previous studies, we did not observe an association of CIVI CSA administration with acute GVHD. Among patients intolerant of bolus CSA infusions, a brief transition to CIVI CSA appears to be a safe and acceptable route of administration without increased risk of GVHD or adverse effects on overall survival.

Although hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic cell transplantation (alloHCT), its risk factors and effects on survival are not well-known. We evaluated HC in a large cohort (n=1321, 2003 – 2012) receiving alloHCT from all graft sources, including umbilical cord blood (UCB). We compared HC patients with non-HC (control) patients and examined clinical variables at HC onset and resolution. Of these 1321 patients, 219 (16.6%) developed HC at a median of 22 days after alloHCT. BK viruria was detected in 90% of 109 tested HC patients. Median duration of HC was 27 days. At the time of HC diagnosis, acute graft-versus-host disease (GVHD), fever, severe thrombocytopenia, and steroid use were more frequent than at the time of HC resolution. In univariate analysis, male sex, age

Mycophenolate mofetil (MMF) is frequently used in hematopoietic cell transplantation (HCT) for graft-versus-host disease (GVHD) prophylaxis and to facilitate engraftment. We previously reported that a higher level of mycophenolic acid can be achieved with an MMF dose of 3 g/day than with 2 g/day. Here, we retrospectively compared clinical outcomes of reduced-intensity conditioning (RIC) double umbilical cord blood (dUCB) HCT recipients receiving cyclosporine A with MMF 2 g (n = 93) versus 3 g (n = 175) daily. Multiple regression analysis adjusted for antithymocyte globulin in the conditioning revealed that MMF 3 g/day led to a 49% relative risk (RR) reduction in grade II to IV acute GVHD rate (RR, .51; 95% confidence interval, .36 to .72; P

BEAM conditioning is well-tolerated and yields similar survival in obese and non-obese patients with lymphoma: no requirement for weight-based dose modifications

Advanced systemic mastocytosis (advanced SM), a rare disease closely associated with KIT mutations (most commonly KIT D816V), encompasses three variants: systemic mastocytosis (SM) with an associated hematologic clonal non-mast cell disorder, aggressive SM, and mast cell leukemia. All variants are associated with shortened survival. Although interferon-alpha or cladribine exhibit efficacy in selected patients, they do not result in cure. Imatinib is approved for the minority of aggressive SM patients with negative or unknown KIT D816V status. The multikinase/KIT inhibitor midostaurin is a promising agent for patients with advanced SM and is currently available on an investigational basis. We recently reported the largest retrospective study of allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with advanced SM (n=57). The evidence from this study and a few case reports indicate that it can cure some patients and lead to long-term survival. However, there is still a significant gap of knowledge regarding the use of this high-intensity therapy in advanced SM. The present paper provides a consensus opinion on methods to optimize decision-making regarding the use of alloHCT in this patient population in light of currently available data. In addition, we outline strategies that combine midostaurin in the peritransplant setting. Such protocols should generate useful outcome data regarding the safety and efficacy of KIT inhibition in conjunction with high-intensity therapy in the treatment of advanced SM.

Patients undergoing hematopoietic cell transplantation (HCT) with reduced intensity conditioning (RIC) commonly receive fludarabine. Higher exposure of F-ara-A, the active component of fludarabine, has been associated with a greater risk of nonrelapse mortality (NRM). We sought to develop a model for fludarabine dosing in adult HCT recipients that would allow for precise dose targeting and predict adverse clinical outcomes. We developed a pharmacokinetic model from 87 adults undergoing allogeneic RIC HCT that predicts F-ara-A population clearance (Clpop) accounting for ideal body weight and renal function. We then applied the developed model to an independent cohort of 240 patients to identify whether model predictions were associated with NRM and acute graft versus host disease (GVHD). Renal mechanisms accounted for 35.6% of total F-ara-A Clpop. In the independent cohort, the hazard ratio of NRM at day 100 was significantly higher in patients with predicted F-ara-A clearance (Clpred) 6.00μg × h/mL (P=0.01). A lower Clpred was also associated with more NRM at month 6 (P=0.01) and trended toward significance at 12months (P=0.05). In multivariate analysis, low fludarabine clearance trended toward higher risk of acute GVHD (P=0.05). We developed a model that predicts an individual's systemic F-ara-A exposure accounting for kidney function and weight. This model may provide guidance in dosing especially in overweight individuals and those with altered kidney function.

Mycophenolate mofetil is used increasingly to provide immunosuppression after nonmyeloablative allogeneic hematopoietic cell transplantation. There is wide variability in the pharmacokinetics of mycophenolic acid (MPA), the active metabolite, and low concentrations are associated with rejection after organ transplantation. We hypothesized that low MPA was associated with poorer engraftment and a higher incidence of acute graft versus host disease. We evaluated the pharmacokinetics in 87 adult subjects undergoing nonmyeloablative-related and nonmyeloablative-unrelated hematopoietic cell transplantation who were receiving 1 g mycophenolate mofetil orally or intravenously every 12 hours plus cyclosporine (INN, ciclosporin). Subjects with an unbound MPA area under the curve (AUC) from 0 to 6 hours of less than 150 ng . h/mL had a higher cumulative incidence of grade II-IV acute graft versus host disease than subjects with a greater AUC (68% versus 40%, P = .02). An unbound AUC from 0 to 12 hours of less than 300 ng . h/mL was also associated with more frequent acute graft versus host disease (58% versus 35%, P = .05). There was no association between graft versus host disease and trough concentrations (P < or = .62). A higher cumulative incidence of engraftment was associated with total MPA trough concentrations greater than 1 microg/mL (P < .01). All engraftment failures occurred in the cord blood recipients. About one half of subjects were below the unbound AUC target after oral dosing with nearly a 5-fold variability in AUC. Intravenous dosing achieved unbound targets better than oral dosing. The current practice of dosing with 1 g twice daily provides inadequate plasma concentrations in many patients, and doses of at least 3 g/d are likely necessary. Therapeutic monitoring of MPA concentrations with dose adjustment into the therapeutic target appears to be necessary for the most effective use of mycophenolate mofetil.

Cyclosporine-based immunosuppression is common after allogeneic hematopoietic stem cell transplantation (HSCT). Elevated cyclosporine concentrations are associated with significant toxicity and often result in the temporary cessation or discontinuation of cyclosporine. Low blood concentrations also result in significant immunologic risks, primarily graft-versus-host disease and loss of stem cell graft. The pharmacokinetics of cyclosporine are highly complex, and maintaining therapeutic and safe cyclosporine concentrations are challenging. Several clinical factors are known to independently influence in vivo cyclosporine pharmacokinetic behavior. However, in the critically ill patient, several of these clinical factors are generally present simultaneously. Unfortunately, there are no studies that have evaluated the combined effects of these clinical factors on cyclosporine disposition in HSCT. The objective of our study is to determine the population pharmacokinetic parameters of intravenous and oral cyclosporine, evaluate the effects of clinical covariates on cyclosporine pharmacokinetics, and develop a model that estimates clearance (Cl) and dose requirements for an individual HSCT patient with these clinical covariates. The authors analyzed 740 cyclosporine steady-state whole blood concentrations in 129 adult patients obtained between day 0 and discharge or 60 days posttransplant, whichever came first. Patients received intravenous cyclosporine at 2.5 mg/kg every 12 hours if body weight was greater than 50 kg, 2.5 mg/kg every 8 hours if less than 50 kg, or 5 to 7.5 mg/kg/d given as a continuous infusion, beginning on day-3. Patients were converted to oral therapy as tolerated. The influence of clinical covariates on the Cl of cyclosporine was tested with a nonlinear mixed effects model (NONMEM). The tested clinical covariates were age, height, body weight on admission, body surface area, sex, type of hematologic malignancy, transplant type, preparative regimen, baseline serum creatinine, T-cell depletion of graft, number of methotrexate doses, day of onset, and maximum grade of acute graft-versus-host disease. The route and frequency of cyclosporine administration, day posttransplant, total bilirubin level, serum creatinine level, actual body weight, presence of concurrent CYP450 enzyme inhibitors and inducers, or nephrotoxins on the day of the cyclosporine blood measurement were also evaluated. Cyclosporine Cl significantly decreased each week posttransplant. The authors found no significant effect of any of the other tested covariates including total bilirubin on Cl. The final regression model for the estimation of Cl is: Cl (L/hr) = ([body weight in kg − 70] ∗ 0.183 + 22.3) ∗ (day posttransplant factor). The corresponding day posttransplant factor estimates are 1.46, 1.32, 1.20, and 1.0 during days 0 to 7, 8 to 14, 15 to 21 and greater than 21 posttransplant, respectively. The interindividual variability in Cl was 27.7%. The dose of intravenous or oral cyclosporine can be calculated using the estimated Cl. Understanding cyclosporine pharmacokinetics and the clinical events that lead to alterations in Cl and exposure is critical in optimizing immunosuppressive therapy. The authors found that cyclosporine Cl significantly decreased posttransplant until day 21. A pharmacokinetics model was developed that incorporates the day posttransplant to predict cyclosporine Cl. Cyclosporine dose requirements in an individual HSCT patient to achieve the desired therapeutic blood target can be estimated using this model.

To determine the comparative anti-emetic efficacy of ondansetron and granisetron in patients undergoing bone marrow transplantation, we performed a double-blind, randomized trial in pediatric and adult patients receiving transplants at the University of Minnesota. The results in 187 patients stratified by age ( or =18 years, n = 136) were analyzed. The average number of emetic episodes in the entire group from day -7 to 2 was 0.86/day for patients receiving ondansetron and 0.73/day for those receiving granisetron (p = 0.32). No differences were noted between the two drugs in total days of complete or major control of emesis or in the number of requests for additional drugs to alleviate symptoms of nausea. The use of total-body irradiation-containing conditioning regimens was associated with a decreased number of emetic episodes compared with regimens of chemotherapy alone. Perceived nausea was evaluated using a nausea scoring system, and no differences were apparent between the granisetron and ondansetron groups; however, reported nausea was significantly higher in females (p

Painful oral mucositis is a common complication after bone marrow transplantation (BMT). Glutamine is a nutrient for rapidly dividing cells and the major energy source for intestinal epithelium. This study tested whether an oral glutamine preparation could decrease the severity of oral mucositis in patients undergoing BMT. Glutamine or a placebo (glycine) were administered from admission until day +28 in 193 BMT patients in a randomized, double-blind, placebo-controlled study at a dose of 1.0 g amino acid/m2/dose swish and swallow four times a day. In autologous BMT patients (n = 87) glutamine was associated with significantly less mouth pain by self report and by opiate use (5.0+/-6.2 days of morphine for glutamine vs 10.3+/-9.8 days for placebo; P= 0.005). Matched sibling BMT patients had no effect by self report and an increased duration of opiate use (23.2+/-5.7 days for glutamine vs 16.3+/-8.3 days for placebo) (P = 0.002). However, day 28 survival of allogeneic patients was improved by glutamine. No significant differences in TPN use, rate of relapse or progression of malignancy, parenteral antibiotic use, acute or chronic GVHD, or days of hospitalization were observed in either autologous or allogeneic recipients. No toxicity of glutamine was observed. We conclude that oral glutamine can decrease the severity and duration of oropharyngeal mucositis in autologous BMT patients but not in allogeneic BMT patients, possibly due to interaction with methotrexate.

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. Our objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute graft vs host disease (GVHD), treatment-related mortality (TRM) and survival after HCT. The preparative regimen consisted of cyclophosphamide 50 mg/kg/day i.v. day −6; plus fludarabine 30-40 mg/m2/day i.v. on days −6 to −2 and TBI 200 cGy on day −1. F-ara-A pharmacokinetics were performed with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A AUC (0-∞) was 5.0 ug*hr/mL (2.0-11.0), clearance 15.3 L/hour (6.2-36.6), Cmin 55 ng/mL (17-166), and concentration on dayzero 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced overall survival. Patients with an AUC(0-∞) greater than 6.5 ug*hr/mL had 4.56 greater risk of TRM and significantly lower survival. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT.

The biological activity of recombinant interleukin-2 in intravenous admixtures containing gentamicin sulfate, tobramycin sulfate, amikacin sulfate, ticarcillin disodium, piperacillin sodium, morphine sulfate, or total parenteral nutrient (TPN) solution was investigated. Recombinant interleukin-2 in a formulation containing human serum albumin was diluted to a therapeutic dose and mixed with the other drugs in test tubes to simulate mixing distal to the Y-site of an i.v. administration set. All test tubes were visually observed for precipitates. Triplicate test samples of recombinant interleukin-2 and interleukin-2 with drug were added to microplate wells containing lymphocyte tissue culture media (an interleukin-2-dependent murine cytotoxic T cell line, CTLL-2) using serial dilutions. The microplates were incubated then pulsed with mouse lymphocyte media containing tritiated thymidine (3H-thymidine). The amount of 3H-thymidine incorporated into lymphocyte DNA was measured using a beta counter. The average counts per minute (cpm) of a sample was analyzed as a function of the logarithm of sample dilution; one interleukin-2 unit was defined as 50% of the maximum cpm measured in the samples. At minimum dilutions, ticarcillin disodium reduced the effect of interleukin-2 on CTLL-2 growth; the other antibiotics and morphine sulfate had no effect. Interleukin-2 mixed with TPN solutions showed slightly enhanced growth of the CTLL-2 line compared with the interleukin-2 standard. Mixtures of multiple antibiotics, morphine, and TPN solutions with and without 20% fat emulsion had no effect on interleukin-2 activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Mycophenolic acid (MPA) is the active component of mycophenolate mofetil (MMF). Low MPA exposure is associated with a higher incidence of acute GVHD and possibly worse engraftment. Therapeutic plasma targets have been proposed in hematopoietic cell transplantation (HCT), however, are difficult to achieve in adult patients with MMF doses of 2 g/day. Mycophenolate pharmacokinetics was prospectively studied in adults undergoing nonmyeloablative HCT who received MMF 3 g/day with CYA. The first 15 individuals received 1.5 g every 12 h and the second 15 received 1 g every 8 h. Sampling was performed in each patient with i.v. and oral administration. There were no differences in total or unbound MPA 24-h cumulative area under the curves (AUCs), concentrations at steady state (Css) or troughs between the two dosing regimens (all P>0.01). The previously proposed total MPA Css target of 3 microg/ml and trough >or=1 micro/ml were achieved in only 13-27% and 20-53% of patients, respectively, on 3 g/day. However, the 3 g/day regimens readily achieved satisfactory unbound 24-h cumulative AUC targets of 0.600 microg(*)h/ml in 87-100% of subjects. There appears to be no significant difference in daily MPA exposure when MMF of 3 g/day is divided into two or three equal doses.

Purpose Because the secretory diarrhea of acute graft-versus-host disease (GvHD) of the gut induces serious metabolic and nutritional disturbances, this study was initiated to assess the use of a somatostatin analogue, octreotide acetate, as adjunctive therapy for severe GvHD of the gut with massive diarrhea. Patients and methods In a pilot study, six patients with biopsy-confirmed acute gut GvHD after allogeneic bone marrow transplantation received octreotide 50 to 250 μg three times a day subcutaneously. Results Three of the six treated patients had a prompt and dramatic reduction in stool volume within 1 to 3 days of initiation of octreotide therapy. Conclusions Somatostatin and its analogues have been used successfully in diarrheal states by antagonism of neuropeptide overproduction, although other potential therapeutic mechanisms include inhibition of fluid secretion, enhanced salt absorption, and inhibition of gut motility. Somatostatin and its analogues may be promising adjunctive agents in the treatment of gastrointestinal GvHD, although assessment in a controlled trial will be required to confirm their therapeutic efficacy.

This study determined the oral bioavailability of mycophenolic acid, the active metabolite of mycophenolate mofetil, in patients undergoing nonmyeloablative hematopoietic cell transplantation. Eighteen adults receiving a preparative regimen containing fludarabine, cyclophosphamide, and total body irradiation were studied. Immune suppression consisted of cyclosporine and mycophenolate 1 g twice daily. Pharmacokinetic variability was high after intravenous and oral dosing. Intravenous dosing resulted in a median area under the curve (AUC) of 28.3 microg x h/mL (range, 9.96-70.4) and an oral AUC of 16.7 microg x h/mL (range, 9.38-35.3). Cmax after intravenous and oral dosing was 12.18 and 5.29 microg/mL, respectively. The median oral bioavailability was 72.3% (20.5%-172%), with 8-fold variability. Five patients (28%) had an oral bioavailability < or = 50%. At time of oral pharmacokinetics, 15 patients (83%) had an AUC(0-12) < 30 microg x h/mL. The initial oral dose should be at least 25% greater than the intravenous dose with follow-up assessment of plasma concentrations.

Background. This study examines the effects of the most commonly used graft-versus-host disease (GVHD) prophylactic drugs on inducing apoptosis and suppressor cell function of human umbilical cord blood (UCB) CD4 + 25 + Treg and CD4 + 25 - cells. Methods. Cyclosporin A (CSA), methylprednisolone (MP), methotrexate (MTX), and mycophenolic acid (MPA) were added to the final 6 days of expansion cultures of Treg or CD4 + 25 - T-cells isolated from the same donor and each concurrently cultured under the same conditions. Cell viability was measured for CD4 + 25 + as compared to CD4 + 25 - T-cells and Treg function was assessed. The effects of these immunosuppressive drugs, Treg cells, or both also were tested in a primary allogeneic mixed lymphocyte response (MLR) response. Results. The cell viability percentages were lower for CD4 + 25 - cells than for Treg cells when MP, MTX, or MPA was added for the last 6 days of an expansion culture. Under these interleukin (IL)-2 based expansion conditions, CSA had no effect. The addition of any of the four GVHD prophylactic agents to the expansion phase of culture did not reduce the MLR suppressive capacity of Treg cells. Overall MLR suppression was increased when Treg cells were added along with CSA and MP to a primary MLR culture, whereas MTX modestly reduced Treg suppression. Conclusion. These data indicate a general resistance of expanded UCB Treg cells to GVHD immune suppressive agents and support trials to test UCB Treg infusions under the cover of GVHD prophylactic drugs in hematopoietic cell transplantation.

Renal transplant patients with suboptimal mycophenolic acid (MPA) areas under the curves (AUCs) are at greater risk of acute rejection. In hematopoietic cell transplantation, a low MPA AUC is also associated with a higher incidence of acute graft versus host disease. Therefore, a limited sampling model was developed and validated to simultaneously estimate total and unbound MPA AUC0-12 in hematopoietic cell transplantation patients.Intensive pharmacokinetic sampling was performed at steady state between days 3 to 7 posttransplant in 73 adult subjects while receiving prophylactic mycophenolate mofetil 1 g per 12 hours orally or intravenously plus cyclosporine. Total and unbound MPA plasma concentrations were measured, and total and unbound AUC0-12 was determined using noncompartmental analysis. Regression analysis was then performed to build IV and PO, total and unbound AUC0-12 models from the first 34 subjects. The predictive performance of these models was tested in the next 39 subjects.Trough concentrations poorly estimate observed total and unbound AUC0-12 (r0.48). A model with 3 concentrations (2-, 4-, and 6-hour post start of infusion) best estimated observed total and unbound AUC0-12 after IV dosing (r0.99). Oral total and unbound AUC0-12 was more difficult to estimate and required at least 4 concentrations (0-, 1-, 2-, and 6-hour post dose) in the model (r0.85). The predictive performance of the final models was good. Eighty-three percent of IV and 70% of PO AUC0-12 predictions fell within +/-20% of the observed values without significant bias.Trough MPA concentrations do not accurately describe MPA AUC0-12. Three intravenous (2-, 4-, 6-hour post start of infusion) or 4 oral (0-, 1-, 2-, and 6-hour post dose) MPA plasma concentrations measured over a 12-hour dosing interval will estimate the total and unbound AUC0-12 nearly as well as intensive pharmacokinetic sampling with good precision and low bias. This approach simplifies AUC0-12 targeting of MPA post hematopoietic cell transplantation.

Fludarabine (FLU) is a chemotherapeutic and immunosuppressive agent used in reduced intensity conditioning (RIC) regimens prior to hematopoietic stem cell transplantation. High exposure to F-ara-A, the active metabolite of FLU, has been associated with more treatment related mortality (TRM). No standard dosing models allow estimation of exposure and individualized dosing. We developed a population pharmacokinetic model for adults that estimates F-ara-A clearance (Cl) from which area under the curve (AUC0-∞) is calculated.(Clin Pharmacol Ther, Vol95, S87, March 2014) We retrospectively tested the performance of the model by associating individual predicted AUC 0-∞to clinical outcomes. TV F-ara-A CL (L/hr) = (7.04 + 3.9 * (CrCl/85) * (70/IBW)) * (IBW/70)0.75 AUC 0-∞ (μg-hr/ml) = Administered dose in F-ara-A equivalents (mg)/Estimated TV F-ara-A Cl (L/hr) Adult HCT patients (n=301, 2008 to 2014) who received IV FLU in their conditioning regimen were included. FLU doses, actual body weight, height, serum creatinine, along with TRM, engraftment and acute GVHD were reviewed. TRM was defined as death without relapse or disease progression. GVHD was staged and graded according to the standard GVHD criteria. The median age (range) was 58 yrs. (18-75). 131(43.5%) received PBSCT, 31(10.3%) bone marrow and cord blood in 139(46.2%). FLU doses were 25-40 mg/m2/day; nearly all x 5 days. The median (range) daily dose was 67 mg (38 mg-100 mg). The pharmacokinetic model was used to estimate the F-ara-A Cl and then predict their AUC0-∞ from the first dose and the total cumulative AUC0-∞. Recursive partitioning regression analysis was used to determine the optimal cut points for the first dose AUC0-∞ and cumulative AUC0-∞towards clinical outcomes. The cumulative incidence of engraftment, TRM and acute GVHD (grades II-IV and III-IV) was calculated using death prior to event as a competing risk. The proportional hazards model of Fine and Gray was used to assess the association of F-ara-A exposures towards TRM, acute GVHD and engraftment. The median (range) F-ara-A Cl, AUC0-∞ and cumulative AUC0-∞ predicted from the model were 10.92 L/hr (7.51-15.37), 4.79 μg-hr/ml (2.40 -7.52) and 23.93 μg-hr/ml (11.20-37.62), respectively. Patients with a higher first dose AUC0-∞ ≥6 μg-hr/ml had a higher incidence [95%CI] of day 100 TRM (20% [7-33%] vs 6% [4-9%], p An AUC0-∞ ≥4 μg-hr/mL led only to a marginally higher risk of 6 month GVHD grades II-IV and III-IV (42% [35-48%] vs 28% [14-41%] p=0.07 and 43% [37-50] vs. 30%[16-44%], p=0.06, respectively) compared to Lower F-ara-A clearance and higher AUC 0-∞ were associated with greater risks of TRM and acute GVHD. These data support personalizing FLU dose rather than using empirical body surface area based dosing. Targeting FLU therapy may improve outcomes after HCT. Disclosures No relevant conflicts of interest to declare.

CY and FLU are chemotherapeutic agents often used in RIC regimens. RIC regimens may yield lower transplant related complications and toxicities as compared to myeloablative conditioning. However TRM at 12 months still approximates 30%. We previously reported that high F-ara-A (active metabolite of FLU) exposure was associated with more TRM at a FLU dose of 40 mg/m2, but the relationship is unknown at lower doses. Similarly, phosphoramide mustard (PM, the active metabolite of CY) may influence clinical outcomes. Thus we studied the relationship between clinical outcomes and systemic exposure of F-ara-A at lower doses and PM. Forty adults undergoing allogeneic RIC HCT were prospectively studied from March 2013 to May 2014. All patients received FLU, CY and TBI as conditioning and cyclosporine or sirolimus, plus mycophenolate for posttransplant immunosuppression. Median age was 62 years (21-72). 22 were male and 18 female. The stem cell sources were sibling or unrelated donor PBSC (n=22, 55%), cord blood (n=13, 32.5%) or bone marrow (n=5, 12.5%). CY 50mg/kg was administered IV over 2 hrs on day -6. Pharmacokinetic samples were obtained at predose and 2, 4, 6, 21, 24 and 45 hrs after the end of infusion. PM was derivatized with diethyldithiocarbamate and measured by ultraviolet detection with HPLC. PM area under the curve (AUC0-last), AUC0-6 and AUC0-24 were calculated using non-compartmental methods (Phoenix WinNonlin Professional 6.3). Fludarabine dosing was 30 mg/m2/d (n=35), 32 mg/m2/d (n=1), 35 mg/m2/d (n=2) and 40 mg/m2/day (n=2) x 5 doses depending on protocol and was administered IV over 1 hr on days -6 to -2. In addition, F-ara-A troughs were obtained at 24 hours after the start of the first infusion on day -6 and 24 hours after start of 2nd infusion. F-ara-A quantification was performed using HPLC-UV. TRM was defined as death due to any cause other than relapse or disease progression. GVHD was staged and graded according to the standard GVHD criteria based on clinical and pathological criteria Recursive partitioning regression analysis was used to determine optimal cut points for PM and F-ara-A pharmacokinetic measures towards TRM at day 100, 6 months and 12 months and the incidence of acute graft vs host disease (GVHD). The cumulative incidence of engraftment, TRM and acute GVHD (II-IV and III-IV) was calculated using death prior to event as a competing risk. The proportional hazards model of Fine and Gray was used to assess the association of F-ara-A exposures towards TRM, acute GVHD and engraftment. The incidence of TRM at day 100 was 13%, 20% at 6 months and 47% at 12 months. The incidence of grades 2-4 and 3-4 acute GVHD was 39% and 25%. In univariate analysis, day 100 TRM risk was significantly higher in patients with a PM AUC0-24 ≥85 ug-hr/ml (relative risk (RR) 36%, [95% CI 9-64%]) vs. AUC0-24 Patients with F-ara-A trough concentration after the second dose ≥75 ng/ml had significantly higher risk of day 100 TRM as compared to patients in whom F-ara-A was Higher PM exposures were associated with increased risk of TRM at day 100 and 6 months. Higher F-ara-A exposures were associated with greater risk of TRM at day 100. No associations were observed towards acute GVHD. These data for the first time show that TRM is associated with high PM exposure. These data also support our earlier findings that overexposure to F-ara-A may be harmful in RIC regimens. Multivariate models adjusting for other important clinical factors will be evaluated as enrollment continues to a larger cohort. In the future predictive pharmacokinetic models may be beneficial in personalizing fludarabine and cyclophosphamide doses. Disclosures No relevant conflicts of interest to declare.

Introduction The use of RIC reduced intensity conditioning (RIC) hematopoietic cell transplant (HCT) has extended the availability of transplantation to older and less medically fit patients. Despite the increased tolerability of RIC HCT, treatment related mortality (TRM) still remains a significant problem. Biomarkers of chemotherapy exposure which are predictive of toxicity or efficacy would be clinically useful in making treatment decisions. We studied phosphoramide mustard (PM), one of the final active metabolites in the complex metabolic pathway of cyclophosphamide (CY), as a biomarker of toxicity and/or efficacy. PM is highly active and undergoes further non-enzymatic degradation to produce nornitrogen mustard which alkylates the guanine on DNA, thereby preventing DNA replication and ultimately leading to cellular death. This is the first report of PM in RIC HCT recipients. Methods We studied 10 patients undergoing allogeneic RIC HCT at the University of Minnesota from March 2013 to June 2013 for PM pharmacokinetics. Median age was 60 years (range 34 - 72). Four patients were male and six female. Patients were transplanted for MDS (n=3), AML (n=2), CLL, CMML, B-cell ALL, Hodgkins lymphoma and mantle cell lymphoma. Allogeneic donor sources were double umbilical cord blood (n=4), sibling peripheral blood (n=4) and matched unrelated donor peripheral blood (n=2). RIC preparative regimen consisted of CY 50 mg/kg x1 dose infused over 2 hours on day-6. CY doses were based on actual body weight except for 2 obese patients whose doses were based on an adjusted body weight and received 15 and 25% dose reductions. Preparative regimen also included fludarabine 30-40 mg/m2/day x5 on days -6 to -2 plus single fraction TBI 200 cGy. PM plasma pharmacokinetics were conducted with the single CY dose at times 0 (prior to infusion), 4, 6, 8 and 26 hours after start of CY infusion. PM was derivatised with DDTC and measured by HPLC with ultraviolet detection. Pharmacokinetic measures were calculated using noncompartmental analysis. Results Median (range) total body weight was 76.7 kg (47.9-108.7) and CY dose was 3680mg (2395 - 5210mg). PM was readily measurable in all plasma samples. AUC0-inf was 108.6 hr*mcg/mL (54.0 – 133.9), Cmax was 6.3 mcg/mL (3.7-7.5), concentration at 24 hours was 0.87 mcg/mL (0.06-2.0) and half-life 7.5 hr (2.9 - 12.9). Since not all patients received the same dose, AUC0-inf was normalized to total CY dose and was 0.028 hr*mcg/mL/mg (0.019 - 0.037). There was a weak correlation between dose normalized AUC0-inf, and CrCl, SCr, BMI and BSA (all r2 Seven patients are alive. Two patients died with TRM at days 37 and 55 posttransplant. Causes of death were graft failure, septic shock secondary to multiple infectious organisms (HHV6, VRE, mucor), and progressive neurological decline, HHV6 encephalopathy and recurrent PRES, respectively. A third patient died of disease progression at posttransplant day 39. The two patients with TRM had 2 of the 3 highest AUCs; 133.9 and 129.8 hr*mcg/mL, respectively. Conclusion We have demonstrated that PM is readily measurable for at least 26 hours in the plasma after CY treatment. Preliminary analysis suggests that PM exposure may be associated with pretransplant total protein. Renal function appears to play a small role in PM exposure although the range of renal function in this cohort was limited. Additional data are needed to determine the relationship between PM exposure and clinical outcomes. Special acknowledgment for financial support from the American Society of Hematology and the Trainee Research Award program (AW). Disclosures: No relevant conflicts of interest to declare.

Fludarabine is a purine analog antimetabolite with antitumor and potent immunosuppressive activity. It is a prodrug that undergoes rapid dephosphorylation to the systemically circulating active compound, F-ara-A. Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of F-ara-A are poorly characterized in HCT recipients and exposure-response relationships remain undefined. Our objective of this study was to study the association between F-ara-A systemic exposures and engraftment, acute graft vs host disease (GVHD) and treatment related mortality (TRM). Eighty seven adult patients with a median age of 55 (range 20–69) years undergoing sibling peripheral blood or bone marrow (n=22) or unrelated cord blood (n=65) donor HCT were enrolled in this pharmacokinetic-pharmacodynamic study. Underlying diseases were ALL (n=6), AML (n=26), CML (n=1), myelodysplasia (n=14), NHL (n=17), Hodgkins (n=8) and other (n=15). Patients received a nonmyeloablative regimen of fludarabine 40 mg/m2/day intravenously (IV) as a single daily dose × 5 days on days -6 to -2 given over one hour (9 were dose reduced and received 30–35 mg/m2/day), cyclophosphamide 50 mg/kg/day IV day -6 and TBI 200cGy single fraction on day -1. Equine antithymocyte globulin 15 mg/kg every 12 hours from days -3 to -1 was administered to 40 subjects. Cyclosporine and mycophenolate mofetil were given beginning on day –3. Pharmacokinetic sampling was performed with the first dose of fludarabine at times 0, 1.6, 2, 3, 4, 6, 8, 12, 24 after the start of the infusion and quantified with HPLC. Median (range) F-ara-A area under the curve (AUC)0-∞ was 5,000 (2,000–11,5000) ng hr/mL, clearance (CL) 15.3 (6.2–36.6) L/hour, concentration 24 hours after the first dose 55 (17–166) ng/mL and concentration on day zero 16.0 (0.1–144.1) ng/mL. Median serum creatinine and creatinine clearance on the first day of fludarabine was 0.9 (0.4–1.5) mg/dL and 82.1 (49.5–153.2) ml/min, respectively. Median time to neutrophil recovery was day 11 (1–38) posttransplant. Graft failure occurred in 14 (16%) individuals. Acute GVHD II-IV and III-IV developed in 47 (54%) and 15 (17%), respectively. TRM occurred in 18 (21%) individuals by 6 months posttransplant. Primary causes of death were organ failure, infection, hemorrhage and ARDS. Higher F-ara-A exposure was associated with greater TRM. The cumulative incidence (95% CI) of TRM at 6 months for individuals with an F-ara-A AUC >6500 ng hr/mL was 50% (23–77) vs 15% (7–23) for AUC ≤ 6500 ng hr/mL (p=0.0005), CL ≤ 12.5 L/hr 45% (24–67%) vs for CL >12.5 L/hr 12% (4–20%)(p=0.0002), concentration at 24 hours >80 ng/mL 64% (33–94%) vs ≤ 80 ng/mL 15% (7–24%) (p30 ng/mL 53% (28–78) vs ≤ 30 14% (5–22%) (p=0.0004). Sixteen percent of subjects had an F-ara-A AUC >6,500 ng hr/ml, 25% had an F-ara-A clearance 80 ng/mL and 20% with a day zero concentration >30 ng/mL. The F-ara-A exposures remained significant towards TRM in multivariate analysis. There was no association between F-ara-A exposures and engraftment or acute GVHD. These data suggest that elevated F-ara-A concentrations are associated with a greater risk of TRM. Prospective testing of fludarabine dose modifications based on pharmacokinetics is needed and may protect patients from the toxicities of fludarabine overexposure.

Mycophenolate mofetil (MMF) is frequently used as part of the immunosuppressive regimen after allogeneic nonmyeloablative HCT. We and others have previously shown that low mycophenolic acid (MPA) exposure, the active component of MMF, is associated with poorer rates of engraftment and increased risk of graft-vs-host disease (GVHD). As therapeutic plasma targets are difficult to achieve in adult HCT recipients with doses of MMF 2 gm/day, higher doses are required. To determine if higher MMF doses of 3 gm/day would achieve the therapeutic plasma targets we conducted a prospective pharmacokinetic study in adult recipients of nonmyeloablative HCT treated with cyclophosphamide 50 mg/kg, fludarabine 200 mg/m2 and total body irradiation 200 cGy in combination with cyclosporine and MMF as either 1.5 gm every 12 hours (n=15) or 1 gm every 8 hours (n=15). MMF was initiated on day -3 intravenously and switched to the oral form within the first week at the same dose. Pharmacokinetic sampling at steady state was performed once in each patient between days -1 and +5 while on intravenous therapy and then repeated once between days 5 and 14 posttransplant after oral administration. There were no differences in total or unbound MPA 24 hour cumulative area under the curve (AUC), concentration at steady state (Css) or troughs between the two dosing regimens. Total MPA 24 hour AUC (median, [range]) exposures were not different between intravenous 1 gm every 8 hours (53.59 [22.86–101.99] mcg*hr/mL) and intravenous 1.5 gm every 12 hours (60.90 [35.89–127.24] mcg*hr/mL) regimen (p=0.34). Unbound MPA 24 hour AUC exposures were also not different between the intravenous 1 gm every 8 hours (0.942 [0.389–1.722] mcg*hr/mL) and intravenous 1.5 gm every 12 hours (1.081 [0.610–2.194] mcg*hr/mL)(p=0.25). Following oral therapy, total and unbound MPA 24 hour AUC exposures after 1 gm every 8 hours and 1.5 gm every 12 hours were also not different (p≥0.43). Total MPA Css after intravenous 1 gm every 8 hours, oral 1 gm every 8 hours, intravenous 1.5 gm every 12 hours, oral 1.5 gm every 12 hours were 2.23 [0.95–4.25], 2.05 [1.32–3.24], 2.53 [1.46–5.24] and 2.35 [1.47–4.05] mcg/ml, respectively (p≥0.15). We previously found that an unbound 24 hour cumulative MPA AUC 0.600 mcg*hr/mL in 87–100% of subjects. All patients with the every 8 hour dosing had neutrophil recovery (ANC >500 cells/uL x 3 consecutive days) at a median [range] of day 10 [6–38] as compared to day 12 [0–31] in those with every 12 hour dosing. Acute GVHD grades II–IV developed in 3 (20%) and 6 (40%) patients in the MMF every 8 hour and every 12 hour dosing cohorts, respectively. When compared to our historical controls, MPA exposure is higher with MMF 3 gm/day compared to 2 gm/day regardless of dosing schedule and achieves adequate exposure in most adult patients. In conclusion, MMF 3 g/day should be considered the standard starting dose for adult patients undergoing nonmyeloablative HCT.

Chemotherapy related complications and risk of graft vs host disease limit HCT to younger patients with good clinical status and organ function. Non-myeloablative (NMA) transplant is now being widely used to extend access to HCT for patients not fit for conventional allografting. However, the incidence of engraftment and toxicity of this procedure can vary. Most NMA preparative therapies include fludarabine, a purine analog antimetabolite infrequently associated with neurotoxicity. In vivo, fludarabine undergoes rapid dephosphorylation to the active compound, F-ara-A which is 40 % renally eliminated and accumulates in renal dysfunction. Given that patients receiving a NMA HCT are often older or have poor renal function we hypothesized that variability in toxicities and clinical outcomes may be related to differences in exposure to F-ara-A. We evaluated the pharmacokinetics of F-ara-A in 29 subjects receiving a fludarabine based NMA HCT and the relationship between pharmacokinetics, engraftment and neurotoxicity. All received fludarabine 40 mg/m2/day IV x 5 days (infused over 1 hour) on days −6 to −2 in combination with cyclophosphamide 50 mg/kg/day IV on day −6 and TBI 200cGy single fraction day −1. Sampling was performed with the 1st and 5th dose of fludarabine. F-ara-A plasma concentrations were measured by HPLC. Patients underwent weekly neurotoxicity evaluation. The median age and weight of subjects was 54.8 years (range, 36–69) years and 79 kg (range, 54.6–134), respectively. Diagnoses were leukemia (n=13), lymphoma (n=7), myelodysplastic syndrome (n=5) and other (n=4). Subjects were transplanted with peripheral blood stem cells from related donors (n=10) and unrelated donor umbilical cord blood (n=19). Median CrCl and total bilirubin on admission was 100 ml/min (range, 49–190) and 0.5 mg/dL (range, 0.2–1.2), respectively. Median F-ara-A area under the curve (AUC0-∞) was 5261 ng hr/mL (range, 2935–7762), half life 9.6 hr (range, 3.1–26.6), clearance 14.5 L/hr (range, 9.4–25.6) and Cmax 851 ng/mL (range, 409–1146). F-ara-A plasma concentrations were slightly higher with dose 5. Correlation (r2) between AUC and age, weight, CrCl, SCr and total bilirubin were all ≤0.1. F-ara-A concentrations were detectable, 13.8 ng/mL (range, 5.7–38.2), on day 0 in all patients. Twenty five (cumulative incidence 89%, 95% CI: 77–100%) patients engrafted at a median of day 7. While neutrophil engraftment occurred in 100% with an AUC >5261 ng hr/mL (n=14), the incidence was 80% (95% CI 60–100%) for those with an AUC

Background: Mycophenolate mofetil (MMF) is a commonly used immune suppressant in nonmyeloablative HCT for establishment of engraftment and prevention of graft vs host disease. MMF is an ester prodrug, which was formulated to enhance the bioavailability of the active form, mycophenolic acid (MPA). MMF is rapidly and extensively (95%) hydrolyzed to MPA by esterases and glucuronidated by UDP glucuronosyltransferases to the primary inactive metabolite, mycophenolic acid glucuronide (MPAG). MPAG is transported to the gut via the bile or excreted into the urine and eliminated. MPAG present in the bile is subject to deglucuronidation where it is converted back to MPA and reabsorbed into the systemic circulation through enterohepatic recycling. Oral MPA AUC is low and highly variable after HCT. Potential reasons for variability are poor and erratic bioavailability due to mucositis, diarrhea, poor motility and diminished oral intake. MPA concentrations are not routinely monitored in many centers, thereby allowing poor oral absorption to go undetected. Since low MPA concentrations are associated with a higher incidence of poor engraftment and graft vs host disease, bioavailability may be of great importance. This study evaluates the oral bioavailability of mycophenolate in the early transplant period, a critical period for immune suppression, when bioavailability is most likely to be perturbed. Methods: Adult recipients of nonmyeloablative HCT who received a prophylactic MMF (1 gm BID) and cyclosporine (5–7.5 mg/kg/day IV) were studied. Pharmacokinetic sampling was performed at steady state with one IV 1g dose of MMF between day -2 and 0 and then again between days 1–10 post-transplant with one PO 1g dose (four 250mg capsules). Total MPA concentration-time data were analyzed using noncompartmental analysis. Bioavailability was determined by the ratio of PO:IV AUC0–12. Results: Thirteen subjects have been studied with a median (range) age of 53 (25–68) yrs and weight of 56.6 (82.5–134 kg). Diagnoses leading to HCT were leukemia (n=6), lymphoma (n=6) and multiple myeloma (n=1). Median (range) total MPA AUC0–12 after IV and PO dosing was 28.6 mcg*hr/mL (9.8–70.4) and 16.3 (9.4–35.3), respectively. Oral bioavailability was calculated for each subject. Median oral bioavailability was 71% with high variability (range 20.5–172.0). Median (range) total MPA Cmax after IV and PO dosing was 12.1 mcg/mL (4.4–35.3) and 5.6 (1.49–15.7), respectively. Conclusion: Oral bioavailability (71%) is substantially less than reported by the manufacturer. Bioavailability was 8 fold). Standard clinical practice is to convert IV to PO dosing on a 1:1 basis. However, most patients will require higher oral doses to achieve exposure similar to IV therapy. Therapeutic monitoring of MPA during oral therapy and after dosage form conversion is indicated to avoid under dosing and inadequate immunosuppression.