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• Previous studies have shown that pharmacokinetic (PK)-directed therapeutic dose monitoring (TDM) of i.v.-administered busulfan results in a larger proportion of patients receiving desired busulfan exposure. • Comparison of PK-directed dosing of busulfan as part of preparative regimen for autologous stem cell transplantation (ASCT) did not appear to improve outcomes of historical controls with non-Hodgkin lymphoma (NHL) treated with standard BEAM chemotherapy, but a prospective trial showed improved relapse and nonrelapse morality in patients with AML/MDS undergoing allogeneic stem cell transplantation with PK-directed versus weight-based dosing of busulfan. • In the present study of sequential cohorts of patients with NHL undergoing ASCT using weight-based dosing or TDM of busulfan, we found improvements in relapse rates and progression-free survival using TDM. Optimal administration of busulfan (Bu) is hampered by variable and unpredictable drug metabolism in individual patients. At our institution, Bu was previously administered with fixed weight-based dosing (WBD) in combination with cyclophosphamide (Cy) and etoposide (E) for patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT). In 2014, we adopted real-time pharmacokinetic (PK)-guided therapeutic drug monitoring (TDM) of Bu for all NHL patients undergoing Bu-containing ASCT. Here we compare outcomes of NHL patients who underwent ASCT with Bu/Cy/E using WBD and those who did so using TDM of Bu. We studied 336 consecutive adult NHL patients who underwent ASCT with Bu/Cy/E using WBD from January 2007 to December 2013 (n = 258) or TDM from May 2014 to December 2017 (n = 78), excluding patients with mantle cell lymphoma. Clinical outcomes, including relapse, nonrelapse mortality (NRM), progression-free survival (PFS), and overall survival (OS), hepatotoxicity and pulmonary toxicity were compared in the 2 groups. To adjust for differences in baseline characteristics between the groups, propensity-matched cohorts of WBD and TDM patients were also studied. After the first dose of Bu, the dose was increased in 36% of the patients and decreased in 41%. Changes in pulmonary and liver function from baseline to transplantation were not different between the 2 groups, although these changes showed significantly less variability with TDM than with WBD. Relapse was significantly lower and PFS was improved with TDM; 2-year estimates were 19% for TDM and 38% for WBD for relapse (P =.004) and 69% and 55%, respectively, for PFS (P =.038). No significant between-group differences in NRM or OS were seen. In multivariable analysis, TDM remained prognostic for lower risk of relapse (hazard ratio [HR],.52; 95% confidence interval [CI],.30 to.89; P =.018), but did not remain prognostic for PFS (HR,.74; 95% CI,.48 to 1.16; P =.19). Propensity-matched cohorts displayed similar patterns of outcomes. In subset analysis based on disease status at ASCT, TDM was associated with less relapse and better PFS than WBD for patients who underwent transplantation in less than complete remission (CR) compared with those who underwent transplantation in CR. Compared with WBD, PK-directed TDM of Bu reduces the incidence of relapse when used in combination with Cy and E for patients with NHL undergoing ASCT, particularly for patients in less than CR. These data support the continued use of personalized PK-guided dosing for all NHL patients undergoing ASCT with Bu-containing preparative regimens. [ABSTRACT FROM AUTHOR]

Background: Infections are the most common cause of non‐relapse mortality in adult allogeneic hematopoietic stem cell transplant (allo HSCT) recipients. Acute gastrointestinal graft‐vs‐host disease (GI GVHD) often leads to friable mucosa as well as treatment interventions which can increase risk of infection. Our primary objective was to describe the relationship between increasing grades of acute GI GVHD and incidence of bloodstream infections (BSI). Methods: We reviewed 441 adults who underwent allo HSCT from 2011 to 2017 and were clinically diagnosed with GI GVHD, non‐GI GVHD, or no GVHD based on the modified Glucksberg scale within the first 100 days of transplantation. The maximum grades of acute GI GVHD and non‐GI GVHD were used in the analysis. BSI was defined based on the presence of a blood culture positive for bacteria or fungi and treatment with antibiotics. The incidence of BSI within the first 180 days of transplantation was estimated with the cumulative incidence method. Fine and Gray regression was used to assess association between clinical grade of acute GI GVHD and BSI risk, adjusting for grade of non‐GI GVHD and for other significant baseline patient risk factors for BSI identified by multivariable analysis. Results are shown as hazard ratio (HR) and 95% confidence interval (CI). A similar analysis was conducted in 130 patients with histologic grade of acute GI GVHD. Results: Overall BSI incidence by day 180 was 32%; gram‐negative bacilli were the predominant organisms, followed by gram‐positive cocci and fungi. Patients with grade 4 acute GI GVHD had higher risk of BSI as compared to patients with no GI GVHD (HR 2.98, CI 1.65‐5.37, P <.001), while those with grade 3 acute GI GVHD had similar BSI risk (HR 0.89, CI 0.36‐2.21, P =.81). Grade of GI GVHD had no association with risk of non‐BSI. Results were similar in patients with histologic grade acute GI GVHD. Patients who developed BSI or non‐BSI had significantly higher overall mortality risk compared to those without infectious complications (HR 2.52, CI 1.92‐3.31, P <.001 for BSI; HR 1.60, CI 1.20‐2.13, P =.001 for non‐BSI). Conclusions: Grade 4 acute GI GVHD is associated with a higher risk of BSI, which is in turn associated with a higher risk of overall mortality in this population. Understanding the relationships between acute GI GVHD, BSI, and overall mortality can guide future treatment strategies for adult allo HSCT recipients. [ABSTRACT FROM AUTHOR]

Pre-transplant PET/CT may be prognostic in diffuse large B-cell lymphoma (DLBCL) patients undergoing autologous stem cell transplantation (ASCT). We reviewed relapsed and pre-transplant PET/CT scans of 32 patients with DLBCL treated with ASCT to determine the Deauville score and the maximum standardized uptake value (SUVmax). Patients with a Deauville score of 4 had a significantly inferior prognosis. The 3-year progression-free survival (PFS) for patients with Deauville 1-3 score was 64%, compared to 0% for Deauville 4, while the 3-year overall survival (OS) was 84% and 25%, respectively (p < .001, p = .002). The change in the SUVmax (>66 versus ≤66%) was not predictive of PFS or OS, but a high pre-transplant SUVmax (>6) demonstrated a trend towards an inferior PFS. Pre-transplant PET/CT is a tool for identifying DLBCL patients at high risk for treatment failure with ASCT and could be used to risk-stratify patients in prospective clinical trials of novel transplant strategies. [ABSTRACT FROM AUTHOR]

High-dose busulfan (Bu) is an integral component of commonly used preparative regimens for both allogeneic and autologous transplantation. There is significant interest in comparing the efficacy and toxicity of administering Bu every 6 (Bu6) or every 24 hours (daily Bu). To facilitate a therapeutic dose-monitoring protocol, we transitioned from Bu6 to daily Bu dosing for patients with Hodgkin and non-Hodgkin lymphoma undergoing autologous stem cell transplantation (ASCT). Here, we retrospectively review outcomes of 400 consecutive eligible lymphoma patients who underwent ASCT from 2007 to 2013 with high-dose busulfan (Bu), cyclophosphamide (Cy), and etoposide (E). Bu was given at a fixed dose of either .8 mg/kg every 6 hours for 14 doses for 307 patients or a fixed dose of 2.8 mg/kg every 24 hours for 4 doses (days −9 through −6) for 93 patients who underwent transplantation after the transition from Bu6 to daily Bu was made. Toxicity was assessed using pulmonary and liver function tests (LFT) at specified time points before and after ASCT. Baseline patient and disease characteristics of patients dosed with Bu6 and daily Bu were similar. There was no significant difference in forced expiratory volume in 1 second or diffusing capacity of the lungs for carbon monoxide before and after transplantation in the Bu6 versus daily Bu cohorts. Changes in LFTs with daily Bu were not significantly different than those with Bu6. There were no differences in relapse, nonrelapse mortality, progression-free survival, or overall survival between Bu6 and Bu 24 administration schedules in univariable or multivariable analysis ( P  ≥ .34). For a subset of 23 patients who had first-dose Bu levels measured, we observed significant variation in an median estimated cumulative area under the curve (AUC) of 17,568 µM-minute (range, 12,104 µM-23,084 µM-minute). In conclusion, daily Bu with Cy/E is more convenient than Bu6, has equivalent outcomes, and results in no increase in either hepatic or pulmonary toxicity. Consistent with previous reports, there is a significant range of Bu AUC levels, with a standard deviation of 13%. These data provide rationale for our prospective clinical trial of real-time therapeutic dose monitoring of Bu. [ABSTRACT FROM AUTHOR]

Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone combined with cytarabine and methotrexate) is an intense chemotherapy regimen frequently used for hematologic malignancies including mantle cell lymphoma. To address whether treatment with hyper-CVAD impairs mobilization of peripheral blood stem cells, we retrospectively analyzed mobilization data from 77 consecutive adult patients with mantle cell lymphoma who underwent peripheral blood stem cell (PBSC) mobilization for planned autologous stem cell transplant (ASCT). Compared to patients treated with alternative regimens, patients treated with hyper-CVAD collected fewer CD34++ cells, required more total days of pheresis, and more frequently required a second mobilization attempt, despite being more likely to have undergone mobilization with a VP16-containing regimen. In multivariable linear regression analysis, treatment with hyper-CVAD was associated with a significant reduction in total CD34++ cells mobilized ( p < 0.001). These findings suggest that alternative mobilizing strategies prior to ASCT are needed for patients with mantle cell lymphoma who have received hyper-CVAD. [ABSTRACT FROM AUTHOR]

High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the preferred treatment modality for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). To assess long-term outcomes of these patients, we retrospectively analysed data from 309 consecutive patients who underwent ASCT for DLBCL between 1994 and 2006. We found that non-relapse mortality (NRM) became the major cause of death beginning approximately 8 years after ASCT. The most common causes of NRM during the study period were respiratory failure (31%), infection (13%), cardiac toxicity (15%) and secondary malignancy (15%). The strongest predictor of relapse mortality (RM) was disease status at transplant: patients who were in second or greater complete or partial remission had a higher risk of RM than those in first complete or partial remission [hazard ratio (HR) 3·7, P < 0·001], as did those who were relapsed or refractory (HR 4·9, P < 0·001). We describe the longest reported follow-up of a large cohort of DLBCL patients uniformly-treated with ASCT. Although relapse was initially the more likely cause of death, NRM exceeded RM after 8 years. After ASCT, surviving patients have significantly increased risk mortality rates relative to the general population and this excess risk persists over time. [ABSTRACT FROM AUTHOR]

Transformed lymphoma (TL) is historically associated with a poor prognosis, though autologous stem cell transplantation (ASCT) has been applied successfully. Better patient selection is needed for this intensive therapy. We analyzed the outcomes between de novo and transformed large B-cell lymphoma in patients undergoing ASCT, with regard to the immunohistochemical (IHC) features of potential prognostic utility including CD10, BCL6, MUM-1, Ki67, and BCL2. Of all patients undergoing ASCT for large B-cell lymphoma at the Cleveland Clinic Taussig Cancer Institute between 2003 and 2008, 56 patients (31 de novo and 25 TL) had undergone detailed IHC analysis. Three-year relapse-free-survival (RFS) and overall survival (OS) for TL vs. patients with de novo large B-cell lymphoma were 64%vs. 59% and 63%vs. 59%, respectively. More patients with TL were characterized as germinal-center B cell-of-origin (92%) than patients with de novo large B-cell lymphoma (71%). Immunohistochemistry did not predict relapse-free or overall survival, and ASCT afforded a high rate of PFS in patients with TL. [ABSTRACT FROM AUTHOR]

Elevated pretransplant serum ferritin levels have been associated with an increased incidence of morbidity and mortality after allogeneic haematopoietic stem cell transplantation (HCT). We studied 222 patients who underwent myeloablative allogeneic HCT in whom pretransplantation serum ferritin levels were available. Pretransplantation ferritin > 1910 μg/l was associated with lower overall survival ( P = 0·003), lower relapse-free survival ( P = 0·003), decreased chronic graft- versus-host disease (GVHD) ( P = 0·019) and increased non-relapse mortality (NRM) ( P = 0·042). Similar results were obtained when pretransplantation ferritin was analysed as a continuous variable and by quartiles. Our results indicate that an elevated pretransplant ferritin level adversely impacts transplantation outcomes. The adverse impact of elevated ferritin on NRM and survival was despite its association with lower incidences of acute and chronic GVHD, which are major causes of NRM. The association of ferritin with iron overload and its influence on HCT outcomes requires further prospective validation. [ABSTRACT FROM AUTHOR]

The non-relapse mortality of autologous stem cell transplant is low enough that the procedure has been extended to older patients with non-Hodgkin's lymphoma. We treated 537 non-Hodgkin's lymphoma patients with high-dose chemotherapy consisting of busulfan, cyclophosphamide, and etoposide followed by autologous stem cell transplant. Sixteen patients were identified who died of pulmonary complications at a five-year incidence of 3.6%. Risk factors for pulmonary mortality included older age and lower baseline DCO and FEV1. We conclude that high-dose busulfan is associated with pulmonary mortality after autologous transplant, particularly in older patients. [ABSTRACT FROM AUTHOR]

Background Infections are the most common cause of non-relapse mortality in adult allogeneic stem cell transplant (allo SCT) recipients. Acute gastrointestinal graft-vs.-host disease (GI GVHD) often leads to friable mucosa and interventions increasing infectious risk. We describe the relationships between increasing grades of acute GI GVHD and incidence of bloodstream infections (BSI) at our institution. Methods We reviewed 441 adults who underwent allo SCT from 2011 to 2017 and were diagnosed with GI GVHD, non-GI GVHD, or no GVHD based on the Modified Glucksberg Scale within the first 100 days of transplant. The maximum grades of GI GVHD and non-GI GVHD were used in the analysis. A BSI episode constituted a blood culture positive for bacteria or fungi and antibiotic treatment. The incidence of BSI within the first 180 days of transplantation was estimated with the cumulative incidence method. Results Overall BSI incidence by day 180 was 32%; Gram-negative bacilli were the predominant organisms. Adjusting for grade of non-GI GVHD, patients with acute grade 4 GI GVHD had higher risk of BSI as compared with patients with no GI GVHD (HR 3.02, P < 0.001), while those with grade 3 GI GVHD had similar risk (HR 1.01, P = 0.98). Patients with grade 1 or 2 GI GVHD demonstrated lower BSI risk compared with those with no GI GVHD (HR 0.48, P = 0.015; HR 0.44, P = 0.08, respectively). Results were similar after adjusting for patient- and transplant-related risk factors for BSI. Grade of GI GVHD had no association with non-BSI risk. Patients who developed BSI or non-BSI had significantly higher overall mortality risk compared with those without infectious complications (HR 2.52, P < 0.001 for BSI; HR 1.60, P = 0.001 for non-BSI). Conclusion Acute grade 4 GI GVHD may reliably indicate higher BSI and overall mortality risk in this population. Understanding the relationships between acute GI GVHD and BSI can guide future treatment strategies for adult allo SCT recipients. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Introduction Busulfan (Bu) is integral to many preparative regimens for hematopoietic stem cell transplantation but its metabolism is variable and unpredictable. At our institution, Bu was administered with fixed weight-based dosing (WBD) for NHL patients (pts) undergoing ASCT until 2014 when we initiated a prospective clinical trial (NCT01959477) with pharmacokinetic (PK)-guided therapeutic dose monitoring (TDM) of Bu with cyclophosphamide (Cy) and etoposide (VP16). We subsequently adopted this practice as a standard for all NHL pts. Here, we compare outcomes of NHL pts who received ASCT with WBD vs. PK-directed TDM. Methods We collected clinical features and outcomes of 336 adult NHL pts who underwent ASCT with Bu/Cy/VP16 using WBD (n=258) from 1/2007-12/2013 or TDM from 5/2014-12/2017 (n=78) excluding mantle cell lymphoma. For WBD, Bu was given at 2.8 mg/kg q24 hours on day -9 to -6. For TDM, plasma Bu concentration was serially determined via an in-house liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay as previously described and externally validated. Bu area under the curve (AUC) after first dose was calculated for each pt and used to adjust subsequent doses to target a daily AUC of 4500 μM-minute. Results Baseline features of WBD and TDM pts were similar, although more TDM pts received plerixafor for stem cell mobilization and TDM pts were more often categorized as having a complete remission (CR) prior to ASCT (Table), likely due to more use of PET scan. To adjust for differences, propensity-matched cohorts of WBD and TDM pts were also studied (Table). 36% of TDM pts had increases and 41% had decreases in Bu dose. As shown in the Figure, 24 months after ASCT, relapse was significantly lower with TDM vs. WBD (19% vs. 38%, P = 0.004) and relapse-free survival (RFS) was also improved (69% vs. 55%, P = 0.038). Overall survival (OS) did not differ between WBD and TDM cohorts, likely due to subsequent therapy at the time of relapse. Propensity matched cohorts displayed similar patterns of outcomes. For pts in CR at time of ASCT, RFS did not differ between WBD and TDM (P = 0.79) whereas RFS was improved for pts in

Background: Antibiotic allergy de‐labeling using penicillin allergy skin testing (PAST) can reduce the use and cost of alternative, non‐β‐lactam antibiotics in general inpatient populations. This strategy's role in hematopoietic stem cell transplant (HSCT) recipients is unclear. Methods: This study aimed to determine the effect of a pre‐transplant PAST protocol on antibiotic use, days of therapy (DOT), and cost in an immunocompromised population at a single center from 7/1/2010‐2/1/2019. Patients who received chimeric antigen receptor (CAR) T‐cell therapy and those who underwent transplantation in the outpatient setting were excluded. Results: Of 1560 patients who underwent inpatient HSCT during the study period, 208 reported β‐lactam allergy (136/844 [16%] pre‐ and 72/716 [10%] post‐implementation; P <.001). PAST was performed on 7% and 54% of HSCT recipients pre‐ and post‐implementation, respectively. Only two positive PAST were noted. There were no adverse reactions to PAST. There were no significant differences in the disease and transplant characteristics between the two groups. Days of therapy and cost of alternative antibiotics significantly decreased post‐implementation (mean 788 vs 627 days, P =.01; mean $24 425 vs $17 518, P =.009). Conclusion: Penicillin allergy skin testing adjudicates reported β‐lactam allergy in HSCT recipients, lowering use, DOT, and cost of alternative antibiotics and promoting effective formulary agents to treat immunocompromised HSCT recipients. [ABSTRACT FROM AUTHOR]

The clinical relevance of mismatches at the MHC class I–related chain A (MICA) in hematopoietic stem cell transplantation (HSCT) remains unclear. We investigated the association of MICA donor/recipient mismatch and whether there is an interaction between these and HLA-DPB1 mismatch on clinical outcomes after unrelated donor HSCT. Our study included 227 patients who underwent unrelated donor allogeneic HSCT at our institution between 2000 and 2010. Among these, 177 (78%) received HSCT from a 10/10 HLA-matched donor. MICA genotyping was performed using commercially available kits. In univariable analysis, the risk of grade II to IV acute graft-versus-host disease (GVHD) was greater for patients with MICA mismatch (hazard ratio [HR], 1.73; P = .02) than for those with HLA-DPB1 mismatch (HR, 1.62; P = .07). When MICA and HLA-DPB1 were assessed simultaneously, patients mismatched at both loci had the greatest risk (HR, 2.51; P < .01) and those mismatched at only 1 locus had somewhat greater risk (HR, 1.53; P = .12) than patients matched at both loci; this remained significant in multivariable analysis. The 100-day incidence was 66%, 45%, and 31%, respectively ( P = .03) . Results were similar for grade III and IV acute GVHD, with 100-day incidence 34%, 16%, and 8% ( P = .01). These results are clinically pertinent to donor selection strategies and indicate that patients with mismatch at both MICA and HLA-DPB1 are at increased risk for acute GVHD. [ABSTRACT FROM AUTHOR]

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is frequently performed in patients with hematologic malignancies. ASCT can result in significant nausea, pain, and discomfort. Supportive care has improved, and pharmacologic therapies are frequently used, but with limitations. Music has been demonstrated to improve nausea and pain in patients undergoing chemotherapy, but little data are available regarding the effects of music therapy in the transplantation setting. In a prospective study, patients with lymphoma or multiple myeloma undergoing ASCT were randomized to receive either interactive music therapy with a board-certified music therapist or no music therapy. The music therapy arm received 2 music therapy sessions on days +1 and +5. Primary outcomes were perception of pain and nausea measured on a visual analog scale. Secondary outcomes were narcotic pain medication use from day −1 to day +5 and impact of ASCT on patient mood as assessed by Profile of Mood States (POMS) on day +5. Eighty-two patients were enrolled, with 37 in the music therapy arm and 45 in the no music therapy arm. Patients who received MT had slightly increased nausea by day +7 compared with the no music therapy patients. The music therapy and no music therapy patients had similar pain scores; however, the patients who received music therapy used significantly less narcotic pain medication (median, 24 mg versus 73 mg; P  = .038). Music therapy may be a viable nonpharmacologic method of pain management for patients undergoing ASCT; the music therapy patients required significantly fewer morphine equivalent doses compared with the no music therapy patients. Additional research is needed to better understand the effects of music therapy on patient-perceived symptoms, such as pain and nausea. [ABSTRACT FROM AUTHOR]