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Summary: We enumerated programmed death 1 (PD-1)-positive follicular helper T cells, a potentially important regulator of immune response, in the tumor microenvironment of a series of 91 newly diagnosed follicular lymphomas managed at a single institution. Clinical data were obtained for sex, age, Follicular Lymphoma International Prognostic Index (FLIPI) risk group, presence of bulky disease, presence of B symptoms, and overall survival. Immunohistochemical staining for PD-1 was performed on tissue microarray sections, and the mean number of follicular PD-1-positive cells per 9 high-power fields (1000×, 3 follicles with 3 fields per follicle) was quantified. B-cell CLL/lymphoma 2 (BCL-2) expression, CD68+ extrafollicular lymphoma-associated macrophages, and forkhead box P3 (FOXP3)+ regulatory T cells were evaluated as reported previously. Ninety-one patients were evaluated, with a median age at diagnosis of 58 years and median survival of 11.6 years. PD-1-positive cells correlated with the number of FOXP3+ regulatory T cells (P = .01). On multivariate analysis, independent poor prognostic factors were age 55 years or greater (hazard ratio, 2.77; 95% confidence interval, 1.34-5.73; P = .006), bulky disease (hazard ratio, 2.27; 95% confidence interval, 1.03-5.00; P = .04), CD68+ extrafollicular lymphoma-associated macrophages greater than 16.8 cells/high-power field (hazard ratio, 2.15; 95% confidence interval, 1.14-4.06; P = .02), and PD-1-positive cells greater than 35.6 cells/high-power field (hazard ratio, 1.98; 95% confidence interval, 1.09-3.60; P = .03). These factors allowed construction of a risk score defining 3 distinct prognostic groups with 10-year overall survival of 85%, 60%, and 15%. PD-1-positive follicular helper T cells and CD68+ extrafollicular lymphoma-associated macrophages appear to predict overall survival in follicular lymphoma, and our findings support strategies aimed at modulating their function in follicular lymphoma. Future studies, performed prospectively on uniformly treated patient cohorts, should be performed to validate these findings. [Copyright &y& Elsevier]

Purpose: The aim of this study was to review advances in radioimmunotherapy (RIT) for non-Hodgkin’s lymphoma (NHL) and to discuss the role of the radiation oncologist in administering this important new form of biologically targeted radiotherapy. Methods and Materials: A review of articles and abstracts on the clinical efficacy, safety, and radiation safety of yttrium Y 90 (90Y) ibritumomab tiuxetan (Zevalin) and iodine I 131 tositumomab (Bexxar) was performed. Results: The clinical efficacy of RIT in NHL has been shown in numerous clinical trials of 90Y ibritumomab tiuxetan and 131I tositumomab. Both agents have produced significant responses in patients with low-grade, follicular, or transformed NHL, including patients with disease that had not responded or had responded poorly to previous chemotherapy or immunotherapy. Reversible toxicities such as neutropenia, thrombocytopenia, and anemia are the most common adverse events with both agents. Conclusions: Radioimmunotherapy is safe and effective in many patients with B-cell NHL. 90Y ibritumomab tiuxetan and 131I tositumomab can produce clinically meaningful and durable responses even in patients in whom chemotherapy has failed. Treatment with RIT requires a multispecialty approach and close communication between the radiation oncologist and other members of the treatment team. The radiation oncologist plays an important role in treating patients with RIT and monitoring them for responses and adverse events after treatment. [Copyright &y& Elsevier]

Purpose: We combined external beam radiotherapy (EBRT) with yttrium-90 ibritumomab tiuxetan (90Y-IT) in an attempt to improve therapeutic response in patients with relapsed or refractory bulky follicular lymphoma (RRBFL). Methods and Materials: Between February 2006 and September 2007, 11 patients with RRBFL were treated with EBRT followed by 90Y-IT. Bulky disease (BD) was defined as >5 cm. EBRT was delivered to BD as 2,400 cGy in eight fractions using computed tomography (CT)–based planning. BD was contoured as the gross tumor volume. A planning margin of 1 to 2 cm was added depending on anatomical location. After recovery of complete blood counts (CBC), 90Y-IT was administered at a dose of 0.3 or 0.4 mCi/kg depending on platelet counts. Hematologic toxicity was monitored through weekly CBC. Response was measured by positron emission tomography/CT or CT 3–4 months after 90Y-IT. Results: Only 2 patients required prolonged breaks between EBRT and 90Y-IT. The median time after 90Y-IT for platelets to recover to >100,000/ml was 55 days (range, 41–128 days). Platelet counts for 1 patient, who had received 4 previous chemotherapy regimens, never reached 100,000/ml. The complete and overall responses to combined therapy as measured 3–4 months after 90Y-IT were 64%. No patients relapsed within the EBRT field. With a median follow-up of 36.1 months, 6 patients have relapsed, 2 of whom have died. Median progression-free survival was 17.5 months. Conclusions: In contrast to prior failure analysis data for RRBFL patients treated with 90Y-IT alone, a brief course of EBRT prevented relapse in sites of BD. EBRT used to pretreat bulky sites may improve clinical outcomes and potentially extend survival when combined with 90Y-IT. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate two potential approaches to predicting site-specific patterns of recurrence after yttrium-90 ibritumomab tiuxetan radioimmunotherapy (RIT) for CD20+ B-cell Non-Hodgkin's lymphoma. These predictive methods may be useful in evaluating the utility of local intensification of individual nodal or extranodal sites using external beam radiotherapy. Methods and Materials: Records and images were evaluated for 20 patients previously treated with yttrium-90 ibritumomab RIT. Intensity of isotope uptake on the pretreatment two-dimensional antibody scans and maximal extent of tumor deposits found on computed tomography images of each anatomic site were correlated with response and subsequent patterns of recurrence or progression. Results: Our data failed to suggest a significant correlation between the site-by-site two-dimensional image intensity on the pre-RIT scan and the likelihood of response at those sites. In contrast, an analysis of pretreatment target volumes did correlate significantly with progression. A collective analysis of disease sites from all 20 patients found that 83% (10/12) sites of "bulky" (maximal diameter > or = 5 cm) disease displayed evidence of progression vs. 28% (26/93) of "nonbulky" disease sites containing gross disease but no area measuring >5 cm (p < 0.001). All patients with at least one site of bulky disease had initial disease progression occur at a bulky site, with a bulky site being the sole first site of progression in approximately 50%. In patients with only nonbulky disease sites, approximately one third progressed initially at an entirely new site of disease. Conclusion: We conclude that we can use tumor bulk to establish a statistical hierarchy of likely tumor progression sites and use this pattern to direct the use of additional external beam radiotherapy to augment treatment. [ABSTRACT FROM AUTHOR]

Advance care planning (ACP) includes having conversations with loved ones and health care providers regarding health care wishes in various circumstances. It also includes completing advance directives such as a health care power of attorney and living will as well as preparing a will for finances and estate planning. This process helps patients make plans for their future health care goals and is particularly useful when they are unable to make their own medical decisions. ACP in hematopoietic stem-cell transplant (HSCT) recipients can be particularly challenging, given the treatment's significant morbidity and mortality yet curative potential. (Wang, W. S. et al, 2017). Recognizing this challenge, the Cleveland Clinic Blood and Marrow Transplant Program created a multi-disciplinary committee of social workers, physicians, advanced practice providers (APPs), nurse coordinators and nurses to address the gap in ACP for HSCT recipients to improve the overall quality of care provided to patients and families. As part of this initiative, we created a survey to assess perceptions of ACP within the program and comfort level. A confidential, fourteen question survey was created and administered to providers. The survey included questions on: 1) perceptions of the current approach to ACP in our program, 2)the comfort level of the provider in discussing goals of care, prognosis, and code status, 3) provider's current knowledge base and prior training. Open-ended feedback was also elicited. A total of 38 responded to the survey including 15 physicians, 7 APPs, 8 nurse coordinators, 3 social workers, and 3 inpatient nurses. The years of experience ranged from 0.5 to 21 plus years. The majority of providers felt our current approach to ACP was very good (n=11) or good (n=16). While the perception was overall favorable, less than half of the providers (n=14) felt we had adequate training to have goals of care discussions. Only 7 providers report having formal training in goals of care. Despite not having formal training, nearly all (n=37) thought it was important. The survey also assessed comfort level of initiating goals of care discussions, prognosis, and code status. The majority of providers reported feeling comfortable in all these areas: initiating goals of care n=25 (Figure 1), prognosis n=20 (Figure 2), and code status n=22 (Figure 3). Of the 21 who were comfortable initiating goals of care discussions 21 reported initiating these conversations in their clinical practice. Many providers (n= 37) also felt it was appropriate for all members of the team to initiate these discussions. ACP is an important part of HSCT multi-disciplinary care of patients and their families. This survey demonstrates our institution's perceptions of ACP, need for formal training to improve comfort levels, and highlights the need for ACP in HSCT to be approached by a multi-disciplinary team effort. [ABSTRACT FROM AUTHOR]

• 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]

• Survival improves with longer time in remission after autologous transplant for DLBCL. • Mortality risk approaches that of the general population with time. • Older age at transplant and relapse are associated with overall mortality risk. Autologous hematopoietic cell transplantation (AHCT) is standard therapy for patients with chemosensitive, relapsed, diffuse large B cell lymphoma (DLBCL). We performed a retrospective cohort study to delineate subsequent (conditional) and relative survival in 371 adult patients with DLBCL who underwent AHCT between 2000 and 2014 and had survived for 1, 2, 3, or 5 years after transplant. The probability of overall survival at 10 years after AHCT was 62%, 71%, 77%, and 86%, respectively, for the 4 cohorts, whereas that of progression-free survival (PFS) was 55%, 65%, 72%, and 81%, respectively. The respective cumulative incidence of nonrelapse mortality (NRM) at 10 years after transplantation was 13%, 12%, 11%, and 8%, respectively. In multivariable analysis, older age was associated with greater mortality risk among all but 5-year survivors; relapse within the landmark time was associated with greater mortality risk in all groups. Older age and relapse within the landmark time were associated with worse PFS in all groups. Standardized mortality ratio (SMR) was significantly higher than an age-, gender-, and race-matched general population, with the magnitude of SMR decreasing as the landmark time increased (4.0 for 1-year, 3.0 for 2-year, 2.4 for 3-year, and 1.8 for 5-year survivors). Our study provides information on long-term survival and prognosis that will assist in counseling patients with DLBCL who have received AHCT. Survival improves with longer time in remission post-transplant, although patients continue to remain at risk for NRM, underscoring the need for continued vigilance and prevention of late complications. [ABSTRACT FROM AUTHOR]

• BEAM conditioning before AHSCT resulted in a statistically significant improved PFS and OS and lower relapse when compared with BUCYVP16. • Patients with shorter remission time from diagnosis and in non-CR at time of AHSCT benefited most from BEAM conditioning. High-dose chemotherapy followed by autologous hematopoietic stem cell transplant (AHSCT) is a standard of care for patients with relapsed Hodgkin lymphoma. Different conditioning regimens before AHSCT have been used, with the 2 most common being BEAM (carmustine, etoposide, cytarabine, and melphalan) and BUCYVP16 (busulfan, cyclophosphamide, and etoposide). We retrospectively compared the outcomes of patients treated with BEAM (n = 128) or BUCYVP16 (n = 105) followed by AHSCT. After a median follow-up of 4.2 years for BEAM and 3.8 for BUCYVP16 from AHSCT, the 5-year cumulative incidence of relapse was 29% with BEAM compared with 56% with BUCYVP16 (P <.001). Median progression free survival (PFS) and overall survival (OS) were not reached with BEAM and were 2.0 and 7.8 years with BUCYVP16, respectively. Improved PFS (P <.001) and OS (P =.001) were observed with BEAM for patients who needed transplant within 24 months from diagnosis and for patients not in complete remission (non-CR; P =.001 and P <.001, respectively) at AHSCT. In this large retrospective comparison the use of BEAM conditioning before AHSCT resulted in a statistically significant improved PFS and OS and lower relapse compared with BUCYVP16. This supports the use of BEAM as a frontline conditioning regimen before AHSCT for early relapsed and non-CR Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]

Although day +100 survival among allogeneic hematopoietic cell transplantation (HCT) recipients has improved over time, longer-term survival remains a challenge. The aim of this study was to identify prognostic factors for survival among patients surviving longer than 100 days using baseline characteristics and factors identified within the first 100 days after transplantation. Of 413 patients undergoing a first allogeneic HCT between 2006 and 2014, 335 survived >100 days post-transplantation. The majority underwent a myeloablative transplantation (75%) with a bone marrow (BM) (52%) graft source. One-year all-cause mortality (ACM) was 29%, with 16% relapse mortality (RM) and 12% nonrelapse mortality. In multivariable analysis, high-risk disease (hazard ratio [HR], 1.55; P  = .003), non-cytomegalovirus infection (HR, 1.79; P  = .003), more days hospitalized (HR, 1.16; P  < .001), and relapse (HR, 4.38; P  < .001) within the first 100 days were associated with increased risk of ACM. Patients with higher income (HR, .89; P  = .024) and those who received BM (HR, .52; P  < .001) or umbilical cord blood (HR, .40; P  = .002) relative to peripheral blood stem cells had lower risk of ACM. Our study identifies risk factors for adverse long-term survival in 100-day survivors, a time point when patients frequently are discharged from transplantation centers. In addition to disease- and transplantation-related factors, low socioeconomic status was associated with worse long-term survival, highlighting the need for focused efforts to improve outcomes in vulnerable patient populations. [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]

Allogeneic hematopoietic cell transplantation conditioning regimen intensity has varied for patients with acute myeloid leukemia and myelodysplastic syndrome. A comparative effectiveness analysis was performed to assess outcomes of busulfan and fludarabine (BuFlu) versus those of fludarabine and 400 cGy total body irradiation (FluTBI) conditioning. Thirty-three subjects received BuFlu and 38 received FluTBI. The BuFlu group received more red blood cell transfusions ( P  = .02) and had a longer time to platelet recovery ( P  = .004). There were no differences between the regimens regarding incidence of acute or chronic graft-versus-host disease (GVHD), quality of life, or 2-year outcome estimates for relapse (48; 95% confidence interval [CI], 30 to 64 and 50; 95% CI, 33 to 65), nonrelapse mortality (29; 95% CI, 14 to 45 and 29; 95% CI, 15 to 44), relapse-free survival (27; 95% CI, 13 to 43 and 29; 95% CI, 16 to 44), and overall survival (35; 95% CI, 19 to 51; and 37; 95% CI, 22 to 52), respectively. These comparable outcomes have implications for health care resource utilization. Future prospective investigation comparing these regimens with larger patient cohorts and additional strategies to prevent relapse and limit toxicities as well as cost-effectiveness analyses are warranted. [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]

Autologous hematopoietic cell transplantation (AHCT) is standard therapy for eligible patients with multiple myeloma. Health care disparities can influence transplantation outcomes. However, the association of socioeconomic status (SES), a major indicator of health care disparities, with outcomes in patients with myeloma after AHCT has not been previously described. We analyzed 346 consecutive AHCT recipients with myeloma who underwent transplantation between 2003 and 2013 in this retrospective cohort study. Zip code of residence at the time of AHCT was obtained to assess annual household income based on 2010 US census data (median, $49,054; range, $16,546 to $127,313). SES groups were divided into < $45,000 (low; n = 120), $45,000 to $60,000 (middle; n = 116), and > $60,000 (high; n = 110). The low-income cohort had smallest portion of Caucasians (69% versus 89% versus 91%); otherwise, patient, disease, and transplantation characteristics were comparable among cohorts or different without significant patterns found. Median follow-up was 49 months. There was no difference among SES groups in overall survival, progression-free survival, nonrelapse mortality, or relapse in univariate and multivariable analysis. Similarly, SES was not associated with survival in a subset analysis of 303 patients who had survived for 1 year after transplantation. [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]

Patient readmission within 30 days from discharge has been perceived by the Centers for Medicare and Medical Services as an indicator of poor healthcare quality for specific high-cost medical conditions. Patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) are often being readmitted. Our study identified the risk factors for 30-day readmission among 618 adult recipients of myeloablative allo-HCT from 1990 to 2009. Two hundred forty-two (39%) of 618 patients (median age = 42 years [range: 18-66]) were readmitted a median of 10 days (range: 1-30) from their hospital discharge. Median duration of readmission was 8 days (range: 0-103). Infections (n = 68), fever with or without identified source of infection (n = 63), gastrointestinal complications (n = 44), graft-versus-host disease (GVHD) (n = 38), and other reasons (n = 29) accounted for 28%, 26%, 18%, 16%, and 12% of readmissions, respectively. During their index admission, patients who were subsequently readmitted had more documented infections (P < .001), higher hematopoietic cell transplantation comorbidity index (HCT-CI) (P < .01), total body irridiation (TBI)-based conditioning (P < .001), unrelated donor (P < .001), and peripheral stem cell (P = .014) transplantation. In multivariable analysis, HCT-CI (odds ratio [OR] = 1.78; 95% confidence interval [CI], 1.25-2.52), TBI-based preparative regimen (OR = 2.63; 95% CI, 1.67-4.13), and infection during admission for allo-HSCT (OR = 2.00; 95% CI, 1.37-2.92) predicted 30-day readmission. Thirty-day readmission itself was an independent predictor of all-cause mortality (hazard ratio [HR]Adj = 1.66; 95% CI, 1.36-2.10). Our data emphasize the importance of a risk-standardized approach to 30-day hospital readmission if it is used as a quality-of-care metric for bone marrow transplantation. [ABSTRACT FROM AUTHOR]

Vitamin D (VD) deficiency can cause osteomalacia, bone pain, muscle weakness, fatigue, and increased risk of fracture, and may precipitate or exacerbate osteopenia and osteoporosis. Patients receiving treatment for acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) may have limited exposure to sunlight and often experience gastrointestinal side effects that may decrease their ability to maintain an adequate VD level. We hypothesized that patients with AML and ALL would have a low VD level after allogeneic hematopoietic cell transplant (HCT), and that these patients would have a high incidence of osteoporosis/osteopenia. We therefore studied the incidence of low VD level and low bone mineral density after HCT. Of 289 patients with AML or ALL undergoing HCT between January 1, 2000, and January 31, 2009, at the Cleveland Clinic, 58 (20.1%) patients had VD testing after HCT. Of these, 52 (89.7%) patients had a low VD level, and 6 (10.3%) had a normal level. Most patients with VD testing had graft-versus-host disease (GVHD) and were taking corticosteroids (94.8% and 98.3%, respectively). Of the 49 patients with VD testing who also had bone mineral density testing, 65% had abnormal (low bone density) results. Only 21% of patients with VD testing were taking VD supplements prior to testing, and 65% had an elevated parathyroid hormone level. We found that most patients did not have VD testing after HCT, but those that did were very likely to have a low level and have low bone mineral density. Those with a low VD level were likely to have received corticosteroids, have GVHD, and have an elevated parathyroid hormone (PTH) level. Given the potential morbidity of low VD level, VD deficiency should be considered after HCT. Prospective study of VD level and its impact on morbidity and mortality after HCT is warranted. [Copyright &y& Elsevier]

Purpose: We combined external beam radiotherapy (EBRT) with yttrium-90 ibritumomab tiuxetan ((90)Y-IT) in an attempt to improve therapeutic response in patients with relapsed or refractory bulky follicular lymphoma (RRBFL). Methods and Materials: Between February 2006 and September 2007, 11 patients with RRBFL were treated with EBRT followed by (90)Y-IT. Bulky disease (BD) was defined as >5 cm. EBRT was delivered to BD as 2,400 cGy in eight fractions using computed tomography (CT)-based planning. BD was contoured as the gross tumor volume. A planning margin of 1 to 2 cm was added depending on anatomical location. After recovery of complete blood counts (CBC), (90)Y-IT was administered at a dose of 0.3 or 0.4 mCi/kg depending on platelet counts. Hematologic toxicity was monitored through weekly CBC. Response was measured by positron emission tomography/CT or CT 3-4 months after (90)Y-IT. Results: Only 2 patients required prolonged breaks between EBRT and (90)Y-IT. The median time after (90)Y-IT for platelets to recover to >100,000/ml was 55 days (range, 41-128 days). Platelet counts for 1 patient, who had received 4 previous chemotherapy regimens, never reached 100,000/ml. The complete and overall responses to combined therapy as measured 3-4 months after (90)Y-IT were 64%. No patients relapsed within the EBRT field. With a median follow-up of 36.1 months, 6 patients have relapsed, 2 of whom have died. Median progression-free survival was 17.5 months. Conclusions: In contrast to prior failure analysis data for RRBFL patients treated with (90)Y-IT alone, a brief course of EBRT prevented relapse in sites of BD. EBRT used to pretreat bulky sites may improve clinical outcomes and potentially extend survival when combined with (90)Y-IT. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (SCT) for patients who have previously undergone allogeneic or autologous SCT is potentially curative, but dangerous. To identify patient, disease, and treatment characteristics associated with outcome, we analyzed prognostic factors in 98 consecutive patients who underwent second transplants using allogeneic donors at the Cleveland Clinic between May 1987 and October 2008. Inclusion criteria included age ≥18 years, first SCT either autologous or allogeneic, and second SCT allogeneic. Patients whose second transplant was myeloablative (MA) had shorter survival (median 3.2 versus 14.7 months, P < .001) than patients whose second transplant was nonmyeloablative (NMA). In multivariable analysis, MA second transplant was associated with a higher risk of NRM (hazard ratio [HR] 2.01, P = 0.022) and death (HR 2.13, P = 0.002). Improved survival after NMA second transplant occurred primarily in patients without acute leukemia and when the first transplant was allogeneic. Among 17 patients transplanted within 3 months of first transplant, mortality was 100% and median survival was 2.3 months. MA transplantation within 3 months of prior SCT carries an unacceptably high rate of NRM. NMA second transplants were associated with substantially less NRM and despite a higher incidence of relapse, significantly improved survival compared to MA second transplants. [Copyright &y& Elsevier]

Elevated serum ferritin is associated with reduced survival following allogeneic transplantation and an increased risk of toxic and infectious complications after autologous hematopoietic stem cell transplantation (ASCT). We studied 315 patients who underwent ASCT for Hodgkin (HL) or non-Hodgkin lymphoma (NHL) at our institution in whom pretransplantation ferritin was available to determine its association with survival. On multivariate analysis, a pretransplantation ferritin >685 ng/mL was associated with significantly lower overall (OS; P = .002) and relapse-free survival (RFS; P = .021). Ferritin >685 ng/mL was associated with a higher incidence of relapse (P = .005) and relapse mortality (P < .001), but not of nonrelapse mortality (NRM; P = .23). Similar results were seen when pretransplantation ferritin was analyzed as a continuous variable and by quartiles. Our results indicate the need for studies designed to correlate an elevated ferritin with iron overload and to analyze the benefit of strategies to reduce the extent of iron overload. [Copyright &y& Elsevier]

Objective: T-cell large granular lymphocyte leukemia (T-LGL) is a chronic clonal lymphoproliferation of cytotoxic T cells often complicated by cytopenia. Because the outcomes of splenectomy in patients with T-LGL have been only reported sporadically, we objectively assessed the outcomes of splenectomy. Materials and Methods: When a cohort of 56 T-LGL patients was analyzed, patients with splenomegaly (n = 34) and had higher frequency of bi- and pancytopenia than patients with no splenomegaly (70% vs 27%; p = 0.001). We identified 15 patients who, in their clinical course, underwent splenectomy and studied their hematological and clinical outcomes. Results: Indications for splenectomy included symptomatic splenomegaly and/or severe refractory cytopenia. Median spleen weight was 1300 g, consistent with diagnosis of splenomegaly; T-cell receptor (TCR)-γ rearrangement and typical T-LGL were detected by immunophenotype in all specimens. There was no surgery-related mortality, with the median follow-up and survival of 719 and 498 days, respectively. Two patients died due to causes possibly related to the splenectomized state and/or primary disease. All patients showed lineage-specific hematologic response and achieved transfusion independence; however, precise molecular analysis of TCR and variable chain Vβ flow cytometry showed persistence of the LGL clones. Conclusion: We conclude that splenectomy constitutes a viable and safe therapeutic option for patients with T-LGL, splenomegaly, and refractory cytopenia. [Copyright &y& Elsevier]

Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). While transplant-related mortality has decreased substantially over the last few decades, little progress has been made in outcomes and no standard of care exists for patients (pts) with post-alloHCT relapse. In the recent era, several new therapies, including targeted agents, have been approved for ALL, AML, and MDS. We conducted a study to evaluate outcomes of pts with these diseases who relapse after alloHCT in the contemporary period with routine availability of these newer therapeutic agents. We performed a single-institution retrospective cohort study to review treatment strategies and outcomes of relapse post-alloHCT. We identified 420 adults who received their first alloHCT in 2010-2018 using any conditioning regimen or donor source. Overall, 115 (27%) pts experienced relapse (ALL=17/64 [27%], AML=67/242 [28%], MDS=31/114 [27%]) and were included in the analysis. Myeloablative (54%) matched-unrelated donor grafts (50%) were the most common types of HCTs. Peripheral blood stem cell graft (49%) and bone marrow graft (48%) were used the most. Median time from alloHCT to relapse was 5 (range 1-65) months, and 83% of relapses occurred within the first year. Only 24% and 11% of pts experienced grade II-IV acute and any chronic graft-versus-host disease (GVHD) prior to relapse, respectively. Seven of 17 pts had Ph+ ALL. Mutation panel was tested in 56% of AML and MDS. Median follow-up period after relapse was 19 (range 6-80) months. The estimated survival after relapse is shown in figure 1. Table 1 summarizes the treatments used for relapse after alloHCT. Targeted therapy was associated with a trend towards better survival compared to other therapies (Fig 2, HR 0.65, 95% CI 0.41-1.03, p=0.06). Matched unrelated (vs. matched sibling, HR 1.70, p=0.027) or haploidentical donor grafts (HR 2.69, p=0.003), presence of grade II-IV acute GVHD before relapse (HR 2.46, p<0.001), and <12 months from HCT to relapse (<6 vs. >12 months, HR 6.34, p<0.001; 6-12 vs. >12 months, HR 3.16, p=0.005) were adverse prognostic features with survival after relapse post-alloHCT (Table 2). Outcomes of pts with ALL, AML, and MDS who relapse following alloHCT remain poor in the contemporary era when several newer therapies, including targeted agents, are available for their treatment. Targeted agents were used only in a minority of post-alloHCT relapses likely due to the combination of pt status, absence of the target mutation, the agents' availability, and other factors. Pts who developed grade II-IV acute GVHD and had shorter "disease-free" duration from unrelated or haploidentical donor grafts had the significantly shorter survival following relapse. More innovative treatment strategies to prevent and treat relapse post-alloHCT are needed. [ABSTRACT FROM AUTHOR]

PROs are increasingly used in HCT to capture symptoms, quality of life, and functional status. At the Cleveland Clinic, PROs are systematically collected prior to ambulatory visits and used in routine clinical care to identify patients (pts) with distress in real-time through a data capture initiative called the "Knowledge Program." Instruments include the Patient Health Questionnaire (PHQ-9), National Comprehensive Cancer Network Distress Thermometer (DT), and Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Health (PH) and Mental Health (MH) assessments. There are limited data on the use of these instruments in the HCT population. We evaluated these PRO measures in HCT recipients and their association with post-HCT outcomes. We identified 292 adult pts undergoing first allogeneic HCT from 2015-2018. Of those, 257 had at least one PRO assessment and were included in this analysis. Time intervals evaluated were: pre-HCT (within 3 months [mos]), 0-6 mos, 6-12 mos, 1-2 years (yrs), and 2-5 yrs post HCT. PHQ-9 assesses depression and categorized as minimal (score 0-4), mild (5-9), moderate (10-14), moderately severe (15-19), and severe (20-27). Higher DT scores indicate more distress and categorized as mild (0-3), moderate (4-7), severe (8-10). Lower scores on PROMIS indicate poorer PH or MH respectively. We evaluated PRO data descriptively for each time interval. Pre-HCT scores were analyzed for association with grade 2-4 acute graft-versus-host disease (GVHD), relapse, non-relapse mortality (NRM), and survival. Figure 1 shows boxplots for mean PHQ-9 and DT scores pre- and post-HCT. Mean scores for the PHQ-9 ranged from 1.1 ± 2.4 (SD) occurring >2 yrs post-HCT to 2.4 ± 3.0 pre-HCT. Mean DT scores were overall low, with highest distress (2.0 ± 2.2) seen pre-HCT. Mean scores for PH and MH were similar at each time intervals, with means ranging 47-48 for PH and 49-51 for MH. Higher PHQ-9 pre-HCT was associated with higher NRM (HR 1.21, 95% CI 1.09-1.34, P<0.001) and worse overall mortality (HR 1.12, 95% CI 1.02-1.23, P=0.016). Higher PROMIS PH and MH scores were associated with lower NRM (HR 0.49, 95% CI 0.26-0.94, P=0.031 and HR 0.28, 95% CI 0.14-0.56, P<0.001), respectively. DT scores had no associations with any outcome. Pts who developed acute GVHD had significantly higher PHQ-9 scores (mean 2.8 vs 1.9, P=0.014), PROMIS-PH (mean 45 vs 49, P=0.029) and MH scores (mean 47 vs 52, P=0.011) relative to those who did not have acute GVHD. PROs such as the PHQ-9, DT, and PROMIS have important clinical utility in allogeneic HCT recipients. Routine clinical use of these assessments not only help identify pts with high levels of distress or depression in real-time, they also demonstrate prognostic value for post-HCT survival outcomes. [ABSTRACT FROM AUTHOR]

Busulfan (Bu) based conditioning regimens are associated with serious toxicities including myelosuppression, hepatotoxicity, and sinusoidal obstructive syndrome (SOS). Previous literature reports increased risk of toxicities when the daily AUC concentrations exceed 6000 uM-minute. Bu TDM has also been associated with improved overall and progression free survival in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. We implemented real time pharmacokinetic (PK)-guided therapeutic dose monitoring (TDM) of Bu for myeloablative conditioning (MAC) regimens. Compare toxicity of IV Bu before and after implementation of TDM. The primary endpoint was incidence of hepatotoxicity, defined as days of elevation of AST or ALT > 3 times the upper limit of normal (ULN) or total bilirubin >1.5 times ULN. Secondary outcomes included time to neutrophil and platelet engraftment, duration of IV opioid administration, breakthrough antiemetic use, incidence of SOS, hospital length of stay (LOS), incidence of Bu dose adjustment, and repeat Bu PK. A Bu PK-guided TDM program was implemented in April 2018 for patients receiving busulfan/ cyclophosphamide (BuCy) MAC regimens for allo-HSCT. Medical records were retrospectively reviewed with weight-based dose (WBD) BuCy conditioning from August 2017 through March 2018 (N=14) and TDM from April 2018 through December 2018 (N=22). Bu was given at a fixed dose of 0.8 mg/kg/dose every 6 hours for 16 doses on days -8 to -4 for WBD patients. For TDM patients, after a WBD of 3.2 mg/kg/dose on day -7 (Bu 1), serial plasma Bu concentrations were used to calculate Bu area under the curve (AUC) for subsequent dose adjustment on days -6 to -4 to target a daily AUC of 5000 μM-minute. If the AUC actual /AUC target exceeded 1.2 or was less than 0.8, the second dose of Bu (Bu 2) was changed by no more than ± 20%, repeat PK samples were drawn, and the process was repeated for TDM for the third dose of Bu. Recipients of Bu TDM were younger than those receiving WBD (median 45 vs. 58 years, p=0.008). No other baseline differences were observed. There was no difference in hepatotoxicity between TDM and WBD (median 1 vs. 0 days, p=0.40), time to neutrophil (median 17 vs. 17 days, P=0.18) or platelet engraftment (median 29 vs. 25 days, p=0.75), IV opioid administration (median 4 vs. 4 days, p=0.83), breakthrough antiemetic use (median 59 vs. 58 doses, p=0.99), SOS (4.5 vs. 7.1%, p=1.0), or LOS (median 28 vs. 27 days, p=0.95). In the TDM group, 45% of patients had increases and 41% had decreases in Bu dose after Bu 1. 32% of patients required repeat PK after Bu 2. A PK dose monitoring program for MAC IV Bu regimens may be considered a safe practice in allo-HSCT recipients. The majority of patients receiving PK-guided TDM required dose changes, and TDM patients had no significant difference in toxicity compared to those receiving WBD. [ABSTRACT FROM AUTHOR]

Use of Axi-cel in patients with refractory and relapsed (R/R) large B-cell lymphoma (BCL) is associated with significant inpatient and outpatient resource utilization, which has not been systematically evaluated. We characterized resources used around Axi-cel infusion and identified factors that lead to longer hospitalization during the first 100 days of therapy. We reviewed medical records of consecutive adult patients with R/R large BCL treated with Axi-cel at our center from May 2018 to June 2019. Resource utilization data were collected across 3 time points and sorted into categories that reflect inpatient and outpatient resources (Table 1). We evaluated the number of "days alive and out-of-hospital through Day 100 from cell infusion" (DAOH 100), as a surrogate for institutional resource utilization and to identify factors leading to prolonged hospitalization. Axi-cel was used in 27 patients with R/R BCL; 18 were male (67%) with median age 63 years (IQR 48-68), median IPI 2 (IQR 2-3), 20 (74%) had ECOG PS < 2 and 24 (89%) had stage ≥ 3 disease. Median number of prior therapies was 3 (IQR 3-5) and HCT-CI score was 2 (IQR 0-3). The median length of stay for the initial hospitalization was 13 days (IQR 9-16) and through Day 100 was 16 days (IQR 12-30). Eight (30%) patients required ICU admission for a median of 2.5 days (IQR 1-9.8), while vasopressors, mechanical ventilation and dialysis were used in 6 (22%), 3 (11%) and 2 (7%) patients respectively. Patients had a median of 5 (IQR 3-7) outpatient clinic visits through Day 100. The median number of radiological studies and cardiac/neurological evaluation through Day 100 were 6 (IQR 4-11) and 1 (IQR 0-6) respectively. Pharmaceutical resources are summarized in Table 1. Cytokine release syndrome (CRS) and CAR-related encephalopathy syndrome (CRES) were seen in 22 (82%) and 20 (74%) patients, with ≥ Grade 2 CRS (Lee, et al) and CRES (CARTOX-10) in 16 (59%) and 13 (48%) patients respectively. By Day 100, 24 (89%) patients were alive and 4 (15%) had disease progression. The median DAOH 100 were 84 days (IQR 69-88). DAOH 100 were higher in patients with favorable ECOG PS (< 2) compared to unfavorable (≥ 2) (median DAOH 100 86 vs 70 days, P=0.04). Patients with no or mild CRES (< grade 2) had higher DAOH 100 compared to those with moderate to severe CRES (≥ grade 2) (median DAOH 100 86 vs 70 days, P=0.01). DAOH 100 did not differ with respect to age, HCT-CI score, IPI, number of prior therapies or CRS grade (Table 2). In this single institutional experience of using Axi-cel therapy for R/R BCL, we demonstrated utilization of substantial resources in terms of hospitalization, ICU stay, diagnostic studies and pharmaceutical products. Patients with favorable PS and no or minimal CRES spend a higher number of days at home (alive and out-of-hospital), in first 100 days of Axi-cel therapy. [ABSTRACT FROM AUTHOR]

Abstract: Busulfan (Bu)-based preparative regimens have not been extensively investigated in Hodgkin disease (HD). The purposes of this study were to investigate the toxicity and efficacy of a novel preparative regimen of Bu 14 mg/kg, etoposide 50-60 mg/kg, and cyclophosphamide 120 mg/kg in patients with primary refractory and relapsed HD. One hundred twenty-seven patients with a median age of 33 years (range, 14-67 years) underwent transplantation. The regimen was well tolerated, with 5.5% treatment-related mortality at 100 days after transplantation. With a median follow up of 6.7 years, the 5-year progression-free survival was 48 ± 5%, and the 5-year overall survival was 51 ± 5%. A Cox proportional hazards model identified refractory disease at time of transplantation as the only significant factor affecting relapse and overall survival, whereas disease bulk >10 cm affected overall survival. Five patients died between 5.3 and 9.3 years of late complications, including secondary myelodysplasia or acute myeloid leukemia, secondary solid malignancies, and pulmonary toxicity. This novel Bu regimen is comparable to other radiation-free preparative regimens in its effectiveness in the control of HD and with a low-risk of early treatment-related mortality. [Copyright &y& Elsevier]

Abstract: Results were analyzed for 48 consecutive patients with acute myeloid leukemia not in remission who underwent unrelated donor bone marrow or stem cell transplantation between 1991 and February 2003 at 2 transplant centers. Forty-six were adults with a median age of 32 years (range, 4-58 years). Forty-two were HLA-A, -B, and -DR matched with their respective donors, and 6 were mismatched at 1 of these loci. The conditioning regimen was myeloablative in all cases: busulfan/cyclophosphamide/etoposide in 34 patients, busulfan/cyclophosphamide in 10 patients, and total body irradiation based in 4 patients. Median follow-up for survivors was 540 days (range, 145-2716 days). Only patients with <5000 peripheral blood blasts per microliter at the time of transplantation survived 2 years (18% versus 0%; P = .003). Similarly, patients with <20% blasts in the marrow at the time of transplantation had superior 2-year survival compared with those who had ≥20% (33% versus 5%; P = .04). Patients with <20% blasts who had ≥3 prior therapies also fared poorly. Cause of death was more commonly treatment related rather than relapse related. This study confirms that patients with acute myeloid leukemia not in remission can achieve prolonged survival with myeloablative conditioning and unrelated donor cell transplantation. However, sustained survival occurs only in patients with a low disease burden at the time of unrelated donor stem cell transplantation, and patients with a high disease burden may benefit from added counseling regarding the high risk of death due to both treatment-related toxicities and disease relapse. [Copyright &y& Elsevier]

Advances in allogeneic hematopoietic cell transplantation (HCT) have led to significantly improved day 100 survival over time. Longer-term (≥1 year) survival, however, has not changed significantly. In an effort to improve outcomes and identify patients (pts) at higher risk for 1-year mortality, we created a day 100 risk assessment tool. The Day 100 Risk Assessment tool includes 11 items: HCT-co-morbidity index, distance from transplant center, performance status (PS) at day 100, GVHD requiring systemic corticosteroids, infection requiring intravenous antimicrobials, caregiver support, poor coping skills/motivation, substance abuse, poor health literacy/access, medication compliance, and "other" concerns from the care team. Pts were given a point for each identified factor and categorized as low risk (score 0-2) or high risk (score≥3). High risk pts were targeted for closer follow up beyond 100 days. Cox regression was used to identify risk factors for overall survival (OS) within the first year after HCT. Between 11/2015-6/2018, 208 pts underwent allogeneic HCT and 161 pts survived without relapse at day 100 (Table). Median follow up is 12 months (range 3-33). 1-year OS for low-risk pts was significantly better than for high-risk pts (82% vs 68%, P=0.006; Figure). Multivariable analysis accounting for both pre-transplant and Day 100 risk factors identified older age (≥55), (HR 2.92, 95% CI 1.21-7.08, P=0.017); high disease risk (HR 2.93, 95% CI 1.34-6.39, P=0.007), and day 100 high-risk score (HR 2.29, 95% CI 1.17-4.48, P=0.015) as significant factors for poor OS. Univariate analysis of individual components of the day 100 risk score identified poor PS at day 100, infection, and caregiving concerns as significant variables, P<0.004. A second multivariable model including individual factors demonstrated that poor PS (HR 2.68, P=0.013), infection (HR 2.57, P=0.009) and older age (HR 2.55, P=0.041) remained significantly associated with poor OS. In sum, we developed a Day 100 Risk Assessment tool and identified factors occurring within the first 100 days beyond traditional pre-transplant variables which significantly impact longer-term outcome. Targeted close follow up of these higher risk pts may help to improve survival of this at-risk population. [ABSTRACT FROM AUTHOR]

Background Relapse is a challenge after allogeneic hematopoietic cell transplantation (alloHCT) in MDS. MHC class I chain-related gene A (MICA) is a ligand of the natural killer (NKG2D) receptor on immune effector cells. There have been conflicting reports in regards to MICA mismatch and relapse after alloHCT in hematologic malignancies (Carapito Blood 2016, Askar BBMT 2017). However, these studies did not assess somatic mutations, which have shown to impact relapse (Coleman NEJM 2017). We first assessed risk factors for relapse within 6 and 12 months after alloHCT. We then assessed for an effect of somatic mutations and MICA dimorphisms on relapse. Methods We conducted a single center, retrospective analysis of adults with MDS who underwent 1st alloHCT with T-cell replete HLA-8/8 matched related (MRD) or unrelated donor (MUD). In addition to cytogenetic risk stratification, a subset of patients had a 36-gene somatic mutation panel assessed prior to alloHCT by next-generation sequencing. Dimorphisms of MICA-129 were categorized as weak (valine/valine; V/V), intermediate (methionine/valine; M/V), or strong (methionine/methionine; M/M) receptor affinity. Results From 2000 - 2017, 128 adult MDS patients met inclusion criteria. Median age at alloHCT was 56 years (range, 20-76). IPSS-R scores at diagnosis included 2% very good, 42% good, 23% intermediate, 19% poor, and 14% very poor risk. 62% had MUDs and 87% had a myeloablative regimen. Among 78 patients with data, donor/recipient MICA mismatch was present in 8% while donor MICA-129 dimorphisms were 49% V/V, 42% M/V, and 9% M/M In multivariable analysis, the presence of at least 1 of these less favorable mutations (ASXL1, DNMT3A, FLT3, KRAS, NRAS , and TP53) was a risk factor for relapse within 6 mos (HR 4.30, CI 1.40-13.3, P=0.011; Figure 1); 6-mo relapse incidence (CI) was 45% (22-65) for those with at least 1 of the above mutations vs. 15% (9-22) for all others. A MRD graft was a risk factor for relapse within 12 mos (HR 2.27, CI 1.12-4.59, P=0.023); 12-mo relapse incidence was 36% (23-50) for those with a MRD vs. 19% (11-28) for MUDs. In a 41-patient subset with both MICA and mutation data, although not significant, patients with both donor V/V dimorphism and at least 1 of these less favorable somatic mutations had higher relapse incidence (40% at 12 mos) than those with only 1 of these adverse factors (28%) or neither factor (9%) (P=0.12; Figure 2). Conclusion The presence of at least 1 of the 6 less favorable somatic mutations in our cohort was associated with a risk of relapse within 6 mos after alloHCT for MDS. Our data suggest an additive effect of both weak NK cell activation and less favorable somatic mutations in increasing the risk of relapse, but was not statistically significant. Future investigation of larger cohorts and mechanistic studies are needed to better assess potential interactions between these two elements and the risk of relapse. [ABSTRACT FROM AUTHOR]

Background BuCyVP and BEAM are two commonly used conditioning regimens for AHCT. Previous literature has reported improved outcomes with BEAM compared to BuCyVP in Hodgkin lymphoma (HL) patients, although results in non-Hodgkin lymphoma (NHL) patients are scarce but similar. Our institution switched from using BuCyVP to BEAM as AHCT conditioning for HL in 2016. We conducted a retrospective study to evaluate tolerability and resource utilization with the two regimens. Given limited data and comparable outcomes, this may influence decisions to use one regimen over the other in patients with NHL. Objectives Assess resource utilization and toxicity of BEAM vs. BuCyVP in patients undergoing AHCT for HL. The primary endpoint was hospital length of stay (LOS). Secondary outcomes were 30-day readmission rates, incidence of fever, time to neutrophil and platelet engraftment, incidence of transfer to intensive care unit (ICU), time on intravenous (IV) opioids, and incidence of diuretic and breakthrough antiemetic use. Methods Beginning March 2016, BEAM replaced BuCyVP as the standard conditioning regimen for AHCT for HL at our institution. We retrospectively reviewed medical records of HL patients receiving BuCyVP with pharmacokinetic (PK)-guided therapeutic dose monitoring (TDM) of busulfan from October 2014 through March 2016 (N = 19) and BEAM from April 2016 through September 2017 (N = 18). Results BuCyVP recipients had significantly longer average hospital LOS, relative to both admission date (21 vs. 19 days, p < 0.001) and transplant date (12 vs. 11 days, p = 0.028), increased incidence of fever (89.5% vs. 33.3%, p < 0.001), increased average days of IV opioid administration (8 vs. 1, p < 0.001), and increased average number of doses of furosemide (3 vs. 0, p < 0.001). BuCyVP resulted in shorter average days to platelet engraftment compared to BEAM (17 vs. 20, p = 0.021). No patients were re-admitted to the hospital within 30 days of discharge in either group. There was no difference in average time to neutrophil engraftment (10 vs. 10 days, p = 0.22), average number of breakthrough antiemetic doses (89 vs. 102, p = 0.17), or incidence of transfer to an ICU (10.5% vs. 0%, p = 0.49) between groups. Conclusions Compared to BuCyVP, patients receiving BEAM as conditioning for AHCT for HL had significantly shorter hospital LOS, fewer episodes of fevers and required less IV opioids and furosemide. However, there was no difference in other endpoints evaluated (e.g., neutrophil engraftment, ICU transfer and breakthrough antiemetic use). Our study provides the background information on expected resource utilization and toxicities for the two regimens and will assist in decisions regarding use of these regimens in NHL patients where outcomes between the two are comparable [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

Pharmacists are increasingly identified as vital members of the HSCT multidisciplinary team. At our institution, pharmacists recently established roles providing clinical pharmacy services in the outpatient setting focused on performing interventions during the pre-HSCT clinic visit. The primary objective was to evaluate the number of medication discrepancies identified during pre-HSCT clinic visits performed by pharmacists, defined as addition, removal, or dose adjustment of current medications. Secondary objectives were to evaluate the number of interventions made by pharmacists for drug interactions, chemotherapy dose adjustments, and other medication recommendations for all patients prior to HSCT. A retrospective review of all patients admitted for HSCT from August 2018 to 2019 was performed. Patients are seen by their HSCT provider about 1 week prior to HSCT. At this visit, oncology trained pharmacists specializing in HSCT meet with the patient and provide services such as medication reconciliation, screening for drug interactions, screening for pertinent medication allergies/ intolerances and identifying alternatives, assessing medication adherence, evaluating need for chemotherapy dose adjustments, and identifying barriers to medication access. Patients that are unable to be seen by the pharmacist receive extensive chart review prior to admission to identify medication interventions. HSCT pharmacists performed 150 pre-HSCT clinic visits for 88 (59%) autologous, 46 (31%) allogeneic, and 16 (11%) Chimeric Antigen Receptor Therapy (CAR- T) recipients. A total of 511 medication discrepancies were identified in 128 (85%) patients seen (Figure 1). In addition to the 150 patients seen, 88 patient charts were reviewed by a pharmacist. A total of 66 significant drug interactions requiring intervention were identified in 52 (22%) patients and 30 chemotherapy dose adjustments were implemented in 29 (12%) patients. Other medication recommendations were made to the provider for 109 (46%) patients. Examples of these interventions include stopping oral chemotherapy prior to HSCT, modifying supportive care medications to reflect patient preference and prior response, modifying hydration due to cardiac history, coordinating steroid tapers before haploidentical HSCT or CAR-T, adjusting prophylactic antimicrobials due to allergies or to meet institutional standards, coordinating refills, and developing a plan for non-formulary medications. Pharmacists play a crucial role in providing safe and effective care to HSCT patients, and their involvement in the multidisciplinary team can lead to significant clinical interventions. Future directions include expansion of the role of HSCT pharmacists through Pharmacy Consult Agreements, focusing on HSCT patients post-transplant and within a Survivorship Clinic. [ABSTRACT FROM AUTHOR]

Introduction High-dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT) offers cure for appropriate patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) sensitive to chemotherapy. Post-AHCT consolidative radiation therapy (RT) has been associated with improved outcomes in R/R DLBCL patients with bulky [based on computed tomography (CT)] disease after AHCT. We and others have demonstrated that patients with a Deauville score 4-5 (high-risk) on pre-AHCT FDG positron emission tomography (PET) have significantly worse outcomes as compared to those with Deauville 1-3 (low risk). We here examined the impact of consolidative post-AHCT RT in R/R-DLBCL patients with high-risk functional imaging based on Deauville score) on pre-transplant FDG PET scan on AHCT outcomes. Therefore, we retrospectively studied the effect of post-ASCT RT within 6 months after ASCT on survival in patients with R/R-DLBCL with high-risk pre-ASCT PET scans. Methods We retrospectively studied 193 consecutive adult patients with R/R-DLBCL identified from the Cleveland Clinic and University of Minnesota who had available pre-transplant FDG PET scans and adequate clinical follow-up. PET scans were re-reviewed and scored Deauville 4-5 were considered high risk. Patients that died within 6 months of ASCT (n=20) were excluded from the final survival analyses. Univariate analysis was performed using the Kaplan-Meier method, and the log-rank test was used to compare the subgroups. Results The mean (SD) age of diagnosis was 54 (11) years and 61% patients were male. The mean follow-up for alive patients was 43 (32.6) months. We identified 69 patients with pre-transplant Deauville scores 4 (n=41) or 5 (n=28). Seventeen (25%) received RT at median 58 days post AHCT (IQR 39-79 days). Receiving post-ASCT RT did not impact overall survival in univariable (Figure 1) or multivariable analyses adjusted for age and gender. Conclusion Within the limits of the study design, we did not observe a benefit to RT on overall survival in patients with RR-DLBCL with high-risk pre-AHCT PET scans. Alternative treatment approaches for high risk patients based on pre-transplant PET should be investigated in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Background ES is a potential complication following AHCT. First-line treatment typically involves corticosteroids (CS). In 2002, due to historically high ES incidence resulting in prolonged hospitalizations requiring CS treatment, our institution adopted the practice of administering prophylactic CS in patients undergoing AHCT. Due to lack of contemporary evidence supporting ES prophylaxis as well as potential intolerance of prophylactic CS noted in our patient population, a pilot was instituted to remove prophylactic CS from MEL conditioning regimen for multiple myeloma (MM) or amyloidosis. Objectives The primary objective was to evaluate the impact of prophylactic CS on the incidence of ES. Secondary objectives included hospital length of stay (LOS), duration of intravenous (IV) opioid administration during hospitalization, and incidence of infection, fever, or 30-day readmission due to any cause. Methods Beginning December 2016, CS for ES prophylaxis were removed from our standard of care in patients receiving MEL. Prior to this pilot, patients received methylprednisolone 40 mg IV daily from day +5 to day +15 or hospital discharge (whichever occurred sooner). We retrospectively reviewed the charts of patients receiving MEL from June 1 to December 15 of 2016 (CS group) and December 16, 2016 to June 30, 2017 (CS-free group). ES was defined as noninfectious fever >38°C and new documented rash at the time of engraftment (between day +7 to +11). Results A total of 76 patients were reviewed (CS group, n = 40; CS-free group, n = 36). Baseline characteristics were similar between groups in terms of median age (63 vs. 63 years, p =.65), sex (62.5% vs. 56% male, p =.54), and median CD34+ cell dose (6.36 vs. 6.43 × 106 cells/kg, p =.75). There was no difference in the incidence of documented ES between the CS and CS-free groups (2.5% vs. 0%, p = 1.00). There were no significant differences in median hospital LOS (14 vs. 14 days, p =.67), incidence of infection (17.5% vs. 22.2%, p =.61), incidence of fever (25% vs. 25%, p =.81), and 30-day readmission rate (17.5% vs. 11.1%, p =.43) in CS vs. CS-free groups, respectively. Patients in the CS group received significantly more days of IV opioid administration (median 4.5 vs. 4.0, p =.01). A greater proportion of patients received treatment with CS for suspected ES in the CS-free group compared to the CS group (8.3% vs. 2.5%, p =.34), possibly due to the strict conditions required for our definition of ES or the preemptive use of CS. Conclusions These results suggest a low overall incidence of ES in MM or amyloidosis patients undergoing AHCT using MEL. The use of prophylactic CS did not have a significant impact on incidence of ES which could be attributed to the pre-specified definition of ES. A preemptive strategy of using CS in patients with suspected ES may be sufficient in ameliorating symptoms associated with this syndrome. [ABSTRACT FROM AUTHOR]