Search

The relative efficacy of autologous hematopoietic cell transplant (auto-HCT) vs chimeric antigen receptor T-cell (CAR-T) therapy in patients with diffuse large B-cell lymphoma (DLBCL) who achieve a partial remission (PR) after salvage chemotherapy is not known. Using the Center for International Blood & Marrow Transplant Research registry database, we identified adult patients with DLBCL who received either an auto-HCT (2013-2019) or CAR-T treatment with axicabtagene ciloleucel (2018-2019) while in a PR by computed tomography or positron emission tomography scan. We compared the clinical outcomes between the 2 cohorts using univariable and multivariable regression models after adjustment for relevant baseline and clinical factors. In the univariable analysis, the 2-year progression-free survival (52% vs 42%; P = .1) and the rate of 100-day nonrelapse mortality (4% vs 2%; P = .3) were not different between the 2 cohorts, but consolidation with auto-HCT was associated with a lower rate of relapse/progression (40% vs 53%; P = .05) and a superior overall survival (OS) (69% vs 47%; P = .004) at 2 years. In the multivariable regression analysis, treatment with auto-HCT was associated with a significantly lower risk of relapse/progression rate (hazard ratio = 1.49; P = .01) and a superior OS (hazard ratio = 1.63; P = .008). In patients with DLBCL in a PR after salvage therapy, treatment with auto-HCT was associated with a lower incidence of relapse and a superior OS compared with CAR-T. These data support the role of auto-HCT as the standard of care in transplant-eligible patients with relapsed DLBCL in PR after salvage therapy.

Background: Nonmyeloablative (NMA) and reduced-intensity conditioning (RIC) regimens are offered for patients with hematologic malignancies requiring allogeneic stem cell transplantation (HSCT) but are not candidates for myeloablative conditioning (MAC). The intensity of the conditioning regimen (CR) is important and contributes to the ability of HSCT to provide a cure. There is no consensus regarding the best RIC regimen and efficacy is not equal amongst RIC regimens. The combination of 2 days of intravenous Busulfan (total of 6.4 mg/Kg) and Fludarabine (total of 120-160 mg/m2) (Flu/Bu2) has been validated and widely adopted. While this regimen is well tolerated, relapses are common and remain the leading cause of death. Total body irradiation (TBI) has been widely used in the CR and provides the advantage of potent anti-cancer effect, immunosuppression and the ability to reach certain 'sanctuary sites' for chemotherapy (i.e. CNS). The 2 most commonly used TBI levels are 1200 cGy in MAC regimens and 200 cGy in NMA and RIC regimens. We hypothesize that the addition of 400 cGy (200 cGy two fractions per day, 6 hours apart) TBI to Flu/Bu2 will reduce the relapse rate without increasing its toxicity. In this retrospective study, we compared the safety and efficacy of Flu/Bu2/TBI400 with Flu/Bu2 CR amongst a diverse group of hematologic diseases. Methods: From 2006 to 2018, 137 adult patients with different hematological diseases were treated using one of two RIC regimens, either Flu/Bu2/TBI400 or Flu/Bu2 followed by HSCT from HLA-matched related or unrelated donors. The primary endpoint was OS defined as the time from the date of transplant to death from any cause. The secondary endpoints included PFS, relapse rate, cumulative incidence of relapse (CIR), non-relapse mortality (NRM), causes of death, aGVHD, cGVHD and engraftment. PFS was defined as the time from the date of transplant to disease progression as documented by the treating physician, based on pathological, imaging or clinical findings of the individual disease, or death from any cause. NRM was defined as time of death without evidence of progressive disease with relapse or progressive disease as a competing risk event (data not shown in the abstract). Relapse was defined as progression or disease relapse with NRM as a competing risk event. These endpoints were censored at the time of last follow-up. Results: A total of 137 patients were included in this study. 74 patients were treated with Flu/Bu2/TBI400 and 63 patients were treated with Flu/Bu2. The 2 groups were comparable in terms of patient-, disease- and transplant-related characteristics; however, Flu/Bu2/TBI400 patients had a higher HCT-CI score and a lower KPS. CNI-MTX GVHD prophylaxis was used in a higher proportion in Flu/Bu2/TBI400. Most of the Flu/Bu2 transplants occurred from 2006 to 2012. The median age was 62 in both groups and patients had comparable disease type distribution and DRI (Table 1). The median follow-up time was 4.62 years. Flu/Bu2/TBI400 showed improvement of PFS over Flu/Bu2; the 5-year PFS was 50% in the TBI arm vs. 34% in the no-TBI arm (p=0.06 of marginal statistical significance). There was a numerical improvement of OS in favor of the TBI arm but this was not statistically significant; The 5-year OS was 53% with TBI vs. 39% without TBI (p=0.13). Cumulative incidence of relapse was not different between the 2 groups (p=0.29), see figures 1, 2 and 3. There was no difference in aGVHD incidence between the 2 groups (p=0.21). The TBI arm had significantly lower incidence of cGVHD compared to no-TBI arm (29% vs. 54%, p=0.005). Advanced DRI, grade III-IV aGVHD, cGVHD, use of ATG and MUD were associated with worse OS (univariate analysis). The same factors, with the exception of cGVHD, were associated with worse PFS. Multivariable Cox regression model revealed that grade III-IV aGVHD was associated with worse OS (p=0.001) while advanced DRI was associated with marginally inferior OS (p=0.07) (Table 2). Conclusion: This is the largest retrospective study of RIC Flu/Bu2/TBI400 regimen for HSCT with a median follow-up approaching 5 years. Our data suggests that RIC Flu/Bu2/TBI400 is safe and efficacious for different hematological malignancies. When compared to Bu/Flu2 without TBI, Flu/Bu2/TBI400 had lower incidence of cGVHD and showed a strong trend towards improved PFS and OS though not statistically significant at this time. Grade III-IV aGVHD was associated with poor OS in both groups. Disclosures Hardy: Incyte Corporation: Other: Advisory Board Member; Kite/Gilead: Other: Advisory Board Member; American Gene Technologies: Other: DSMB Member.

Introduction: Secondary hemophagocytic lymphohistiocytosis (HLH) is an aggressive life-threatening activation of the immune system triggered by an underlying condition. Use of chimeric antigen receptor therapy (CAR-T) to treat relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) is associated with cytokine release syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) and development of secondary HLH. Application of HLH scoring systems such as the H-score or HLH-2004 criteria to identify CAR-T triggered HLH is not validated in this setting. Inability to promptly recognize the development of secondary HLH in CAR-T patients and to distinguish it from CRS may lead to delay in HLH specific therapy and increased mortality. We analyzed the utility of applying the H-score and the HLH-2004 criteria to identify possible patients with HLH post-CAR-T for R/R DLBCL. Methods: A single center retrospective analysis of 75 patients with R/R DLBCL following CAR-T was performed. Using a peak ferritin of 500 mcg/L or higher within 30 days of CAR-T administration, 43 out of 75 patients were identified at risk for HLH. The H-score and HLH-2004 criteria were applied retrospectively. Measurement of NK activity was not available for any patients and soluble IL2 was collected intermittently. The mean H-score was calculated, and two sample t-test performed to evaluate for a difference in the mean H-score between low versus high grade CRS, low versus high grade ICANS, as well as presence versus absence of cytopenias at days 30, 90 and 180. Low grade CRS/ICANS was defined as 1, and high grade as 2 or higher. CRS was graded per Lee 2014 criteria and ICANS per CTCAEv.4. The 43 patients were then subdivided by H-score threshold of 169 into H-score Low (< 169) and H-score High (≥ 169). The threshold of 169 was used given a prior validation study showing optimal sensitivity and specificity for identifying acquired HLH in adult patients with an H-score equal to or higher than 169. Both Progression Free Survival (PFS) and Overall Survival (OS) were defined as time from CAR-T infusion until an event of last follow up. Kaplan-Meier curves were produced to describe the distribution of PFS and OS between two subpopulations of low and high H-Score. Results: Median peak ferritin was 1571.8 mcg/L (range: 375 mcg/L - >50,000 mcg/L, table 1). Median H-score was 135 (range 61 -250). Four patients were treated with HLH directed therapy receiving steroids with either tocilizumab, siltuximab and/or anakinra. Of these 4 patients, only 2 met five HLH-2004 criteria. All 4 patients had H-scores above 169 (209, 211, 228 and 250). Of these 4 patients, one died from complications thought secondary to HLH. Fourteen patients (14/43, 32%) had an H-score >169. Ten patients did not require any HLH directed therapy and had no clinical evidence of HLH. The mean H-score was not different between patients with low vs high grade CRS (148.2 vs 141.8, p=0.7) or low vs high grade ICANS (145.9 vs 142.6, p=0.8). No statistical correlation was seen between H-score and cytopenias at any time point. There was no significant difference in PFS or OS between the H-score low vs high subgroups (p=0.7, p=0.1 respectively, figure 1 and 2). Patients with higher H-score tended to have longer length of hospitalization for CAR-T (Pearson correlation coefficient 0.289). Conclusions: In patients with R/R DLBCL post CAR-T, the use of either the H-score or application of HLH-2004 criteria had low utility in identifying possible HLH in patients who screened in based on peak ferritin within 30 days of CAR-T administration. While apparent differences between the H-score high and low categories may not reach statistical significance due to the small number of patients, our exploratory analysis does not support the use of H-Score to evaluate for HLH post-CAR-T. The immediate post-CAR-T period is characterized by a high inflammatory state, which likely results in high H-scores. Results from our study suggest a need for further characterization of HLH following CAR-T and the role for a CAR-T specific HLH scoring system to distinguish secondary HLH from CAR-T related inflammation in this specific patient population. Disclosures Hardy: American Gene Technologies: Other: DSMB Member; Kite/Gilead: Other: Advisory Board Member; Incyte Corporation: Other: Advisory Board Member.

Background: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are known complications of chimeric antigen receptor T-cell (CAR-T) therapy. These clinical syndromes develop as a result of CAR-T activation, proliferation, and tumor lysis with resultant cytokine secretion. In prior reports of CD19 CAR-T therapy patients, those who developed ICANS showed evidence of endothelial activation and disruption of the blood-brain barrier as a result of cytokine release while only approximately one-third demonstrated changes on Brain MRI (Gust et al. Cancer Discov 2017). As such, further predictive markers and studies are needed to identify patients at risk for ICANS to allow for expedited management and improved outcomes. Herein we report a single-center analysis exploring glycolytic activity on PET/CT and the association with clinical outcomes for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) after CAR-T therapy. Methods: An organ-based evaluation of uninvolved sites was conducted in R/R DLBCL patients (n=32) who underwent CD19 CAR-T therapy with evaluable PET/CT imaging at baseline immediately prior to CAR-T therapy and at 30 days post-infusion (D+30). All patients in this analysis were treated with axicabtagene ciloleucel as standard of care therapy after 2 or more lines of therapy. Tumor metabolic volume (TMV) and mean standard uptake value (SUVmean) of various organs were quantified using ROVER [Region of interest (ROI) visualization, evolution, and image registration] software (ABX advanced biochemical compounds GmbH, Radeberg, Germany). Statistical analysis was completed using STATA 14 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). All tests were performed after testing the normality distribution assumption. Temporal changes were assessed using paired t-tests, and between-group analyses were completed with two-sample t-tests. Results: SUVmean increased significantly after CAR-T therapy in the following organs (D+30 v baseline pre-CAR-T PET/CT): cerebral cortex (8.23 v 7.09, p=0.036), cerebellum (6.26 v 5.56, p=0.024), basal ganglia (9.22 v 7.61, p=0.005), parotid gland (1.61 v 1.42, p=0.004), liver (2.47 v 2.17, p=0.002), spleen (2.08 v 1.84, p=0.043), and pancreas (1.76 v 1.48, p Conclusion: For patients with R/R DLBCL undergoing CD19 CAR-T therapy, significantly increased CNS glycolytic activity is seen on PET/CT at D+30 post-infusion when compared to baseline. Interestingly, these changes do not correlate with development of ICANS or lymphoma response; however, changes in cortical activity were associated with CRS grade ≥2. Overall, our findings illustrate a functional and radiographic link between cytokine release and subsequent disruption of the blood-brain barrier as quantified by increased cortical glycolysis 30 days post-CAR-T therapy. While findings are limited by small sample size, further validation in a larger data set is warranted. Disclosures Hutnick: Kite/Gilead: Other: Yescarta Speakers Bureau, Speakers Bureau. Badros:Celgene Corporation: Consultancy; Amgen: Consultancy.

Introduction: Approximately 1.5% of population will be diagnosed with leukemia in their lifetime (SEER Cancer Statistics Review). Diagnosis of acute leukemia has an overwhelming effect on the patient and their families. Besides the diagnosis, effect of chemotherapeutic agents and agony over the ultimate outcome can also affect emotional-behavioral wellbeing. Evolution of depression as a disorder, along the course of acute leukemia has been reported in the past (David et al Procedia Soc & Behav Sci 2014). We investigated the prevalence of mental health disorders in hospitalized patients admitted with acute leukemia diagnosis utilizing Healthcare Utilization Project National Inpatient Sample (HCUP NIS), 2002-2014. HCUP-NIS is the largest publicly available all-payer inpatient health care database in the United States, and is a 20% stratified sample of all hospital discharges. Methods: We identified hospitalizations for acute leukemia using ICD-9 codes (203.XX, 204.XX, 205.XX, 206.XX, 207.XX and 208.XX) in the NIS database. We included patients with a primary diagnosis of acute leukemia (myeloid, lymphoid and plasma cell leukemia) including admissions for inpatient chemotherapy and/or complications requiring hospitalization. Similarly, ICD-9 codes were used to identify patients with mental health disorders of interest (ADHD, adjustment disorder, alcohol abuse, anxiety disorder, mood disorders, personality disorders, schizophrenia, substance abuse, childhood disorders). "Surveyfreq" was used to calculate proportions while "Surveymeans" was used to calculate median length of stay and hospital charges. Cochran-Armitage test was used to analyze trends; Kruskal-Wallis test was used for non-parametric data. We used chi-square for categorical data frequency, P value of < 0.05 was considered statistically significant. All analysis was performed using SAS 9.4. Results: We identified a total of 59,223 patients with mental health disorders (18.4%) out of a total of 321223 hospitalizations for acute leukemia (table 1). Median age for patients with mental health disorders is 56 years. Mood disorder was most prevalent at 8% followed by anxiety disorder at 6%. Within all mental disorders, mood disorders comprised 44% of all cases followed by anxiety disorder at 32% (figure 1). Over 60% of mental health disorders were in patient age group above 50 years (figure 2). Prevalence of mental health disorders has increased from 10% to 28% between 2002 and 2014 (figure 3). Prevalence of anxiety disorder has increased 6 fold between 2002 (2%) and 2014 (12%). It is unclear if this change is due to an actual increase in the prevalence of this condition or better recognition of mental health disorders leading to better coding. Median length of stay (LOS) is significantly longer in patients with mental health disorders compared to those without (18 days vs 9 days respectively). Median charges for hospitalization are also significantly increased in patients with mental health disorders than those without ($119,245 vs $62,132 respectively). Conclusion: Mental health disorders are common in patients with acute leukemia. One in four patients (28%) in 2014 had a mental health disorder compared to 9% in 2002. Given the retrospective nature of our study, it is difficult to determine if this is an actual increase in the incidence and prevalence of mental health disorders or if better recognition and medical coding contributes to this finding. Our study shows a disproportionate burden of mental health disorders in patients above the age 50, which constitutes the majority of the patients diagnosed with acute leukemia. Use of mental health screening tools in this population could provide an avenue for recognition and possible early intervention. Given the retrospective nature of our study, these findings need to be validated in a prospective patient population. Disclosures No relevant conflicts of interest to declare.

Background: Chimeric antigen receptor T-cell (CAR-T) therapy is an FDA-approved therapy for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). A common side effect of CAR-T therapy is cytokine release syndrome (CRS), and its severity ranges from mild to severe, and occasionally resulting in death. Patients at particularly high risk for severe CRS may benefit from earlier supportive care and rescue therapies, such as tocilizumab. Although the median onset of CRS has been reported as two days, no existing prognostic tools adequately assist the bedside clinician with triaging which patients will decompensate and warrant escalation of care. For example, biomarkers such as CRP and ferritin are ineffective in predicting CRS severity. Evaluation of the sublingual microcirculation of patients receiving CAR-T therapy may serve as a valuable surveillance tool. The sublingual microcirculation (defined as blood vessels Methods: Video images are collected in real time. Prior to interpretation, all video clips were assessed for quality based on the current microcirculation consensus document. Each acceptable clip was then analyzed by using two point-of-care (POC) scoring systems: 1) the microvascular flow index (MFI) and 2) the point-of-care microcirculation (POEM) score. The MFI is determined by dividing the video monitor into four equal quadrants and grading the overall flow of each quadrant with a score from 0-3 (0 = no flow; 1 = intermittent flow; 2 = sluggish flow; 3 = normal flow). The POEM score utilizes an ordinal 1-5 scale (1 = critically impaired; 2 = impaired; 3 = normal with marked heterogeneity; 4 = normal with mild heterogeneity; 5 = normal) that is a composite of four measurements assessing flow impairment and heterogeneity. For each enrolled patient, a baseline measurement was made immediately prior to CAR-T cell infusion with follow up measurements occurring every six hours beginning at hour 18 after cell infusion until hour 72. After hour 72, measurements were made daily until they were deemed no longer at risk for CRS. Results: At this time there is mature data on 7 patients. All patients received Axicabtagene Ciloleucel- a CD19 directed CAR-T cell therapy (Yescarta, Kite Pharma). All patients had normal baseline microcirculation (MFI > 2.6, POEM=5) and normal or near-normal microcirculation at the end of the study period. No patients developed severe CRS (grade 3 and above). Three patients developed grade 2 CRS that required tocilizumab. Patients #1 and #2 both had significant microcirculatory impairments ≥12 hours prior to developing symptoms severe enough to warrant tocilizumab. Patient #3 had normal microcirculation through the first four days of therapy and developed hypotension on day six. We captured a subtle change from a normal MFI and POEM score to mild impairment with both scoring algorithms on day five, one day prior to clinical manifestations of decompensation. For logistical reasons, subsequent data were unable to be obtained. MFI and POEM scores for all patients are listed below in Table 1. The remaining four patients developed grade 1 CRS with associated mild microcirculatory changes. Conclusions: In this pilot study, POC microcirculatory assessments were successfully used to monitor patients undergoing CAR-T therapy. Patients with more severe CRS manifested lower MFI and POEM scores and maintained their nadir longer than those with milder CRS. Our data suggest that CAR-T patients developing CRS manifest early signs of sublingual microcirculatory dysfunction. Moreover, these microcirculatory defects present prior to the development of standard clinical abnormalities, such as macrocirculatory derangements. While further investigation is ongoing, this tool could be used for earlier identification of patients at risk for CRS in order to deliver earlier appropriate therapies, and ultimately to improve patient outcomes. Disclosures No relevant conflicts of interest to declare.

Background: Sickle cell disease (SCD) is a common hemoglobinopathy, characterized by vaso-occlusive crises and affects over 100,000 people in United States. It afflicts long-lasting organ damage with a spectrum of clinical severity. Median survival for SCD is shortened to the 6th decade of life despite advances in medical care (Elmariah et al Am J Hematol 2014). Allogeneic stem cell transplant (SCT) is a potentially curative option and is increasingly considered in patients with severe symptomatic SCD. The use of SCT is limited by donor availability and treatment related complications. Several advancements in conditioning regimen and use of alternate donor source have favorably impacted the feasibility of this approach. We identified SCT performed for sickle cell disease in the Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS) from 2002-2014 in an attempt to identify hospitalization outcomes, factors affecting length of stay and healthcare utilization. Methods: HCUP-NIS is a 20% stratified sample of all discharges from hospitals across 46 states in the United States and incorporates weighting algorithms to predict nationwide estimates. We used International Classification of Diseases, Ninth Revision (ICD-9) procedure codes to identify HCT hospitalizations {Bone marrow (BM):41.02, 41.03, Peripheral blood (PB): 41.05, 41.08 and Cord blood (CB): 41.06} for sickle cell disease (282.5,282.6X -282.6X). We excluded patients who underwent SCT for indications other than SCD. Surveyfreq was used to calculate proportions and surveymeans was used to calculate median length of stay and hospital charges. Kruskal-Wallis test was used for non-parametric data. Chi-square for categorical data frequency, P value of < 0.05 was statistically significant. All analysis was performed using SAS 9.4. Results: Outcomes were analyzed from a total of 742 hospitalizations for SCT from 2002-2014 (table 1). Median age for stem cell transplant was 9 years. GVHD occurred in 14% of stem cell transplants. Overall, in-hospital mortality was low at 2.6% while mortality in patients who developed GVHD was 14%. Bacterial infections (including C.difficile) occurred more commonly than viral or fungal infections (table 2). Patients who developed graft vs host disease (GVHD) were also more likely to have bacterial, viral and fungal infections than those without. Pain crisis was noted in 9% of total admissions while stroke occurred in 6%. Median length of stay (LOS) was 35 days and median charges were $359,646. If GVHD developed, median LOS increased to 54 days while median charges increased to $712,324. Similarly, bacterial sepsis was associated with a longer median LOS of 63 days while median charges increased to $626,986 (table 3). Conclusions: The rate of inpatient mortality with SCT in sickle cell disease is lower than the overall inpatient mortality rate for allogeneic SCT (7%; Godara et al bbmt 2018), indicating a favorable outcome for these patients. Infections do occur commonly during the course of hospitalization, especially in association with GVHD. Length of stay is adversely impacted by occurrence of GVHD, bacterial sepsis, C.difficile infection and viral infections. While we are limited by duration of follow up in our study, these patterns suggest some essential modifiers for inpatient morbidity and mortality, therefore require validation in a large prospective study. Disclosures No relevant conflicts of interest to declare.