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BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy, which is approved for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), can be associated with potentially severe and costly neurologic adverse events (AEs). OBJECTIVES: To develop an evidence-based list of treatment-related neurologic AEs in patients with relapsed or refractory DLBCL, including AEs related to CAR T-cell therapies, and to estimate the healthcare costs associated with these neurologic AEs in a real-world setting. METHODS: We identified grade ≥3 neurologic AEs that occurred in ≥2% of patients by reviewing drug prescribing information and published clinical trials with therapies used for relapsed or refractory DLBCL. Data from 3 nationally representative claims databases were used to identify adults with relapsed or refractory DLBCL, who were eligible for the study if they received 1 of 4 types of therapy, including CAR T-cell therapy, high-intensity cytotoxic therapy, low-intensity cytotoxic therapy, or targeted therapies. The rates of neurologic AEs and total healthcare costs were calculated for patients with and without neurologic AEs within 30 days of treatment. The costs were inflated to 2019 first-quarter US dollars. RESULTS: A total of 16 types of neurologic AEs were identified, including 13 events related to CAR T-cell therapy and 5 related to conventional immunochemotherapy regimens, with 2 overlapping event types. Of these AEs, 11 were included in the claims analysis, based on available diagnosis codes. Of the 11,098 adults with relapsed or refractory DLBCL in the study, 118 patients received CAR T-cell therapy, 9483 received a high-intensity cytotoxic therapy, 1259 received a low-intensity cytotoxic therapy, and 238 received a targeted therapy. A total of 299 (2.7%) patients had ≥1 neurologic AEs during the 30-day postindex period. Of these patients, 43 received CAR T-cell therapy (36.4% of the 118 CAR T-cell therapy users). The mean total healthcare cost was $71,982 higher for patients with neurologic AEs than for patients without neurologic AEs. The trend of higher costs in patients with neurologic AEs was consistent across the treatment groups and was most pronounced in CAR T-cell therapy users ($143,309; 95% confidence interval, $5838-$280,779). CONCLUSION: Patients with relapsed or refractory DLBCL who had severe or life-threatening neurologic AEs incur substantially higher costs than their counterparts who do not have neurologic AEs, with the largest cost difference in patients who receive CAR T-cell therapy.

Since the prognosis for children with high-risk osteosarcoma (OS) remains suboptimal despite intensive multi-modality therapies, there is a clear and urgent need for the development of targeted therapeutics against these refractory malignancies. Chimeric antigen receptor (CAR) modified T cells can meet this need by utilizing the immune system’s potent cytotoxic mechanisms against tumor specific antigen targets with exquisite specificity. Since OS highly expresses the GD2 antigen, a viable immunotherapeutic target, we sought to assess if CAR modified T cells targeting GD2 could induce cytotoxicity against OS tumor cells. We demonstrated that the GD2 CAR modified T cells were highly efficacious for inducing OS tumor cell death. Interestingly, the OS cells were induced to up-regulate expression of PD-L1 upon interaction with GD2 CAR modified T cells, and the specific interaction induced CAR T cells to overexpress the exhaustion marker PD-1 along with increased CAR T cell apoptosis. To further potentiate CAR T cell killing activity against OS, we demonstrated that suboptimal chemotherapeutic treatment with doxorubicin can synergize with CAR T cells to effectively kill OS tumor cells.

Aim: To examine real-world treatment patterns in multiple myeloma (MM) patients treated with panobinostat. Materials & methods: Using a US claims database, MM patients treated with panobinostat during 02/01/2015–01/31/2017 were evaluated. Lines of therapy, combination regimens, dosing and duration were measured. Results: Ninety-five patients were included (mean age: 61.4 years). Patients were heavily pretreated, with 88.4% exposed to both a proteasome inhibitor and an immunomodulatory agent. A panobinostat containing regimen was started in the fourth or more (86%) lines of therapy within a median of 3.77 years from initial treatment. The most common treatment combination was bortezomib/dexamethasone/panobinostat (31.6%) with 69.5% receiving the recommended dose (20 mg). Mean duration was 98.8 days. Conclusion: Patients received the recommended dose, most commonly with bortezomib and dexamethasone. Panobinostat was used in heavily pretreated patients within 4 years post-diagnosis, reflecting an advanced MM population.

BACKGROUND Umbilical cord blood (UCB) units collected from African Americans (AAs) have lower total nucleated cell (TNC) and CD34+ cell counts and are more likely to disqualify for banking compared to other ethnic groups. Furthermore, AAs have higher prevalence of 25-hydroxyvitamin D (25(OH)D) deficiency. Given the importance of 25(OH)D in hematopoiesis, we examined the racial differences in UCB unit 25(OH)D content and its correlation with UCB cellular characteristics. STUDY DESIGN AND METHODS A total of 119 UCB units that did not meet the TNC count banking criteria were analyzed. Fifty-one UCB units were collected from AA mothers and 68 from Caucasian mothers. We analyzed UCB volume, hematocrit (Hct), TNCs, mononuclear cells (MNCs), CD34+ cells, plasma 25(OH)D concentration, and progenitor clonogenic capacity measured by colony-forming cell (CFC) assay. RESULTS Compared to Caucasians, AAs had significantly lower UCB 25(OH)D levels (p

BACKGROUND: Autologous umbilical cord blood (AutoUCB) has historically been cryopreserved for potential use in hematopoietic transplantation. Increasingly, private AutoUCB banking is performed for therapies unavailable today. A Phase I trial using AutoUCB treatment for early pediatric Type 1 diabetes afforded us an opportunity to analyze characteristics of AutoUCBs. STUDY DESIGN AND METHODS: Twenty AutoUCBs from AABB-accredited private cord blood banks (CBBs) were evaluated for collection, processing, cryopreservation, and thaw characteristics. Using a standardized thaw-wash method, AutoUCBs were assessed for viable total nucleated cells (vTNCs), viable CD34+ (vCD34+), and colony-forming unit–granulocyte-macrophage counts. Postthaw %vTNC recoveries were compared against processing characteristics and analyzed according to processing method, cryopreservation volume, concentration, container, and length of storage. RESULTS: AutoUCB collection volumes (19.9-170 mL), cryopreserved TNC counts (7.6 × 107-3.34 × 109), %TNC processing recoveries (39%-100%), postthaw %vTNC recoveries (58%-100%), and %vCD34+ recoveries (26%-96%) varied widely. Regarding cell dose requirements, only 11% of evaluable AutoUCBs achieved the minimum TNC count of at least 9.0 × 108 to meet the National Cord Blood Inventory banking threshold, and only 50% met the minimum of 5.0 × 108 TNC count for Food and Drug Administration cord blood licensure eligibility. %vTNC recoveries correlated with %vCD34+ recoveries (R = 0.7; p = 0.03). Length of storage, cryopreservation volume, concentration, and container type did not affect postthaw %vTNC recoveries. CBB processing method, however, was associated with %vTNC postprocessing recoveries, with unmanipulated and plasma-depleted AutoUCBs having the highest postthaw %vTNC recovery, followed by RBC-depleted and density gradient–separated AutoUCBs. CONCLUSION: The high variability and low counts found in AutoUCB banking suggest that further standardization of characterization, collection, and processing procedures is needed.

Autosomal dominant Beta Thalassemias are rare and are due to point or frame shift mutations resulting in production of abnormal unstable beta chains of hemoglobin which precipitate leading to hemolysis and anemia. We describe a case of Hemoglobin Hakkari, a rare variant of dominant Thalassemia arising due to a de novo mutation in the exon 2 of the beta globin gene.

Double-unit cord blood transplantation (DCBT) appears to enhance engraftment despite sustained hematopoiesis usually being derived from a single unit. To investigate DCBT biology, in vitro and murine models were established using cells from 39 patient grafts. Mononuclear cells (MNCs) and CD34+ cells from each unit alone and in DCB combination were assessed for colony-forming cell and cobblestone area-forming cell potential, and multilineage engraftment in NOD/SCID/IL2R-γnull mice. In DCB assays, the contribution of each unit was measured by quantitative short tandem repeat region analysis. There was no correlation between colony-forming cell (n = 10) or cobblestone area-forming cell (n = 9) numbers and clinical engraftment, and both units contributed to DCB cocultures. In MNC transplantations in NOD/SCID/IL2R-γnull mice, each unit engrafted alone, but MNC DCBT demonstrated single-unit dominance that correlated with clinical engraftment in 18 of 21 cases (86%, P < .001). In contrast, unit dominance and clinical correlation were lost with CD34+ DCBT (n = 11). However, add-back of CD34− to CD34+ cells (n = 20) restored single-unit dominance with the dominant unit correlating not with clinical engraftment but also with the origin of the CD34− cells in all experiments. Thus, unit dominance is an in vivo phenomenon probably associated with a graft-versus-graft immune interaction mediated by CD34− cells.

Survival for children with relapsed T cell acute lymphoblastic leukemia (T-ALL) is poor when treated with chemotherapy alone, and outcomes after allogeneic hematopoietic cell transplantation (HCT) is not well described. Two hundred twenty-nine children with T-ALL in second complete remission (CR2) received an HCT after myeloablative conditioning between 2000 and 2011 and were reported to the Center for International Blood and Marrow Transplant Research. Median age was 10 years (range, 2 to 18). Donor source was umbilical cord blood (26%), matched sibling bone marrow (38%), or unrelated bone marrow/peripheral blood (36%). Acute (grades II to IV) and chronic graft-versus-host disease occurred in, respectively, 35% (95% confidence interval [CI], 27% to 45%) and 26% (95% CI, 20% to 33%) of patients. Transplant-related mortality at day 100 and 3-year relapse rates were 13% (95% CI, 9% to 18%) and 30% (95% CI, 24% to 37%), respectively. Three-year overall survival and disease-free survival rates were 48% (95% CI, 41% to 55%) and 46% (95% CI, 39% to 52%), respectively. In multivariate analysis, patients with bone marrow relapse, with or without concurrent extramedullary relapse before HCT, were most likely to relapse (hazard ratio, 3.94; P = .005) as compared with isolated extramedullary disease. In conclusion, HCT for pediatric T-ALL in CR2 demonstrates reasonable and durable outcomes, and consideration for HCT is warranted.

Autologous umbilical cord blood (AutoUCB) has historically been cryopreserved for potential use in hematopoietic transplantation. Increasingly, private AutoUCB banking is performed for therapies unavailable today. A Phase I trial using AutoUCB treatment for early pediatric Type 1 diabetes afforded us an opportunity to analyze characteristics of AutoUCBs.Twenty AutoUCBs from AABB-accredited private cord blood banks (CBBs) were evaluated for collection, processing, cryopreservation, and thaw characteristics. Using a standardized thaw-wash method, AutoUCBs were assessed for viable total nucleated cells (vTNCs), viable CD34+ (vCD34+), and colony-forming unit-granulocyte-macrophage counts. Postthaw %vTNC recoveries were compared against processing characteristics and analyzed according to processing method, cryopreservation volume, concentration, container, and length of storage.AutoUCB collection volumes (19.9-170 mL), cryopreserved TNC counts (7.6 × 10(7) -3.34 × 10(9)), %TNC processing recoveries (39%-100%), postthaw %vTNC recoveries (58%-100%), and %vCD34+ recoveries (26%-96%) varied widely. Regarding cell dose requirements, only 11% of evaluable AutoUCBs achieved the minimum TNC count of at least 9.0 × 10(8) to meet the National Cord Blood Inventory banking threshold, and only 50% met the minimum of 5.0 × 10(8) TNC count for Food and Drug Administration cord blood licensure eligibility. %vTNC recoveries correlated with %vCD34+ recoveries (R = 0.7; p = 0.03). Length of storage, cryopreservation volume, concentration, and container type did not affect postthaw %vTNC recoveries. CBB processing method, however, was associated with %vTNC postprocessing recoveries, with unmanipulated and plasma-depleted AutoUCBs having the highest postthaw %vTNC recovery, followed by RBC-depleted and density gradient-separated AutoUCBs.The high variability and low counts found in AutoUCB banking suggest that further standardization of characterization, collection, and processing procedures is needed.

Antibiotic prophylaxis has been found to have multiple benefits in patients receiving intensive chemotherapy at high risk for infection. Interest continues in identifying what additional groups of high-risk patients might potentially benefit from its use. However, concerns about the potential emergence of antibiotic resistance have led to multiple recent studies exploring this issue.The use of antibiotic prophylaxis in pediatric leukemia, myelodysplastic syndromes, and hematopoietic stem cell transplant populations has been evaluated in recent studies. Several centers have noted increased rates of antibiotic resistance in patients receiving prophylaxis.Several single-center studies have emphasized the concern for the emergence of antibiotic resistance associated with the routine use of fluoroquinolone prophylaxis. The potential for antibiotic resistance continues to be worrisome and warrants further ongoing studies.

Introduction: Persistent AML is a known risk factor for poor outcomes after allo-HCT. The impact of MRD in patients who achieve complete remission (CR) or CR with incomplete count recovery (CRi) has been less well studied. Methods: We retrospectively reviewed the records of AML patients who underwent allo-HCT in morphological remission ( Results: A total of 166 eligible patients were identified. The median follow-up among living patients is 46 months (range, 13-103).Thirty seven (22%) patients had evidence of MRD (13 by flow cytometry only, 17 by cytogenetics/FISH only and 7 by both). MRD was more common in patients with poor risk karyotype at diagnosis and CRi at the time of allo-HCT (Table 1). PFS (P= 0.0016), OS (P=0.002), and CIR (P=0.02) were all significantly worse in MRD+ patients (Figures 1& 2). In univariate analysis, MRD+ patients, assessed by flow cytometry had worse PFS (P=0.0216) and OS (P=0.0314) compared to MRD- patients. Similarly patients with evidence of MRD+ by cytogenetics/FISH had worse PFS (P=0.007) and OS (P=0.0031). In a multivariate cox proportional hazards model 1) any MRD positivity prior to allo-HCT, 2) poor-risk karyotype at diagnosis, and 3) CRi at allo-HCT independently predicted significantly poor PFS and OS. Only poor-risk karyotype was associated with a significant increase in CIR, while MRD positivity showed a trend towards higher CIR. Conclusion: MRD positivity prior to HCT by either flow cytometry or by cytogenetics/FISH independently predicts adverse AML outcomes. Table 1. Comparison of pre-transplant variables Covariate Label MRD + (N=37) MRD - (N=129) P-Value Age(years) < 40 8 (21%) 20 (16%) 0.708 40 - 59 20 (53%) 69 (54%) ≥ 60 10 (26%) 39 (30%) Karyotype risk Favorable/ Intermediate 19 (53%) 95 (74%) 0.011 Poor 18 (47%) 33 (26%) Timing of Allo-HCT 1st remission (CR1) 28 (74%) 97 (76%) 0.792 > CR1 10 (26%) 31 (24%) Allo-HCT after1st relapse(>CR1): duration of CR1 > 12 mo 31 (82%) 113 (88%) 0.285 ≤ 12 mo 7 (18%) 15 (12%) Secondary AML No 23 (60%) 78 (61%) 0.964 Yes 15 (40%) 50 (39%) Complete remission vs CRi CR 28 (74%) 110 (86%) 0.077 CRi 10 (26%) 18 (14%) Conditioning Regimen Ablative 24 (63%) 72 (56%) 0.449 Other 14 (37%) 56 (44%) Donor Type Matched sibling donor 12 (32%) 42 (33%) 0.887 Other 26 (68%) 86 (67%) Female donor: male recipient (FDMR) Other 28 (80%) 91 (78%) 0.844 FDMR 7 (20%) 25 (22%) Disclosures No relevant conflicts of interest to declare.

Despite intensive multi-modality therapies employed in the treatment of osteosarcoma (OS) the prognosis for children with high-risk disease remains suboptimal. Since standard systemic therapy for OS has remained unchanged in the past thirty years, with no new agents identified to complement conventional regimens, there has been a significant plateau in the survival of OS patients thus necessitating the development of more targeted and efficacious therapeutics. Chimeric antigen receptor (CAR) modified T cells can meet this need by utilizing the immune system's surveillance capacity and potent cytotoxic mechanisms against tumor specific antigen targets with exquisite specificity. Since OS highly expresses the GD2 antigen, a viable immunotherapeutic target, we sought to assess if a novel 4th generation CAR modified T cell could target GD2 and induce cytotoxicity against OS. We have engineered a newer generation of CAR T cells that harness the vital co-stimulatory domains imperative for T cell activation while embedding the safety features of suicide induction. The latter, an advanced safety design iCasp9, is based on AP1903-induced caspase 9 dimer formation to trigger apoptosis, which has been incorporated in our CAR design. The 4th generation lentiviral CAR (4S-CAR) encodes a combination of CD28/CD137/CD27 T cell co-stimulatory domains and CD3zeta domain fused with a mutated FKBP12 (F36V) and caspase 9. To illustrate the self-destructive function, 4S-CAR T cells were treated with AP1903 to induce iCasp9 dimerization. High efficiency of apoptosis was observed within 30 min, and in 2 hours, more than 80% CAR T cells died. After demonstrated the ability to screen patient OS samples for GD2 expression, we found that OS cells expressing high levels of GD2 were effectively targeted and killed by 4S-GD2-CAR-T cells. 4S-GD2 CAR modified T cells were shown to overexpress the exhaustion marker PD-1 when in contact with target tumor cells, and multiple OS expressing cell lines were shown to overexpress PD-L1, and the PD-L1 level increased after cocultured with 4S-GD2 CAR modified T cells. The combination effects of immune checkpoint inhibitors such as anti-PD-L1 and anti-PD-1 antibodies with CAR T cells will be further investigated. Anti-GD2 expressing CAR T cells provide a novel targeted approach to eliminate residual disease with consummate specificity. As cellular therapeutics using CAR T cells become further entrenched in the forefront against refractory malignancies, OS provides a new and compulsory niche to further test the feasibility, safety and potential efficacy of this promising new technology. Citation Format: Monrat Chulanetra, Elias Sayour, Lamis Eldjerou, Joanne Lagmay, Rowan Milner, William Slayton, Lung-Ji Chang. Novel GD2-specific chimeric antigen receptor-modified T cells targeting osteosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3157. doi:10.1158/1538-7445.AM2015-3157

Background Umbilical cord blood (UCB) is an important alternative source of stem cells for patients who lack matched adult donors, particularly in ethnic minorities. The infused total nucleated cell (TNC) and CD34+ cell dose are important prognostic factors on transplant outcomes. UCB units collected from African Americans (AA) have lower TNC and CD34+ cell counts and more likely to be disqualified for banking compared to other racial and ethnic groups. Furthermore, AA, including pregnant women, have increased prevalence of vitamin D deficiency. Vitamin D has an established role in hematopoiesis; therefore, we investigated the racial differences in UCB vitamin D content and its correlation with UCB cell composition and hematopoietic potential. Methods 119 UCB units that did not meet the TNC count banking criteria were analyzed. 51 UCB units were collected from AA mothers and 68 from Caucasian mothers. We analyzed UCB variables including volume, hematocrit (HCT), TNCs, mononucleated cells (MNC), CD34+ cells, plasma 25-Hydroxy vitamin D [25(OH)D] and in vitro progenitor cell hematopoietic potential measured by Colony-Forming Cell (CFC) assay. Results The median values of 25(OH)D in UCB units were significantly lower in AA compare to Caucasians (p= Univariate analysis of 25(OH)D effect on UCB variables revealed a correlation between 25(OH)D level and TNC (r= 0.193, 95% CI 0.013-0.36; p= .0353) and UCB HCT (r= 0.196, 95% CI 0.016-0.363; p= .0327). A significantly higher MNC count was noted when 25(OH)D concentration was ≥ 20ng/mL (4.5x 108, range (1.7-9.5) vs. 3.9x 108, range (0.8-9); p= .0329). This correlation between 25(OH)D level and TNC and MNC was not detected after adjustment for race (Figure 1). However, 25(OH)D concentration ≥ 20 ng/mL significantly correlated with CBU HCT in AA race (median 31.9% (24-42) vs. 27.8%, range (21.4 - 40); p= .0124). Conclusion 25(OH)D level, TNC and HCT are all significantly lower in UCB units from AA compare to Caucasians. Independent of race, 25(OH)D directly correlated with TNC and MNC. These data suggest vitamin D and other yet to be determined factors play an important role in the mechanism of low UCB cell and progenitor counts. Disclosures: No relevant conflicts of interest to declare.

With improvements in hematopoietic cell transplant (HCT) outcomes for severe aplastic anemia (SAA), there is a growing population of SAA survivors after HCT. However, there is a paucity of information regarding late effects that occur after HCT in SAA survivors. This study describes the malignant and nonmalignant late effects in survivors with SAA after HCT. A descriptive analysis was conducted of 1718 patients post-HCT for acquired SAA between 1995 and 2006 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The prevalence and cumulative incidence estimates of late effects are reported for 1-year HCT survivors with SAA. Of the HCT recipients, 1176 (68.5%) and 542 (31.5%) patients underwent a matched sibling donor (MSD) or unrelated donor (URD) HCT, respectively. The median age at the time of HCT was 20 years. The median interval from diagnosis to transplantation was 3 months for MSD HCT and 14 months for URD HCT. The median follow-up was 70 months and 67 months for MSD and URD HCT survivors, respectively. Overall survival at 1 year, 2 years, and 5 years for the entire cohort was 76% (95% confidence interval [CI]: 74-78), 73% (95% CI: 71-75), and 70% (95% CI: 68-72). Among 1-year survivors of MSD HCT, 6% had 1 late effect and 1% had multiple late effects. For 1-year survivors of URD HCT, 13% had 1 late effect and 2% had multiple late effects. Among survivors of MSD HCT, the cumulative incidence estimates of developing late effects were all