Candidates For Hematopoietic Cell Transplantation Research Articles

Final Results of a Dual-Institution Phase I Clinical Trial of Targeted Marrow Irradiation (TMI) Intensification of Reduced-Intensity Fludarabine/Busulfan (Flu/Bu) Conditioning for Allogeneic Hematopoietic Cell Transplantation for Medically Frail Patients with High-Risk Hematological Malignancies

Background Reduced-intensity conditioning (RIC) regimens provide insufficient disease control in patients with high-risk hematological malignancies who are ineligible for myeloablative hematopoietic cell transplantation (HCT) due to advanced age or comorbidities. RIC fludarabine/busulfan (Flu/Bu) is generally well tolerated, but is associated with high relapse rates. We hypothesized that intensification of RIC Flu/Bu with targeted marrow irradiation (TMI) would be feasible and improve outcomes in such patients. Methods This dose escalation phase I clinical trial incorporated 3+3 design with expansion. The primary endpoint was to estimate safety and feasibility of TMI combined with Flu/Bu. Secondary endpoints included transplant-related mortality (TRM), disease free survival (DFS) and overall survival (OS). Eligible patients were ≥ 18 years diagnosed with high-risk hematological malignancies who were not candidates for myeloablative HCT. The conditioning regimen consisted of TMI (dose levels: 3 Gy, 4.5 Gy and 6 Gy) delivered at 1.5 Gy/fraction in twice daily fractions on days -10 through -7, fludarabine (30 mg/m2) on days -6 through -2 and busulfan (AUC 4800 µM*minute) on days -5 and -4. Radiation was targeted to bone marrow and spleen using intensity modulated radiation therapy (IMRT) technique while minimizing injury to organs at risk. GVHD prophylaxis included tacrolimus and methotrexate for matched sibling and unrelated donors (UD), and tacrolimus, mycophenolate mofetil and post-cyclophosphamide for haploidentical donors. Antithymocyte globulin (ATG) was added for recipients of UD transplants. Dose limiting toxicity (DLT) was defined as engraftment failure, grade ≥ 4 mucositis and grade ≥ 3 other non-hematological adverse events (AEs) from day -10 to day +32. Results A total of 26 patients (median age 64 years [range, 25-76]; 61% females) were enrolled in two transplant centers (Table 1). Diagnoses included AML (n=15), MDS (n=5), T-PLL (n=2), CLL (n=1), DLBCL (n=1), multiple myeloma (n=1) and myeloproliferative disorder (n=1). Sixteen (61%) patients had intermediate/high HCT-comorbidity index and high/very high disease risk index (DRI). At the time of HCT, 19 (73%) patients had active or residual disease. Donors were UD (n=18), matched sibling (n=5) and haploidentical (n=3). All patients engrafted neutrophils (median, 16 days [range, 10-29]). Most frequent AEs were mucositis (65%), gastrointestinal toxicity (62%), hepatotoxicity (hyperbilirubinemia and/or increased transaminase levels) (65%) and fatigue (69%). Twenty-four grade ≥ 3 AEs occurred in 13 patients; 2 patients experienced reversible DLT (mucositis and hepatotoxicity) at 6 Gy TMI dose level. Additional escalation was halted and 6 Gy cohort was expanded. Only 1 patient experienced reversible hepatotoxicity in the expansion cohort. Grade II-IV and III-IV acute GVHD rates at day +100 were 57% (95% CI, 39%-84%) and 22% (95% CI, 9%-53%), respectively. The 1-year cumulative incidence of chronic GVHD was 42% (95% CI, 24%-74%). The 1-year cumulative incidence of TRM and relapse was 8% (95% CI, 2%-32%) and 26% (95% CI, 13%-52%), respectively (Figure 1A). The overall TRM for 3 Gy, 4.5 Gy and 6 Gy cohorts was 25%, 12.5% and 12%, respectively. With a median follow up of 12.7 months (range, 1.1-36.8), 1-year DFS was 55% (95% CI, 34%-76%) and OS was 65% (95% CI, 46%-85%) (Figure 1B). One-year DFS was equivalent for patients transplanted in CR or with active disease (54% [95% CI, 14%-93%] vs 55% [95% CI, 29%-80%]; p=0.83) (Figure 1C). While no difference in DFS was observed between the 4.5 Gy and 6 Gy cohorts, the 3 Gy cohort was associated with inferior DFS (p=0.004) (Figure 1D). One-year DFS and OS for 6 Gy cohort was 58% (95% CI, 30%-87%) and 82% (95% CI, 59%-100%), respectively. Conclusion Intensification of RIC Flu/Bu with TMI is feasible, with low incidence of TRM in medically frail patients. Reversible mucositis and hepatotoxicity prevented dose escalation beyond 6 Gy. DFS and OS at 6 Gy are promising and deserve further investigation. Disclosures Malek: Janssen: Other: Advisory board, Speakers Bureau; Medpacto: Research Funding; Sanofi: Other: Advisory board; Clegene: Other: Advisory board , Speakers Bureau; Amgen: Honoraria; Takeda: Other: Advisory board , Speakers Bureau; Bluespark: Research Funding; Cumberland: Research Funding. de Lima:Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding; Kadmon: Other: Personal Fees, Advisory board; Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau.

A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102

A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102

Pre-Transplant Psychosocial Assessment Practices: A National Survey of Transplant Centers

Background Hematopoietic cell transplant (HCT) is psychologically and socially demanding of patients. As such, they typically undergo psychosocial assessment pre-HCT to identify high risk factors that require intervention before, or close monitoring throughout transplant. Despite consensus that the assessment is a valuable component of the pre-HCT evaluation, there is a lack of evidence-based guidelines for it. This has led to practice variation among centers and fragmented psychosocial data that limit research. The objective of this study was to describe the content (what is assessed) and the process (who is assessed, by whom, when, and how) of the pre-HCT psychosocial assessment at U.S. transplant centers. Methods A survey was conducted with professionals who conduct pre-HCT psychosocial assessments with adult patients. The researchers developed and pre-tested a 22-item questionnaire with input from social workers. The questionnaire included transplant center characteristics, assessment items including standardized measures, and procedural aspects i.e. how high risk factors are handled. Results Of 139 eligible transplant centers, 92 (66%) had a psychosocial professional respond. The number of autologous transplants performed annually ranged from 15-300 and the number of allogeneic transplants ranged from 5-247. Approximately 81% of the centers reported having 1-2 psychosocial professionals who conduct assessments, while the remainder reported having 3-13. These professionals included licensed social workers with a master's degree (78% of centers), psychologists (21%), and psychiatrists (2%). The majority of centers (86%) reported that all patients undergo pre-HCT psychosocial assessment. Of the 3 psychosocial risk rating scales most commonly applied to HCT candidates, the Stanford Integrated Psychosocial Assessment for Transplantation was used most frequently (10 centers), followed by the Psychosocial Assessment of Candidates for Transplantation (5), and Transplant Evaluation Rating Scale (4). Of the many psychometric measures reported, the Patient Health Questionnaire-9 was used most frequently (20 centers). The majority (63%) reported that the assessment is considered most or all of the time when determining HCT eligibility. The majority (86%) also reported that patients have been declined for HCT based on psychosocial reasons such as active substance use, untreated mental illness, and no caregiver. Conclusion Pre-HCT psychosocial assessment practice varies among centers, particularly in standardized and psychometric measures used. Study results are being used to inform the development of an evidence-based assessment tool that would produce standardized, high-quality psychosocial data. The finding that one-third reported the assessment was not considered most of the time in determining HCT eligibility needs to be further studied.

Development of a Suitability Review Process for High-Risk Allogeneic Hematopoietic Cell Transplantation Candidates

<h3>Introduction</h3> One-year survival outcomes for allogeneic hematopoietic cell transplants (HCT) at an Academic Medical Center's Blood and Marrow Transplant (BMT) program fell outside the risk-adjusted outcomes model developed by the Center for International Blood & Marrow Transplant Research (CIBMTR)[1]. Suitability Review was designed in order to evaluate potential allogeneic HCT recipients deemed high-risk based on CIBMTR survival statistics. <h3>Methods</h3> Center-specific results were used in order to recognize variables identified as clinically significant for allogeneic HCT patients in relation to one-year survival outcomes[1]. Recipients were presented for formal discussion in Suitability Review with the following criteria: • Relapsed/refractory lymphoma, regardless of age • Co-morbidity index (CI) (Sorror Score) >/= 8, regardless of age • Age >/= 65, regardless of CI or diagnosis • Significant clinical decline, disease progression, or prolonged hospitalization within 21 days of HCT preparative regimen Predicted patient one-year survival probability estimate was calculated using the CIBMTR survival calculator tool[2]. Cases were presented to Academic Medical Center's BMT Medical Director and transplant provider team by patient's primary transplant physician. Potential recipients were deemed eligible, ineligible or deferred. The review process was documented in the center's electronic transplant database. <h3>Results</h3> One-year survival for high-risk HCT patients that proceeded to transplant after suitability review was 58%. Expected survivals for this patient populated would be less than 35% based on CIBMTR survival statistics. <h3>Conclusion</h3> Allogeneic HCT remains a potential curative treatment option for high-risk HCT patients. Suitability Review continues to be modified to reflect advances in treatment options while still providing exceptional care to complicated patients with advanced disease and significant co-morbidities.

Results from a multidisciplinary clinic guided by geriatric assessment before stem cell transplantation in older adults

AbstractLimitations found on geriatric assessment (GA) track with worse outcomes after hematopoietic cell transplantation (HCT). We report on a multidisciplinary team clinic (MDC), consisting of a cancer-specific GA and a multidisciplinary team of providers, to assess candidacy and create an individualized optimization plan for allogeneic HCT candidates aged ≥60 years and autologous HCT and adoptive T-cell therapy candidates aged ≥70 years. Among the 247 patients evaluated in the MDC, allogeneic HCT candidates comprised the majority (60%), followed by autologous HCT (37%) with occasional older cellular therapy candidates (3%). Almost all patients meeting program-required minimum ages for MDC optimization at our institution were assessed (98%). Relative to historical control subjects undergoing GA alone, allogeneic HCT patients aged ≥60 years who underwent MDC appraisal had similar frequencies of high-risk disease, reduced intensity regimens, and high comorbidity but fewer GA-graded functional impairments. The MDC cohort experienced fewer inpatient deaths, shorter length of stay, and fewer discharges to nursing facilities compared with control subjects. Improvements in early mortality were observed over time; 1-year overall survival improved from 43% in the pre-MDC era to 70% in the recent MDC era, and 1-year nonrelapse mortality decreased from 43% to 18%. The 31 autologous HCT recipients aged ≥70 years optimized by the MDC achieved 0% nonrelapse mortality and 97% overall survival at 1 year. A GA-guided MDC for older HCT candidates is feasible and seems to reduce transplant-associated morbidity and mortality. An MDC should encourage broader and safer utilization of transplantation in older patients.

Impact of Renal Dysfunction Measured By Estimated Glomerular Filtration Rate (eGFR) on Outcomes after Allogeneic Hematopoietic Cell Transplantation (HCT)

Introduction Renal dysfunction is a recognized risk factor for mortality after HCT, as it is included in the comorbidity index (HCT CI). Yet, further understanding on outcomes in patients with different level of renal dysfunction or undergoing hemodialysis (HD) at time of transplant remains scant. This study explores the impact of different levels renal dysfunction on major HCT outcomes in a large population using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods The study population included 8,102 patients age 40 years and older who received HCT for treatment of malignancies from 2008 to 2016, with available pre-transplant creatinine measurement. eGFR, calculated using CKD-EPI (CKD-epidemiology collaboration) method, was used to assigned patients in four categories: eGFR ≥ 90ml/min (eGFR≥ 90, N=4,237, reference), eGFR 60-90ml/min (eGFR 60-90, N=3,158), eGFR 45-59ml/min (eGFR 45-59, N=538) and eGFR &lt;45ml/min(eGFR&lt;45, N=169). A separate cohort of patients on HD at time of HCT (N=46) was analyzed independently. Multivariate analysis models were built for assessment of overall mortality, transplant-related mortality (TRM), disease relapse or progression, graft-versus-host disease (GVHD), hepatic sinusoidal obstructive syndrome (SOS), thrombotic microangiopathy (TMA), idiopathic pneumonia syndrome (IPS) and need of HD post-transplant. Common patient-, disease- and transplant-related covariates were tested on all models and HCT CI was computed without reported renal dysfunction comorbidity to avoid collinearity. Results Patient characteristics are shown in table 1. The groups were comparable on disease risk index, graft and donor source, but patients with eGFR&gt;90 were younger and received myeloablative conditioning more frequently. The cohort of eGFR &lt;45 had a higher proportion of patients with HCT CI ≥3. TRM and overall survival according to eGFR groups are shown in Figure. In the multivariate analysis models eGFR as the main effect was associated with TRM (p&lt;0.0001), overall mortality (p&lt;0.0001), and requirement of HD post HCT (p&lt;0.0001), but not for relapse/progression (p=0.98), GVHD (grades II-IV, p=0.34; III-IV, p=0.70; and chronic, p=0.20), TMA (p=0.46), SOS (p=0.02) or IPS (p=0.06). Compared to eGFR ≥90, the hazard ratio (HR) for TRM for eGFR 60-89 was 1.12 (p=0.07), for eGFR 45-59 was 1.46 (p&lt;0.001) and for eGFR&lt;45 was 1.74 (p=0.004). Corresponding HRs for overall mortality were 1.0 (p=0.9), 1.17 (p=0.03) and 1.63 (p&lt;0.0001), respectively. Similarly, for the need of HD post HCT, HR for eGFR60-89 was 1.29 (p=0.03), eGFR45-59 was 2.45 (p&lt;0.001) and for eGFR&lt;45 was 3.09 (p&lt;0.0001). Only eGFR&lt;45 was associated with higher risk of SOS (HR2.66, p=0.03). Among 46 patients on HD prior to HCT, one-year probability of overall survival was 20% (95% Confidence Interval [CI] 10-32%) and cumulative incidence of TRM at one year was 67% (95% CI, 50-81%). Conclusion These findings indicate that degree of renal dysfunction is an independent predictor of OS, TRM, probability of receiving HD and SOS when adjusted for other risk factors. The impact of eGFR on the need of HD, a complication that increases morbidity post HCT is an important finding. Additionally, the outcomes of a subset of patients on HD at time of transplants are dismal. These results can further assist the prognostic assessment of candidates for an allogeneic HCT. Disclosures Stadtmauer: Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding. Wingard:Ansun: Consultancy; Pluristem: Consultancy; Celgene: Consultancy; Merck: Consultancy; Shire: Consultancy. Ganguly:Seattle Genetics: Speakers Bureau; Daiichi Sankyo: Research Funding; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. Pasquini:Pfizer: Other: Advisory Board; Amgen: Consultancy; Medigene: Consultancy; BMS: Research Funding; Novartis: Research Funding; Kit Pharma: Research Funding.

Radiation-Free Protocol for Patients with Acute Lymphoblastic Leukemia and Mixed Phenotype Acute Leukemia Undergoing Induction Chemotherapy and Allogeneic Hematopoietic Cell Transplantation - a Multicenter Historical Prospective Study

Introduction: Acute lymphoblastic leukemia (ALL) and mixed phenotype acute leukemia (MPAL) in adults are associated with a cure rate of only 20 and with a tendency for relapse to the CNS. Total body irradiation (TBI)-based high dose therapy and allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for these patients, however, the median age for ALL in adults is 65 years and thus, majority of patients are not suitable candidates for high dose conditioning and HCT. Therefore, novel approaches are needed. Thiotepa is an alkylating lipophilic agent that result in achieving up to 100% cerebrospinal fluid levels and has been used in ablative regimens (total dose of 20 mg/kg), Christopoulos BBMT 2012. Methods: We aimed to test this regimen in patients with ALL/MPAL who were not eligible for a standard TBI-containing regimen and capped the thiotepa dose at 14 mg/kg (for patients given myeloablative regimen divided to 2 doses on Day -5 and -4) or at a dose of 10-12 mg/kg (in patients given a reduced intensity regimen). In addition patients were given BCNU at a dose of 400 mg/m^2 on Day -6 and fludarabine at a dose of 25 mg/m^2 on Day -6 to -4. We omitted entirely cranial irradiation, however Intrathecal (IT) therapy was allowed pretransplant (only) as per physician discretion. GVHD prophylaxis consisted of cycslosporine-methotrexate and ATG in cases of non-sibling donors. Results: Between July 2014 and June 2019, 22 patients from 3 centers in Israel were eligible for the protocol. Median follow up was 17 (range, 3-61) months. Median age at transplant was 51 (range, 22-68), Table. Majority of the patients (59%) had a CR1 with MRD negative disease . Ten patients (45%) were given a myeloablative regimen (&gt;14 mg/kg of thiotepa) and 12 patients (55%) were given a reduced intensity regimen (10-12 mg/kg of thiotepa), majority (7 patients, 32%) because of age&gt;60 years. Eight patients (36%) had a sibling donor, 12 patients (55%) had an unrelated donor and 2 (9%) had a 1 antigen-mismatch unrelated donor. GVHD prophylaxis consisted for all patients cyclosporine and a short course of methotrexate.Three patients (14%) developed sinusoidal obstruction syndrome (1 patient, severe). 7 patients (32%) had microbiology documented infections and 16 patients (73%) had grade 3-4 mucositis. All patients who survived (n=18, 82%) had a day 30-whole marrow donor chimerism &gt; 96%. Cumulative incidences of grade 2-4 and grade 3-4 acute GVHD at day 200 were 51%(95% CI 35%-62%) and 11%(95% CI 5%-24%), respectively. Cumulative incidence of 2 year-moderate-severe chronic GVHD was 52% (95% CI 41%-74%). Relapse occurred in only 3 patients and all occurred within 4 months from HCT with a 2 year cumulative incidence of 17%(95% CI 12%-21%). Cumulative incidences of non-relapse mortality at 30 days, 3 months and 2 years after HCT were 15%(95% CI 8%-17%), 24%(95% CI 12%-32%) and 24%(95% CI 12%-32%), respectively. At time of data extraction 14 patients were alive. Cumulative Incidences of 2-year overall survival for CR1 patients with MRD negative disease and for non-CR1 patients with MRD negative disease at HCT were 70%(95% CI 61%-87%) and 62%(95% CI 50%-73%), respectively (p=.59), Figure. Factors associated in cox regression model with decreased overall survival were CNS involvement at diagnosis (p=.06, HR=2.24) and older age (p=.045, HR=1.5), while disease status at HCT, having a sibling donor, and intensity of conditioning were not predictive. Conclusions: This study shows that a thiotepa based regimen has substantial activity in patients with ALL, even in those who are older than 60 years and in patients intelligible to TBI. Reduced doses of thiotepa may have comparable efficacy and a lower toxicity profile when compared to higher doses and should be further investigated in this cohort of patients. Disclosures No relevant conflicts of interest to declare.

1001. Feasibility and Outcomes of a Pre-Transplant Antibiotic Allergy Evaluation Program for Allogeneic Hematopoietic Cell Transplant (HCT) Candidates

BackgroundAntibiotic allergies impact the management of hematopoietic cell transplant (HCT) patients who are often prescribed antibiotics for infection prophylaxis and treatment. We evaluated the feasibility and outcomes of an antibiotic allergy evaluation program prior to allogeneic HCT.MethodsIn August 2017, we implemented a program to expedite allergy clinic referrals for adult allogeneic HCT candidates who reported an antibiotic allergy at their initial pre-transplant evaluation visit (PTEV). Allergy labels and clinical data including outcomes of allergy evaluation were prospectively collected for patients with PTEVs between 8/10/17 and November 15/18. The use of selected antibiotics was collected in the 100 days following HCT among patients with a reported β-lactam allergy (BLA). Choice of prophylactic agent for Pneumocystis jiroveci among patients with reported sulfa allergies was assessed among HCT recipients after engraftment.ResultsOf 276 allogeneic HCT candidates, 109 (39.5%) reported >= 1 antibiotic allergy (Table 1). Of the 109, 69 (63%) were referred for allergy evaluation; 83% (57/69) of those referred were evaluated at a median of 14 days after PTEV, and a median of 18 days before transplant. Among evaluated patients, 45 (79%) had >= 1 antibiotic allergy de-labeled including 74% (28/38) of those with BLA (Figure 1). Of the 10 patients whose BLAs could not be delabeled, 1 had a possible immediate IgE-mediated reaction, 5 had a delayed type IV hypersensitivity, and 4 had other reactions or required additional testing. Post-transplant antibiotic use among evaluated vs. nonevaluated patients reporting BLA is shown in Figure 2. Among 31 patients with reported sulfa allergies who underwent HCT, those who were evaluated received TMP-SMX rather than alternative prophylaxis more often (48%; 11/23) than those who were not evaluated (25%; 2/8). 10 (43%) of 23 evaluated patients were delabeled; 7 of 10 delabeled patients received TMP-SMX.ConclusionAntibiotic allergies are frequently reported among HCT candidates. Pre-transplant antibiotic allergy evaluation was feasible, led to de-labeling of the majority of reported allergies, and may alter antibiotic prescribing and increase the use of preferred agents following transplant. Disclosures All authors: No reported disclosures.

Treatment response and outcome of children with T-cell acute lymphoblastic leukemia expressing the gamma-delta T-cell receptor

ABSTRACT T-cell malignancies expressing the γδ T-cell receptor (TCR) are often associated with poor prognosis. Here, we determined the clinical outcome of pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) expressing the γδ TCR. Of 100 newly diagnosed T-ALL patients, 93 had γδ TCR analysis performed at diagnosis. Repertoire was evaluated by paired sequencing of the rearranged TCR. All patients received intensified chemotherapy and those with minimal residual disease (MRD) ≥ 1% on day 42–46 became candidates for hematopoietic cell transplantation. Of the 93 T-ALL patients, 12 (13%) had γδ T-ALL and 11 (12%) had early T-cell precursor (ETP) ALL. Compared to the remaining 70 T-ALL patients, the γδ T-ALL patients were more likely to have MRD ≥ 1% on day 15–19 (67% vs. 33%, P = 0.03) and day 42–49 (33% vs. 7%; P = 0.007) of remission induction. The 10-year overall survival for γδ T-ALL patients (66.7% ± 22.2%) were lower than that of T-ALL patients (93.3% ± 7.3%, P = 0.001). TCR analysis demonstrated a conserved clonotype. In conclusion, the data suggest that children with γδ T-ALL may have a poor response to remission induction, based on MRD levels and decreased survival than the other T-ALL patients, despite receiving risk-directed therapy.

Abstract IA02: Engineering T cells to eradicate tumors in the age of synthetic biology

Abstract Unlike cancer vaccines and immune modulators such as checkpoint inhibitors that seek to harness patient immune responses, adoptive therapy with genetically engineered T cells seeks to create responses that don’t exist in the patient’s immune system. Molecular technologies now make it feasible to not only create T cells with specificity for the tumor by introduction of a selected antigen-specific receptor, but also with qualities not naturally found, including improved function and resistance to immunosuppression. We have been exploring in preclinical models and clinical trials methods to reproducibly provide therapeutic T cell responses by transfer of genetically engineered T cells. For human acute myelogenous leukemia (AML), we have pursued targeting WT1, a gene overexpressed in human leukemic stem cells that is associated with promoting leukemic transformation. Preclinical studies performed in a mouse model demonstrated that CD8 T cells expressing a high affinity TCR specific for this oncogene can be safely administered, with no evidence of toxicity to the normal tissues known to express low but detectable levels of WT1. We have advanced this approach to a clinical trial in leukemia patients with poor prognostic factors that place them at high risk of relapse after hematopoietic cell transplant (HCT), using a high-affinity human TCR specific for WT1 to transduce CD8 cells and reproducibly create high-avidity T cells that recognize leukemic cells. Our clinical results demonstrate that such T cells can prevent leukemic relapse and sustain long-term remissions, and can mediate antileukemic activity in patients who have relapsed. This therapy is now being tested in AML patients who have minimal residual disease after induction therapy and are not candidates for HCT, as well as in solid tumors that similarly overexpress WT1. Unfortunately, there are substantive obstacles in targeting established tumors that can preclude even a T cell expressing a high-affinity TCR from being effective. These impediments include the development of T cell dysfunction, particularly within the microenvironment of solid tumors, and we are using genetically engineered mouse models to elucidate the cellular and molecular pathways that need to be modulated to achieve meaningful therapeutic benefit in a variety of hematologic and solid tumor settings, including pancreatic and ovarian cancer. Our preclinical therapy studies reveal promising antitumor activity, but demonstrate that repeated infusions of functional T cells are required to sustain a therapeutic response in the context of the immunosuppressive tumor microenvironment, and we are engineering T cells to overcome these inhibitory signals and enhance efficacy. In place of current strategies that disrupt inhibitory pathways by systemic administration of blocking mAbs, which globally disrupt immune regulation and thus can have significant toxicity to the host, we are creating synthetic immunomodulatory fusion proteins that take advantage of the expression of inhibitory ligands by tumors by still binding the inhibitory ligand but alternatively delivering a costimulatory rather than inhibitory signal. Additionally, as the antitumor activity of CD8 T cells is enhanced by a concurrent CD4 T cell response, we are engineering CD4 T cells as well as CD8 T cells to create an orchestrated antitumor response. The results suggest that cancer therapy with engineered T cells can provide effective antitumor responses and will likely find an increasing role in the treatment of human cancers. Citation Format: Philip D. Greenberg, Kristin G. Anderson, Dan Egan, Sunil R. Hingorani, Shannon K. Oda, Rachel Perret, Tom M. Schmitt, Ingunn M. Stromnes, Leah Schmidt, Aude G. Chapuis. Engineering T cells to eradicate tumors in the age of synthetic biology [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA02.

P010 Heterogeneous flow cytometry crossmatch reactions in the presence of patient sera with pan-dr antibodies

Aim During routine clinical evaluations of antibody profiles using single antigen bead (SAB) assays, several instances of widespread reactivity exclusively to DR antigens (‘pan-DR’ antibodies) were observed. Additional assays were performed to investigate reactivity of these pan-DR positive sera against different antigenic conformations present on bead products and donor cells. Methods Four serum samples taken two months apart from two hematopoietic cell transplant candidates were evaluated. Mixed bead and C1q assays (One Lambda, Inc) were performed to verify that the antibodies being detected were indeed against DR antigens and not cryptic epitopes that are present on SAB. Flow cytometry crossmatch (FCXM) was performed against two different donor cells. ELISA was performed to assess the involvement of AT1R antibodies in positive FCXM reactions based on reports of the capacity of anti- AT1R to cause positive FCXM. Results All sera were negative for Class II antibodies using mixed beads and C1q screening assays, contradicting the Pan-DR reactions with SAB. From patient#2, FCXM showed that serum #3 was T+/B + crossmatched against cell #1 but became T-/B- crossmatched against cell #2. From patient #1, serum #1 was borderline T+/B + when crossmatched against cell #1 but became T+/B- when crossmatched against cell #2. FCXM with all serum samples from both patients against cell#2 were negative. Additionally, auto-crossmatches for both patients were negative despite the presence of auto-antibodies. There was no association between AT1R antibody level and pan-DR observation. Conclusions The presence of antibodies against both naive and denatured antigens was indicated in pan-DR positive SAB/negative mixed beads, and in the positive T-cell FCXM and/or B-cell FCXM reactions. It is plausible that pan-DR antibodies described by the SAB data are not HLA antibodies at all but rather non-HLA antibodies with cross reactivity between cryptic HLA-DR antigens and yet unidentified non-HLA epitopes on lymphocytes.

The Role of Age in Neurocognitive Functioning among Adult Allogeneic Hematopoietic Cell Transplant Recipients

Improvements in supportive care have enabled allogeneic hematopoietic cell transplantation (HCT) to be performed in increasingly older patients. HCT is associated with neurocognitive impairment, which may be exacerbated in older adults due to normal neurocognitive decline associated with aging. The goal of this study was to evaluate whether increasing age of allogeneic HCT recipients is associated with worse neurocognitive outcomes over time relative to a matched sample of individuals without cancer. Patients (n = 140; 42% female; M age, 51 years; range, 20 to 76 years; 31% with acute myelogenous leukemia) completed neurocognitive assessments before transplantation and 3 months and 1 year after transplantation. Controls (n = 75; 56% female; M age, 53 years; range, 21 to 74 years) completed assessments at comparable time intervals. Linear mixed models revealed that regardless of age, patients demonstrated worse performance than controls before transplantation in verbal memory, visual memory, and total neuropsychological performance, and over time in executive functioning. In addition, older age was associated with worse performance in verbal memory (P = .02) and verbal fluency (P = .05) over time in patients compared with controls. Specifically, older (65+ years) patients had worse verbal memory and verbal fluency than older and younger (<65 years) controls post-transplantation (Cohen's d = .22 to .39). These data indicate that age may be a risk factor for worse neurocognitive outcomes after allogeneic HCT. If replicated, our results suggest that older candidates for allogeneic HCT should be counseled regarding the risk of cognitive problems after transplantation.

Editorial introductions

Editorial introductions

The oncologic burden of hepatitis C virus infection: A clinical perspective.

Answer questions and earn CME/CNE Chronic hepatitis C virus (HCV) infection affects millions of people worldwide and is associated with cancer. Direct-acting antivirals (DAAs) have changed HCV treatment paradigms, but little is known about the management of HCV infection in patients with cancer. The substantial burden of HCV infection and the inconclusive evidence regarding its detection and management in patients with cancer prompted the authors to review the literature and formulate recommendations. Patients for whom HCV screening is recommended included all patients with hematologic malignancies, hematopoietic cell transplantation candidates, and patients with liver cancer. There is a lack of consensus-based recommendations for the identification of HCV-infected patients with other types of cancer, but physicians may at least consider screening patients who belong to groups at heightened risk of HCV infection, including those born during 1945 through 1965 and those at high risk for infection. Patients with evidence of HCV infection should be assessed by an expert to evaluate liver disease severity, comorbidities associated with HCV infection, and treatment opportunities. DAA therapy should be tailored on the basis of patient prognosis, type of cancer, cancer treatment plan, and hepatic and virologic parameters. HCV-infected patients with cancer who have cirrhosis (or even advanced fibrosis) and those at risk for liver disease progression, especially patients with HCV-associated comorbidities, should have ongoing follow-up, regardless of whether there is a sustained virologic response, to ensure timely detection and treatment of hepatocellular carcinoma. HCV infection and its treatment should not be considered contraindications to cancer treatment and should not delay the initiation of an urgent cancer therapy. CA Cancer J Clin 2017. © 2017 American Cancer Society. CA Cancer J Clin 2017;67:411-431. © 2017 American Cancer Society.

Abstract IA01: Engineering T cell responses to tumors: Taking the immune system where no responses have gone before

Abstract IA01: Engineering T cell responses to tumors: Taking the immune system where no responses have gone before

Treatment of acute myeloid leukemia under relapsed/refractory conditions or in older adults.

Standard induction chemotherapy regimens achieve complete remission rates of 80% in younger adult patients with acute myeloid leukemia (AML). However, because of disease relapse only 40-50% of patients achieve long-term survival. Five-year survival rates in older patients are only one third of those achieved in younger cases. The adverse prognostic impact of advanced age is attributable to the chemotherapy-resistant nature of the blasts and the limited tolerability these patients have for intensive chemotherapy. For younger patients with relapsed/refractory AML, the therapeutic approach to curing AML is the re-induction of complete remission employing intensive chemotherapy, followed by allogeneic hematopoietic cell transplantation. If this approach is not feasible, less intensive chemotherapy or best supportive care or transplantation without disease remission may be performed. Older patients are unlikely to be candidates for hematopoietic cell transplantation in general. Older patients with newly diagnosed AML of low risk may be treated with intensive chemotherapy, while those with intermediate/high risks may have options including less intensive chemotherapy and best supportive care.

Hematopoietic Cell Transplantation for Myelodysplastic Syndromes.

Allogeneic hematopoietic cell transplantation (HCT) offers the only potential cure for patients with myelodysplastic syndromes (MDS). However, with current approaches to HCT, many older patients with comorbidities are poor HCT candidates, and treatment-related morbidity and mortality may offset benefit for patients with lower-risk disease. Consequently, selection of patients with MDS for HCT should take into consideration disease risk category including mutational status, HCT comorbidity index, functional status, donor options, and available institutional resources. Formal geriatric assessment may further guide use of HCT and, if HCT is chosen, selection of conditioning intensity. Patients with higher-risk MDS should be considered for HCT at the time of diagnosis, whereas expectant nontransplant management is more appropriate for those with lower-risk disease. A high blast burden at the time of HCT increases the risk of subsequent relapse; however, the role of pretransplant cytoreductive therapy and the regimen of choice remain controversial. Patients with MDS younger than 65 years and with an HCT comorbidity index ≤ 4 may benefit from more intense conditioning regimens. The presence of complex or monosomal karyotype or mutations in TP53, DNMT3A, or other genes identify patients with poorer outcomes following HCT. Patients with TP53 mutations have particularly poor survival, and should be enrolled in clinical trials whenever possible. Several important HCT studies are ongoing and will better define the role of HCT in MDS as well as the value of pretransplant cytoreductive therapy or post-transplant relapse-prevention strategies. Given the apparent underuse of HCT in eligible patients and low enrollment in MDS HCT clinical trials to date, timely referral of patients with MDS to such trials and HCT programs is critical.

Haploidentical and Matched Sibling Donor Hematopoietic Cell Transplantation for Patients with HLA-Homozygous Haplotypes

More than 1% of the Japanese population has HLA-homozygous haplotypes. For patients with such haplotypes, HLA-haploidentical family members who have no HLA mismatch in the graft-versus-host direction are readily available donor candidates for hematopoietic cell transplantation (HCT). In this study, the outcomes of patients with homozygous HLA-A, -B, and -DRB1 antigens who received HCT without T cell depletion from a haploidentical related donor with mismatches in the host-versus-graft direction only (hetero-to-homo, n = 78) or from an HLA-matched sibling donor (MSD) (MSD-homo, n = 153) were compared with those in patients with heterozygous haplotypes who received HCT from an MSD (MSD-hetero, n = 7242). Transplant outcomes in the hetero-to-homo group were similar to those in the MSD-hetero group regarding neutrophil engraftment, grades III to IV acute graft-versus-host disease (aGVHD), nonrelapse mortality (NRM), relapse, and overall survival. On the other hand, the incidences of severe aGVHD and NRM in the MSD-homo group were significantly lower than those in the MSD-hetero group (grades III to IV aGVHD: aHR .50, P = .034; NRM: aHR .48, P = .004). In conclusion, patients with HLA-homozygous haplotypes achieved lower GVHD and NRM rates for MSD transplantation than those with HLA-heterozygous haplotypes. When an MSD or an appropriate alternative donor is not available for patients with HLA-homozygous haplotypes who need immediate transplantation, transplantation from a haploidentical donor without T cell depletion is a viable option, given the comparable transplant outcomes for hetero-to-homo HCT and MSD-hetero HCT.

How I treat respiratory viral infections in the setting of intensive chemotherapy or hematopoietic cell transplantation

AbstractThe widespread use of multiplex molecular diagnostics has led to a significant increase in the detection of respiratory viruses in patients undergoing cytotoxic chemotherapy and hematopoietic cell transplantation (HCT). Respiratory viruses initially infect the upper respiratory tract and then progress to lower respiratory tract disease in a subset of patients. Lower respiratory tract disease can manifest itself as airflow obstruction or viral pneumonia, which can be fatal. Infection in HCT candidates may require delay of transplantation. The risk of progression differs between viruses and immunosuppressive regimens. Risk factors for progression and severity scores have been described, which may allow targeting treatment to high-risk patients. Ribavirin is the only antiviral treatment option for noninfluenza respiratory viruses; however, high-quality data demonstrating its efficacy and relative advantages of the aerosolized versus oral form are lacking. There are significant unmet needs, including data defining the virologic characteristics and clinical significance of human rhinoviruses, human coronaviruses, human metapneumovirus, and human bocavirus, as well as the need for new treatment and preventative options.

Factors associated with improved outcomes after second allogeneic hematopoietic cell transplantation for relapsed pediatric leukemia.

A second allogeneic (allo) hematopoietic cell transplant (HCT) is an important therapeutic consideration for patients relapsing after their first. We conducted a retrospective review of 41 pediatric patients with leukemia that underwent a second allo-HCT at our institution. Overall, 53.7 and 43.9% of patients were alive and disease-free at 1 and 5years, respectively, after the second allo-HCT. The factors affecting outcome by both univariate and multivariate analysis were interval between transplants and the use of a myeloablative conditioning (MAC) regimen prior to second transplant. Outcomes were inferior in patients who received their second transplant <6months from their first HCT when compared to patients in whom the interval between HCTs was 6-12 or more than 12months. Interval between HCTs was also significant when each type of leukemia (acute lymphoblastic leukemia (ALL) n = 21, acute myelogenous leukemia (AML) n = 11, and chronic myelogenous leukemia (CML) n = 7) was analyzed separately. In univariate analysis, use of the same donor and use of a matched sibling donor resulted in significant improved outcome. There was not a significant association between disease-free survival (DFS) and age, remission status, use of total body irradiation (TBI) before second HCT, or type of leukemia. Second allogeneic HCT can be a curative therapeutic option for leukemia patients relapsing after their first transplant. As more targeted therapies have become available, patients that relapse after first HCT are more likely to achieve remission. Therefore, it is anticipated that there will be more candidates for second HCT with improved performance and remission status, ultimately leading to a better outcome with the second HCT.