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Purpose Transforming growth factor-β (TGF-β) production in the tumor microenvironment is a potent and ubiquitous tumor immune evasion mechanism that inhibits the expansion and function of tumor-directed responses; therefore, we conducted a clinical study to discover the effects of the forced expression of a dominant-negative TGF-β receptor type 2 (DNRII) on the safety, survival, and activity of infused tumor-directed T cells. Materials and Methods In a dose escalation study, eight patients with Epstein Barr virus–positive Hodgkin lymphoma received two to 12 doses of between 2 × 107 and 1.5 × 108 cells/m2 of DNRII-expressing T cells with specificity for the Epstein Barr virus–derived tumor antigens, latent membrane protein (LMP)-1 and LMP-2 (DNRII-LSTs). Lymphodepleting chemotherapy was not used before infusion. Results DNRII-LSTs were resistant to otherwise inhibitory concentrations of TGF-β in vitro and retained their tumor antigen–specific activity. After infusion, the signal from transgenic T cells in peripheral blood increased up to 100-fold as measured by quantitative polymerase chain reaction for the transgene, with a corresponding increase in the frequency of functional LMP-specific T cells. Expansion was not associated with any acute or long-term toxicity. DNRII-LSTs persisted for up to ≥ 4 years. Four of the seven evaluable patients with active disease achieved clinical responses that were complete and ongoing in two patients at > 4 years, including in one patient who achieved only a partial response to unmodified tumor-directed T cells. Conclusion TGF-β–resistant tumor-specific T cells safely expand and persist in patients with Hodgkin lymphoma without lymphodepleting chemotherapy before infusion. DNRII-LSTs can induce complete responses even in patients with resistant disease. Expression of DNRII may be useful for the many other tumors that exploit this potent immune evasion mechanism.

Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available off-the-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.

e18512 Background: Multiple Myeloma (MM) is the most common hematologic malignancy in Black Americans. Incidence and death rates for MM in Black Americans are more than double those in Whites. Our study aimed to evaluate trends of all cause in-hospital mortality among Black Americans with MM and to investigate characteristics of MM-related hospitalizations. Methods: We conducted a retrospective cross-sectional study of hospitalizations in adult patients with MM during 2008-2017 using the National Inpatient Sample (NIS), the largest all-payer inpatient care database in the US. We used joinpoint regression to assess temporal trends in the national incidence of in-hospital death. We conducted adjusted survey logistic regression to generate adjusted odds ratios to measure the likelihood of in-hospital death among MM related hospitalizations. Results: Admissions related to MM constituted 0.32% of all hospitalizations in the study period (913,967 out of 285,876,821). The prevalence of MM related hospitalizations was higher in Black Americans when compared with Whites (476.0 vs 305.6 per 100,000 hospitalizations, p

158 Background: The importance of assessment and reporting of health related quality of life (QoL) has been increasingly recognized in the field of oncology. QoL measures, which reflect patient’s perceived benefits and satisfaction, might be especially important in hematological malignancies clinical trials, where the intervention may not result in cure with modest overall survival benefit. Methods: Data on health related QoL were obtained from studies’ protocols and product labeling available publicly at Drugs@FDA. Drugs approved from 2016 to 2020 were analyzed. On the basis of publicly available study protocols and Food and Drug Administration (FDA) reviews, the authors reviewed the assessment of health related QoL in 53 clinical trials supporting 50 drug approvals from 2016 to 2020. Those trials resulted in approval of medications to treat leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, and multiple myeloma. Results: A total of 14,819 patients were assessed in the 5 years period after exclusion of unpublished studies. We calculated the frequency of assessment of health related QoL and if QoL measures were reported in the subsequent publications. After exclusion of 7 unpublished studies, we analyzed 46 clinical trials for reporting of HRQOL. Thirty percent of the protocols included assessment of health related QoL with only 43% of them (13% of all the analyzed clinical trials) reported the results of health related QoL. The results were consistent across all subtypes of hematological malignancies and were similar regardless of the studied primary endpoint. Conclusions: QoL measures are under studied in clinical trials of hematological malignancies. Studies that measured health related QoL didn’t report the results in more than half of the time. Although results may be reported in separate future publications, improvement in assessing and reporting of QoL will help to incorporate QoL measures in patient care and therapy choice decision. [Table: see text]

e19525 Background: Myeloablative conditioning (MAC) and unrelated donor (UD) hematopoietic cell transplantation (HCT) are associated with increased non-relapse mortality (NRM) compared with matched related donor (MRD) HCT [18%, 21%, and 32% for MRD, Matched UD (MUD), and mismatched MUD (MMUD), respectively, p < 0.001] (Saber et al, 2012). Our center uses alemtuzumab as means of T cell depletion to mitigate NRM risk in UD HCT. Here, we report outcomes utilizing this strategy. Methods: We retrospectively analyzed adult patients (pts) who received alemtuzumab-based T cell deplete MAC UD HCT from August 2012 to December 2017. Outcomes were estimated via Kaplan Meier and cumulative incidence methods. Results: Sixty-eight pts underwent T cell deplete MAC UD HCT for AML/MDS (n = 32), ALL (n = 18), lymphoma (n = 5), and other diseases (n = 13). Thirty-nine (57.4%) underwent a MUD HCT, while 29 (42.4%) underwent a MMUD (≤ 9/10 match) HCT. Median follow up was 35.5 months (m) (range 1.5 – 71.1). Median age was 46 years (range 21 - 68), 58.8% were male. Nineteen AML pts (67.9% of all AML) were considered high risk defined as secondary AML (n = 3), CR2 or more (n = 9), primary induction failure (n = 6) or having gross residual disease at time of HCT (n = 1). At 24 m, overall survival (OS) for the entire cohort was 65.3% (95%CI (CI) 53.5%- 77.2%), GVHD relapse-free survival (GRFS) was 54.8% (CI 42.8%- 66.9%), NRM was 10.4% (CI 4.5%- 19.2%), and relapse incidence (RI) was 27.3% (CI 17.1%- 38.5%). None of the 68 pts had graft failure or rejection. In the AML/MDS cohort, at 24 m OS was 52.3% (CI 33.9%- 70.7%), GRFS was 41.4% (CI 23.9%- 59%), NRM was 9.7% (CI 2.4%- 23.2%), and RI was 39.1% (CI 21.8%- 56.2%). Non-AML/MDS pts at 24 m had OS, GRFS, NRM and RI of 76.8% (CI 62.6%- 90.9%), 66.7% (CI 51.3%- 82.08%), 11.1% (CI 3.4%- 23.9%), and 16.7% (CI 6.6%- 30.6%), respectively. The table summarizes our outcomes. Conclusions: We show that alemtuzumab-based MAC conditioning for UD HCT has the benefit of being well tolerated with low NRM and high GRFS, while having comparable RI and OS compared to published outcomes of T cell replete MAC UD HCT (Saber et al, 2012). However, the retrospective nature without a comparator is a major limitation which necessitates a future prospective study to validate these findings. [Table: see text]

Purpose Tumor cells from approximately 40% of patients with Hodgkin or non-Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Because T cells specific for these antigens are present with low frequency and may be rendered anergic by the tumors that express them, we expanded LMP–cytotoxic T lymphocytes (CTLs) from patients with lymphoma using autologous dendritic cells and EBV-transformed B–lymphoblastoid cell lines transduced with an adenoviral vector expressing either LMP2 alone (n = 17) or both LMP2 and ΔLMP1 (n = 33). Patients and Methods These genetically modified antigen-presenting cells expanded CTLs that were enriched for specificity against type II latency LMP antigens. When infused into 50 patients with EBV-associated lymphoma, the expanded CTLs did not produce infusional toxicities. Results Twenty-eight of 29 high-risk or multiple-relapse patients receiving LMP-CTLs as adjuvant therapy remained in remission at a median of 3.1 years after CTL infusion. None subsequently died as a result of lymphoma, but nine succumbed to complications associated with extensive prior chemoradiotherapy, including myocardial infarction and secondary malignancies. Of 21 patients with relapsed or resistant disease at the time of CTL infusion, 13 had clinical responses, including 11 complete responses. T cells specific for LMP as well as nonviral tumor-associated antigens (epitope spreading) could be detected in the peripheral blood within 2 months after CTL infusion, but this evidence for epitope spreading was seen only in patients achieving clinical responses. Conclusion Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity. Their earlier use in the disease course may reduce delayed treatment-related mortality.

7112 Background: We investigated the safety and outcome after adding Rituximab to our standard high-dose chemotherapy conditioning regimen with BEAM in patients receiving autologous hematopoietic stem cell transplantation. Methods: Between November 2002 and May 2006, 25 consecutive patients with relapsed high-risk NHL (diffuse large B cell = 15, transformed follicular =10) were enrolled. The high-dose chemotherapy regimen consisted of BEAM with rituximab administered at 375 mg/m2 IV on days −6, +14, +21 and +28. Rituximab associated delayed neutropenia was defined as ANC of < 500 occurring at least 4 weeks after the last dose of rituximab. B cell and T cell reconstitution data was measured using phenotypic analysis for CD3, CD4, CD8, CD56, CD19 and CD20. Results: The median age was 55 years (range 22–69 years). The disease status at transplant included advanced disease (≥CR-2) in 15 while 10 had primary refractory disease. The previous initial and or salvage chemotherapy included Rituximab in all 25 patients. A median of 4.47 ×10 6/kg CD 34 + cells were infused resulting in neutrophil and platelet engraftment at 11 (10–23) and 21 (14–56) days respectively. The median time to T cell reconstitution (CD3 >1,000/uL) was 32 days, B cell recovery was delayed beyond 1 year with median of 72 CD19+ve cells/uL at 1 year. 24 (96%) patients achieved complete remission after transplant and 1 had a partial response. There was no transplant related mortality. Nine patients relapsed at a median of 4 months (2–23 months). 6 patients died at a median of 15 months from transplant (relapsed lymphoma =4 and secondary MDS=2). At a median follow-up of 24 months, the disease free survival and overall survival is 52% and 75% respectively. Rituximab associated delayed neutropenia occurred in 3 (12%) patients at a median of 39 (31–64) days from the last dose of rituximab and resolved at a median of 14 days (7–38) with or without filgrastim support. There were no infectious complications associated with neutropenia or delayed B cell recovery. Conclusion: Incorporation of rituximab into a high dose chemotherapy conditioning regimen is safe. Delayed B cell reconstitution and Rituximab associated delayed neutropenia are common but not associated with significant infectious complications. No significant financial relationships to disclose.

6650 Alemtuzumab appears to be of promise when incorporated as a lymphocyte-depleting agent in reduced intensity conditioning (RIC) stem cell transplants (SCT). However, there is a high incidence o...

6627 Background: Infection is a frequent cause of morbidity and mortality following allogeneic stem cell transplantation. It is still not clear whether RIC regimens have an impact on incidence and severity of infections. Methods: We analyzed infectious complications and outcome in 53 patients with median age of 55 years (range, 16–75 years) who underwent allogeneic stem cell transplantation with a RIC regimen consisting of Fludarabine, total body irradiation, antithymocyte globulin or Campath with or without CD45 monoclonal antibodies. Sixty eight percent (36/53) of patients received Campath based regimen. Donors were HLA identical (24 related and 17 unrelated) or one antigen mismatched (3 related, 9 unrelated). Infectious prophylaxis was Levofloxacin, fluconazole, Ganciclovir and Bactrim. Results: There were 122 episodes of fever or other clinical infections, 54 were before day +30, 46 between day +30 and day +100, and 22 after day +100. Bacteria were isolated in 42% (5 gram negative, 46 gram positive), ...

6544 Background: AML and MDS are more frequent and have worse prognosis with increasing age. Although HSCT with fully ablative conditioning is curative in 30–50% of patients with AML, it is associated with 25–40% treatment related mortality and is therefore unsuited to most AML patients. HSCT using reduced intensity conditioning may be an alternative. Methods: Patients with high risk AML or MDS not eligible for conventional transplant because of age or co-morbidities were conditioned with a single fraction TBI 450 cGY, Fludarabine 120mg/m2, as well as ATG 40mg/kg or Campath 40 mg with or without CD45 monoclonal antibodies. Allogeneic bone marrow (7) or blood stem cells(16) from HLA identical (5 related and 13 unrelated). or one antigen mismatched (3 unrelated, 2 related) donors were infused. Results: 23 consecutive patients with AML (11), MDS (3), AML secondary to MDS (7) and therapy related MDS/AML (2) were enrolled. Median age was 55 (4–75) years with 13 males and 10 females. Cytogenetic studies showed ...