Safety and Efficacy of Standard of Care Ciltacabtagene Autoleucel for Relapsed/Refractory Multiple Myeloma.

Ciltacabtagene autoleucel (cilta-cel) CAR-T therapy was approved in 2022 for patients with relapsed/refractory multiple myeloma (RRMM). We report outcomes with cilta-cel in the standard-of-care setting. Patients with RRMM who underwent leukapheresis for cilta-cel manufacturing between 3/1/2022-12/31/2022 at 16 US academic medical centers were included. RESULTS: 255 patients underwent leukapheresis and 236 (92.5%) received cilta-cel. Of leukapheresed patients, 56% would not have met CARTITUDE-1 trial eligibility criteria. Manufacturing failure rates at first attempt and overall were 6% and 1%, respectively. Median prior lines of therapy were 6. In treated patients (N=236), cytokine release syndrome was seen in 75% (>= grade 3: 5%), immune effector cell-associated neurotoxicity syndrome in 14% (>= grade 3: 4%), and delayed neurotoxicity in 10%. Best overall and >= CR rates were as follows: infused patients (N=236): 89% and 70%; patients receiving conforming CAR-T product (N=191) 94% and 74%; conforming CAR-T product with fludarabine/cyclophosphamide lymphodepletion (N=152): 95% and 76%, respectively. Non-relapse mortality was 10%, most commonly from infection. After median follow-up of 13 months from CAR-T, median progression-free survival (PFS) was not reached, with 12- month estimate being 68% (95% CI: 62-74%). High ferritin levels, high-risk cytogenetics, and extramedullary disease were independently associated with inferior PFS, with a signal for prior BCMA-TT (p=0.08). Second primary malignancies (SPMs) excluding non-melanoma skin cancers were seen in 5.5% and myeloid malignancies/acute leukemia in 1.7%. We observed a favorable efficacy profile of standard of care cilta-cel in RRMM despite more than half the patients not meeting CARTITUDE-1 eligibility criteria.

Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update.

ABSTRACT: Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor-positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval [CI], 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461.

Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma.

BACKGROUND: Patient outcomes are poor for aggressive B-cell non-Hodgkin's lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines. METHODS: We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety. RESULTS: A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P = 0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standard-care group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events. CONCLUSIONS: Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach. (Funded by Novartis; BELINDA ClinicalTrials.gov number, NCT03570892.).

Comparison of biosimilar filgrastim and originator filgrastim for peripheral blood stem cell mobilization for allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Nivestym, a biosimilar granulocyte colony-stimulating factor (G-CSF) to the originator filgrastim (Neupogen), is now being used for the mobilization of peripheral blood stem cells (PBSC) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aim to compare the efficacy of Nivestym and Neupogen for PBSC mobilization in healthy allogeneic donors. METHODS: We conducted a retrospective single-center study including 541 adult allo-HSCT donors receiving Nivestym (January 2013-July 2020), or Neupogen (July 2020-June 2023) for donor PBSC mobilization. Bivariate analysis was conducted using SPSS version 28. Statistical significance was determined at a p-value <.05. RESULTS: Our study included 541 allo-HSCT donors who received Neupogen (n = 345, 64%) or Nivestym (n = 196, 36%) for PBSC mobilization. The median age was 47 years (range 17-76). The median donor weight was 86 kg (95% confidence interval [CI]: 87-91). Donors receiving Neupogen had similar pre-G-CSF white blood cell count, CD34+ percentages, and circulating CD34+ count compared with donors receiving Nivestym. The Neupogen group had similar median PBSC product total neutrophil count, CD34+ percentage, absolute CD34+ count, and infused CD34+ dose compared with the Nivestym group. For donors aged 35 years or younger, the median CD34+ dose was higher in donors who received Neupogen compared with Nivestym (6.9 vs. 6.3 million cells/kg, p = .044). CONCLUSIONS: Nivestym demonstrated similar efficacy for PBSC mobilization compared with Neupogen among allo-HSCT donors. In donors aged 35 years or younger, a slightly lower PBSC product CD34+ count was noted with Nivestym compared with Neupogen.

EGFR as a potent CAR T target in triple negative breast cancer brain metastases.

PURPOSE: There is currently no curative treatment for patients diagnosed with triple-negative breast cancer brain metastases (TNBC-BM). CAR T cells hold potential for curative treatment given they retain the cytolytic activity of a T cell combined with the specificity of an antibody. In this proposal we evaluated the potential of EGFR re-directed CAR T cells as a therapeutic treatment against TNBC cells in vitro and in vivo. METHODS: We leveraged a TNBC-BM tissue microarray and a large panel of TNBC cell lines and identified elevated epidermal growth factor receptor (EGFR) expression. Next, we designed a second-generation anti-EGFR CAR T construct incorporating a clinically relevant mAb806 tumor specific single-chain variable fragment (scFv) and intracellular 4-1BB costimulatory domain and CD3ζ using a lentivirus system and evaluated in vitro and in vivo anti-tumor activity. RESULTS: We demonstrate EGFR is enriched in TNBC-BM patient tissue after neurosurgical resection, with six of 13 brain metastases demonstrating both membranous and cytoplasmic EGFR. Eleven of 13 TNBC cell lines have EGFR surface expression ≥ 85% by flow cytometry. EGFR806 CAR T treated mice effectively eradicated TNBC-BM and enhanced mouse survival (log rank p < 0.004). CONCLUSION: Our results demonstrates anti-tumor activity of EGFR806 CAR T cells against TNBC cells in vitro and in vivo. Given EGFR806 CAR T cells are currently undergoing clinical trials in primary brain tumor patients without obvious toxicity, our results are immediately actionable against the TNBC-BM patient population.

Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial.

Results of 2 parallel phase 2 trials of transplantation of unrelated umbilical cord blood (UCB) or bone marrow (BM) from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18 to 70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo UCB (n = 186) or haploidentical (n = 182) transplant. Reduced-intensity conditioning comprised total-body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for UCB transplantation was cyclosporine and mycophenolate mofetil (MMF) and for haploidentical transplantation, posttransplant cyclophosphamide, tacrolimus, and MMF. The primary end point was 2-year progression-free survival (PFS). Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease, and disease status at randomization. Two-year PFS was 35% (95% confidence interval [CI], 28% to 42%) compared with 41% (95% CI, 34% to 48%) after UCB and haploidentical transplants, respectively (P = .41). Prespecified analysis of secondary end points recorded higher 2-year nonrelapse mortality after UCB, 18% (95% CI, 13% to 24%), compared with haploidentical transplantation, 11% (95% CI, 6% to 16%), P = .04. This led to lower 2-year overall survival (OS) after UCB compared with haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49% to 64%), respectively (P = .04). The trial did not demonstrate a statistically significant difference in the primary end point, 2-year PFS, between the donor sources. Although both donor sources extend access to reduced-intensity transplantation, analyses of secondary end points, including OS, favor haploidentical BM donors. This trial was registered at www.clinicaltrials.gov as #NCT01597778.

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

BACKGROUND: Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. METHODS: We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee. RESULTS: A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52% (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint-related proteins were found. CONCLUSIONS: In this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel. (Funded by Novartis; JULIET ClinicalTrials.gov number, NCT02445248 .).

Leukapheresis guidance and best practices for optimal chimeric antigen receptor T-cell manufacturing.

Chimeric antigen receptor (CAR) T-cell therapy is an individualized immunotherapy that genetically reprograms a patient's T cells to target and eliminate cancer cells. Tisagenlecleucel is a US Food and Drug Administration-approved CD19-directed CAR T-cell therapy for patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia and r/r diffuse large B-cell lymphoma. Manufacturing CAR T cells is an intricate process that begins with leukapheresis to obtain T cells from the patient's peripheral blood. An optimal leukapheresis product is essential to the success of CAR T-cell therapy; therefore, understanding factors that may affect the quality or T-cell content is imperative. CAR T-cell therapy requires detailed organization throughout the entire multistep process, including appropriate training of a multidisciplinary team in leukapheresis collection, cell processing, timing and coordination with manufacturing and administration to achieve suitable patient care. Consideration of logistical parameters, including leukapheresis timing, location and patient availability, when clinically evaluating the patient and the trajectory of their disease progression must be reflected in the overall collection strategy. Challenges of obtaining optimal leukapheresis product for CAR T-cell manufacturing include vascular access for smaller patients, achieving sufficient T-cell yield, eliminating contaminating cell types in the leukapheresis product, determining appropriate washout periods for medication and managing adverse events at collection. In this review, the authors provide recommendations on navigating CAR T-cell therapy and leukapheresis based on experience and data from tisagenlecleucel manufacturing in clinical trials and the real-world setting.

Impact of COVID-19 in hematopoietic stem cell transplant recipients: A systematic review and meta-analysis.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) recipients are at increased risk of mortality and morbidity with coronavirus disease 2019 (COVID-19) due to severe immune dysfunction. METHODS: A literature search was performed on PubMed, Cochrane, and Clinical trials.gov from the date of inception to 12/08/2021. We identified 19 original studies reporting data on COVID-19 in HSCT recipients after screening 292 articles. Data were extracted following preferred reporting items for systematic reviews and meta-analysis guidelines. Quality evaluation was done using the National Institutes of Health (NIH) quality assessment tool. Inter-study variance was calculated using Der Simonian-Laird Estimator. Pooled analysis was conducted using MetaXL. A random-effects model was used to estimate the proportions with 95% confidence intervals (CI). RESULTS: Of 6711 patients in 19 studies, 2031 HSCT patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were analyzed. The median age of patients was 56.9 (range 1-81.6) years, and 63% patients were men according to 14 studies. The median time from transplant to SARS-CoV-2 infection for autologous (auto) and allogeneic (allo) HSCT patients was 23.2 (0.33-350.5) months and 16.4 (0.2-292.7) months, respectively. The median follow-up time after COVID-19 diagnosis was 28 (0-262) days. The COVID-19 mortality rate was 19% (95% CI 0.15-0.24, I2  = 76%, n = 373/2031). The pooled mortality rate was 17% (95% CI 0.12-0.24, I2  = 78%, n = 147/904) in auto-HSCT patients and 21% (95% CI 0.16-0.25, I2  = 60%, n = 231/1103) in allo-HSCT patients. CONCLUSIONS: HSCT recipients have a high risk of mortality and clinical complications due to COVID-19. There is a need for ongoing vigilance, masks, and social distancing, vaccination, and aggressive management of SARS-CoV-2 infection in HSCT recipients.

Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort. METHODS: In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0-1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing. FINDINGS: Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8-43·8), the overall response rate was 53·0% (95% CI 43·5-62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3-4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported. INTERPRETATION: Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). FUNDING: Novartis Pharmaceuticals.

CAR T cells: continuation in a revolution of immunotherapy.

The recent clinical successes of immunotherapy, as a result of a broader and more profound understanding of cancer immunobiology, and the leverage of this knowledge to effectively eradicate malignant cells, has revolutionised the field of cancer therapeutics. Immunotherapy is now considered the fifth pillar of cancer care, alongside surgery, chemotherapy, radiotherapy, and targeted therapy. Recently, the success of genetically modified T cells that express chimeric antigen receptors (CAR T cells) has generated considerable excitement. CAR T-cell therapy research and development has built on experience generated by laboratory research and clinical investigation of lymphokine-activated killer cells, tumour-infiltrating lymphocytes, and allogeneic haemopoietic stem-cell transplantation for cancer treatment. This Review aims to provide a background on the field of adoptive T-cell therapy and the development of genetically modified T cells, most notably CAR T-cell therapy. Many challenges exist to optimise efficacy, minimise toxicity, and broaden the application of immunotherapies based on T cells.

Chimeric Antigen Receptor T Cell Therapy During the COVID-19 Pandemic.

The SARS-CoV-2 coronavirus (COVID-19) pandemic has significantly impacted the delivery of cellular therapeutics, including chimeric antigen receptor (CAR) T cells. This impact has extended beyond patient care to include logistics, administration, and distribution of increasingly limited health care resources. Based on the collective experience of the CAR T-cell Consortium investigators, we review and address several questions and concerns regarding cellular therapy administration in the setting of COVID-19 and make general recommendations to address these issues. Specifically, we address (1) necessary resources for safe administration of cell therapies; (2) determinants of cell therapy utilization; (3) selection among patients with B cell non-Hodgkin lymphomas and B cell acute lymphoblastic leukemia; (4) supportive measures during cell therapy administration; (5) use and prioritization of tocilizumab; and (6) collaborative care with referring physicians. These recommendations were carefully formulated with the understanding that resource allocation is of the utmost importance, and that the decision to proceed with CAR T cell therapy will require extensive discussion of potential risks and benefits. Although these recommendations are fluid, at this time it is our opinion that the COVID-19 pandemic should not serve as reason to defer CAR T cell therapy for patients truly in need of a potentially curative therapy.

Effect of Aging and Predonation Comorbidities on the Related Peripheral Blood Stem Cell Donor Experience: Report from the Related Donor Safety Study.

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59 × 106/L; age 41 to 60, 81 × 106/L; age 18 to 40, 121 × 106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50 × 109/L (26% and 57% after 2 and 3days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P = .01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P < .001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P = .004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.

Related peripheral blood stem cell donors experience more severe symptoms and less complete recovery at one year compared to unrelated donors.

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18-60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P<0.001] and severe (OR 8.91; P<0.001) pain and toxicities (OR 1.84; P<0.001) with collection. Related stem cell donors were at increased risk of persistent toxicities (OR 1.56; P=0.021) and non-recovery from pain (OR 1.42; P=0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors reporting grade ≥2 pain had significant decreases in Health-Related Quality of Life (HR-QoL) scores at one month and one year post donation (P=0.004). In conclusion, related PBSC donors with comorbidities are at increased risk for pain, toxicity, and non-recovery at one year after donation. Risk profiles described in this study should be used for donor education, planning studies to improve the related donor experience, and decisions regarding donor deferral. Registered at clinicaltrials.gov identifier:00948636.

Long-term results of a pilot study evaluating hyperbaric oxygen therapy to improve umbilical cord blood engraftment.

Umbilical cord blood (UCB) transplantation is a promising option for hematopoietic stem cell transplantation in patients with hematologic malignancies who lack an HLA-matched sibling or well-matched unrelated donor; however, it has a higher incidence of delayed or failed engraftment because cell doses are low and bone marrow homing is inefficient. We have demonstrated that pre-treating irradiated immune-deficient mice with hyperbaric oxygen (HBO) prior to UCB CD34+ cell transplantation lowered host systemic erythropoietin (EPO) and improved UCB CD34+ cell homing and engraftment. These findings suggested that EPO-EPO-R signaling plays a role in UCB CD34+ homing and engraftment. In a pilot clinical trial, we showed that recipients of HBO therapy prior to UCB cell infusion had reduced systemic EPO, which was associated with improved kinetics of blood count recovery. Although early clinical outcomes at day 100 were encouraging, with improved overall survival, the long-term effects of HBO therapy on UCB-transplanted patients were not evaluated. In this study, we examined the long-term outcome of patients in our pilot study, compared with a historic control group, and correlated their clinical outcomes to serum EPO response to HBO. While 50% of HBO-treated patients received single UCB units, ~ 90% of the control patients received double UCB units. Although HBO patients had much better rates of survival at 6 months, their 1-year survival did not significantly differ from the control group. HBO-treated patients had on average lower relapse and non-relapse mortality rates, and less chronic graft versus host disease (GVHD), but had increased acute GVHD. However, these differences were not statistically significant, probably because of the small sample size. In the HBO-treated cohort, immune reconstitution analysis showed significant improvement in early B cell recovery, with a trend toward improvement in early NK cell recovery. When we evaluated the ratio of 8 h to baseline EPO levels, we found a non-significant trend toward lower EPO values in those who neither relapsed nor died by 1 year, compared to those who died or relapsed. This result suggests that EPO response to HBO may be associated with better outcomes. Disease progression-free survival was also improved in those who had more than 80% reduction in EPO levels in response to HBO. Our study highlights the long-term safety of HBO therapy when used prior to UCB transplantation. Future UCB transplant patients who receive HBO should have their serum EPO response measured, as it may be a marker of relapse/mortality.

Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation.

Umbilical cord blood (UCB) engraftment is in part limited by graft cell dose, generally one log less than that of bone marrow (BM)/peripheral blood (PB) cell grafts. Strategies toward increasing hematopoietic stem/progenitor cell (HSPC) homing to BM have been assessed to improve UCB engraftment. Despite recent progress, a complete understanding of how HSPC homing and engraftment are regulated is still elusive. We provide evidence that blocking erythropoietin (EPO)-EPO receptor (R) signaling promotes homing to BM and early engraftment of UCB CD34+ cells. A significant population of UCB CD34+ HSPC expresses cell surface EPOR. Exposure of UCB CD34+ HSPC to EPO inhibits their migration and enhances erythroid differentiation. This migratory inhibitory effect was reversed by depleting EPOR expression on HSPC. Moreover, systemic reduction in EPO levels by hyperbaric oxygen (HBO) used in a preclinical mouse model and in a pilot clinical trial promoted homing of transplanted UCB CD34+ HSPC to BM. Such a systemic reduction of EPO in the host enhanced myeloid differentiation and improved BM homing of UCB CD34+ cells, an effect that was overcome with exogenous EPO administration. Of clinical relevance, HBO therapy before human UCB transplantation was well-tolerated and resulted in transient reduction in EPO with encouraging engraftment rates and kinetics. Our studies indicate that systemic reduction of EPO levels in the host or blocking EPO-EPOR signaling may be an effective strategy to improve BM homing and engraftment after allogeneic UCB transplantation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT02099266).

Effect of Rituximab on Pulmonary Function in Bronchiolitis Obliterans Syndrome due to Graft-Versus-Host-Disease.

PURPOSE: Rituximab is an anti-CD20 monoclonal antibody that is used to suppress B-cell function in graft-versus-host-disease (GVHD). We sought to determine the effects of rituximab treatment on lung function in those patients with bronchiolitis obliterans syndrome (BOS) as a manifestation of GVHD. METHODS: Thirteen patients were treated with rituximab with a diagnosis of BOS and a significant reduction in the forced expiratory volume in 1 s (FEV1) after hematopoietic stem cell transplantation (HSCT). The changes in their pulmonary function for 12 months following treatment with rituximab were followed, along with other intervention performed and daily average dosing of prednisone. RESULTS: Following rituximab administration, there was an improvement in the slope of decline in lung function from -5.12 ml/month prior to rituximab infusion to -0.31 ml/month after 3 months and to +2.27 ml/month 12 months later. Seven of the 13 patients had an increase in their FEV1 after treatment with rituximab. Additionally, the mean daily dose of prednisone decreased from 27 mg prior to rituximab treatment to 11 mg 12 months after treatment. Nine out of 13 patients survived 12 months after rituximab treatment. All of the patients with improvement in FEV1 following rituximab treatment were receiving concomitant extracorporeal photopheresis. CONCLUSION: Rituximab is safe with the potential to stabilize or improve lung function in patients with BOS after HSCT and should be considered as a treatment option in those patients.

Effect of extracorporeal photopheresis on lung function decline for severe bronchiolitis obliterans syndrome following allogeneic stem cell transplantation.

Extracorporeal photopheresis (ECP) is a commonly used treatment for severe graft-versus-host-disease (GVHD). We sought to evaluate the effects of ECP over a prolonged period on forced expiratory volume in 1 s (FEV1) in patients with pulmonary GVHD. We identified eight patients who developed new airflow obstruction following allogeneic stem cell transplantation and a substantial decline in FEV1 despite receiving corticosteroids and standard therapy for pulmonary GVHD. Those eight patients were treated with ECP for a period of 1 year, with a primary endpoint of FEV1 change during this treatment period. Over the first 3 months of ECP, there was no further decline in FEV1 in seven of the eight patients. However, over the 1 year period, only two of the eight patients had stability in FEV1. The rate of FEV1 decline was substantially less once ECP was initiated, though the median FEV1 continued to decline over 1 year of therapy. All patients survived through the first year of ECP therapy. There was a significant decrease in the median dose of prednisone per patient throughout the 12 months of ECP treatment. ECP shows promise in slowing rate of decline of FEV1 in pulmonary GVHD, though the effects may not be long lived. J. Clin. Apheresis 31:347-352, 2016. © 2015 Wiley Periodicals, Inc.

Hyperbaric oxygen improves engraftment of ex-vivo expanded and gene transduced human CD34⁺ cells in a murine model of umbilical cord blood transplantation.

Delayed engraftment and graft failure represent major obstacles to successful umbilical cord blood (UCB) transplantation. Herein, we evaluated the use of hyperbaric oxygen (HBO) therapy as an intervention to improve human UCB stem/progenitor cell engraftment in an immune deficient mouse model. Six- to eight-week old NSG mice were sublethally irradiated 24 hours prior to CD34⁺ UCB cell transplant. Irradiated mice were separated into a non-HBO group (where mice remained under normoxic conditions) and the HBO group (where mice received 2 hours of HBO therapy; 100% oxygen at 2.5 atmospheres absolute). Four hours after completing HBO therapy, both groups intravenously received CD34⁺ UCB cells that were transduced with a lentivirus carrying luciferase gene and expanded for in vivo imaging. Mice were imaged and then sacrificed at one of 10 times up to 4.5 months post-transplant. HBO treated mice demonstrated significantly improved bone marrow, peripheral blood, and spleen retention and subsequent engraftment. In addition, HBO significantly improved peripheral, spleen and bone marrow engraftment of human myeloid and B-cell subsets. In vivo imaging demonstrated that HBO mice had significantly higher ventral and dorsal bioluminescence values. These studies suggest that HBO treatment of NSG mice prior to UCB CD34⁺ cell infusion significantly improves engraftment.

Pulmonary manifestations of the pre-engraftment syndrome after umbilical cord blood transplantation.

Pre-engraftment syndrome (PES) is a condition occurring after umbilical cord blood transplantation (UCBT) characterized by fever and erythematous skin rash prior to neutrophil engraftment. We sought to determine the incidence and characterize the pulmonary manifestations of PES. A retrospective review of patients who underwent UCBT at the University of Kansas Medical Center over a 5-year period was performed. Data collected included patient baseline characteristics, presence of PES, pulmonary findings, treatments, and survival. Forty-four patients underwent UCBT with 22 of those patients developing PES. Full-intensity myeloablative conditioning regimen was found to be a risk factor for development of PES. Of those 22 patients, 13 had resting hypoxemia. The most common radiographic findings included diffuse ground glass opacities with pleural effusions. Fifteen patients with PES received corticosteroids, of which 12 had improvement in fevers and rash. These patients had a trend toward worse mortality than those not receiving corticosteroids. There was a nonsignificant trend toward worse survival in patients with PES and hypoxemia compared to those without hypoxemia. PES is a common complication following cord blood transplantation, with hypoxemia being present in over half of patients with PES. Hypoxemia with PES and treatment with corticosteroids may portend a worse prognosis.