Long-term outcomes in patients with Burkitt lymphoma older than 65 years: an analysis of the Texas Cancer Registry.

Burkitt lymphoma (BL) is an extremely aggressive but curable subtype of non-Hodgkin lymphoma. While younger patients have excellent outcomes in response to aggressive chemoimmunotherapy, the rarity of this disease in older patients and limitations caused by age, comorbidities, and performance status may negate survival advantages. This analysis assessed outcomes of older adults with BL through data provided by the Texas Cancer Registry (TCR). Patients ≥65 years with BL were assessed. Patients were dichotomized into 1997-2007 and 2008-2018. Median overall survival (OS) and disease-specific survival (DSS) were assessed using Kaplan-Meier methodology, and covariates including age, race, sex, stage, primary site, and poverty index were analyzed using Pearson Chi-squared analysis. Odds ratio (OR) with 95% confidence intervals (CI) was used to assess factors contributing to patients not offered systemic therapy. P value <0.05 was considered statistically significant. Non-BL mortality events were also categorized. There were 325 adults, 167 in 1997-2007 and 158 in 2008-2018; 106 (63.5%) and 121 (76.6%) received systemic therapy, a trend that increased with time (p = 0.010). Median OS for 1997-2007 and 2008-2018 was 5 months (95% CI 2.469, 7.531) and 9 months (95% CI 0.000, 19.154) (p = 0.013), and DSS was 72 months (95% CI 56.397, 87.603) (p = 0.604) and not reached, respectively. For patients that received systemic therapy, median OS was 8 months (95% CI 1.278, 14.722) and 26 months (95% CI 5.824, 46.176) (p = 0.072), respectively, and DSS was 79 months (95% CI: 56.416, 101.584) and not reached, respectively (p = 0.607). Age ≥75 years (HR 1.39 [95% CI 1.078, 1.791], p = 0.011) and non-Hispanic whites (HR 1.407 [95% CI 1.024, 1.935], p = 0.035) had poorer outcomes, and patients at the 20-100% poverty index (OR 0.387 [95% CI 0.163, 0.921], p = 0.032) and increasing age at diagnosis (OR 0.947 [95% CI 0.913, 0.983], p = 0.004) were less likely to receive systemic therapy. Of 259 (79.7%) deaths, 62 (23.9%) were non-BL deaths, and 6 (9.6%) of these were from a second cancer. This two-decade analysis of older Texas patients with BL indicates a significant improvement in OS over time. Although patients were more likely to receive systemic therapy over time, treatment disparities existed in patients residing in poverty-stricken regions of Texas and in advancing age. These statewide findings reflect an unmet national need to find a systemic therapeutic strategy that can be tolerated by and augment outcomes in the growing elderly population.

Azacitidine Maintenance Therapy Post-Allogeneic Stem Cell Transplantation in Poor-Risk Acute Myeloid Leukemia.

OBJECTIVE/BACKGROUND: Allogeneic hematopoietic stem cell transplant (HSCT) is the potential curative modality for poor-risk acute myeloid leukemia (AML), relapse remains the main reason for transplant failure. Early-phase studies showed azacitidine is safe for post-transplant maintenance therapy in AML. METHODS: We performed a single institutional prospective cohort study to evaluate the benefit of azacitidine maintenance therapy following allogeneic HSCT in poor-risk AML. The main objective of this study is to generate a hypothesis aiming to optimize post-transplantation outcomes in poor-risk AML. Forty-nine adults with poor-risk AML who underwent allogeneic HSCT were evaluated in a nonrandomized prospective cohort fashion. Thirty-one participants received post-transplant azacitidine (32 mg/m2) on Days 1-5 for a 28-day treatment cycle beginning approximately 40 days after transplantation. The study was controlled using 18 matched individuals who were on a noninterventional surveillance protocol. RESULTS: The relapse rate was significantly higher in the control cohort (66.67%) versus (25.81%) in the azacitidine maintenance cohort ( p < .005). Time to relapse was significantly prolonged by azacitidine maintenance, not reached versus 4.1 months in the control arm ( p < .0001). In addition, median overall survival was lower in the control cohort at 7.6 versus 27.4 months in the interventional cohort ( p < .0001). At a median follow-up of 24 months, incidence of graft-versus-host disease (GVHD) did not differ between study groups ( p = .325). In both cohorts, minimal residual disease was correlated with higher hazard of relapse (95% confidence interval, 2.31-13.74; p < .001). CONCLUSION: We conclude that low dose azacitidine maintenance following allogeneic HSCT in poor-risk AML, decreased relapse rate, and increased both the time to relapse and overall survival without increased risk of GVHD.

Incidence and risk factors for graft failure in the modern era of cord blood transplantation.

BACKGROUND AND OBJECTIVES: Graft failure (GF) after cord blood transplant (CBT) has decreased with improved supportive care and cord selection strategies. We aimed to evaluate cord blood selection and factors associated with retransplantation on the incidence of GF, determine risk factors for GF including host antibodies to Kell antigen and evaluate survival after GF. MATERIALS AND METHODS: We retrospectively reviewed 84 patients who underwent CBT at the University of Oklahoma between 2000 and 2016 and compared outcomes in patients with/without engraftment by Day 28. The nonengraftment cohort was further divided into patients who underwent retransplantation. Kaplan-Meier curves with log-rank tests were calculated to assess the association between mortality and engraftment. RESULTS: Engraftment following CBT was high at 81%, with 52% engrafting by Day 28 and an additional 29% engrafting by a median of 36 days. Retransplantation led to 88% engraftment at a median of 53 days. Overall, 75% of the 40 patients who did not engraft by Day 28 died. Female sex and total nucleated cell count < 3.5/kg were significantly associated with lack of engraftment and higher mortality. Antibodies to Kell fetal antigen were not identified. Retransplantation by Day 28 for primary GF conferred a survival advantage. CONCLUSION: This study demonstrates that failure to engraft by 28 days was associated with increased mortality, and risk was mitigated with early retransplantation. Female sex and low total cell dose were associated with increased mortality. Early identification of GF coupled with early retransplantation can reduce mortality in CBT.

Prognostic impact of natural killer cell recovery on minimal residual disease after autologous stem cell transplantation in multiple myeloma.

INTRODUCTION: Natural killer cells are a potent effector lymphocyte subset that can induce cytotoxicity without the need for antigen sensitization or presentation. NK cells are a tempting target -for immune therapy, monoclonal antibody, or genetic engineering-to enhance immune surveillance mechanisms against myeloma cells. MATERIALS AND METHODS: We hypothesized an association between natural killer cell recovery after autologous stem cell transplantation (ASCT) and disease outcomes in multiple myeloma patients. We concluded a prospective study that started enrolling patients in January 2020 to identify the association between absolute NK cell count two to three after ASCT and disease outcomes after autologous stem cell transplantation in multiple myeloma using univariate and multivariate analysis. RESULTS: Natural killer cell recovery was evaluated during the third month after ASCT, day +60 to +90 post-ASCT. Our patients had a mean NK cell count of 90.53, ranging from 14 to 282 Cell/µL (Std Dev 84.64 Cell/µL). The odds of having a minimal residual disease (MRD-positivity) among patients with partial remission before transplantation is four times higher than patients with very good partial response or better (95% confidence interval 0.45-35.79). Our patients were classified into two groups based on MRD status after ASCT, an MRD-negative group of eight participants and an MRD-positive group of seven participants. The mean absolute NK cell count was significantly higher in the MRD-negative cohort, 131.38 Cell/µL, versus 43.86 Cell/µL in the MRD-positive group (p = 0.049). CONCLUSION: We conclude that for multiple myeloma patients treated with ASCT, high absolute NK cell counts two to three months after ASCT is an independent predictor for MRD negativity.

Type 2 innate lymphoid cells from Id1 transgenic mice alleviate skin manifestations of graft-versus-host disease.

BACKGROUND: Acute graft-versus-host disease (aGVHD) is one of the most common causes of morbidity for patients undergoing allogeneic stem cell transplantation. There is preliminary evidence that activated Group 2 innate lymphoid cells (ILC2s) from wild type (WT) mice reduces the lethality of aGVHD and is effective in treating lower gastrointestinal (GI) tract manifestations of aGVHD. This raises the prospect that ILC2s may be used for cell-based therapy of aGVHD but vigorous investigation is necessary to assess their impacts on different aspects of aGVHD. Genetically engineered mice which either express Id1 protein (Id1tg/tg), an inhibitor of E protein transcription factors or have E protein genes knocked out (dKO) in the thymus produce massive numbers of ILC2s, thus allowing extensive evaluation of ILC2s. We investigated whether these ILC2s have protective effects in aGVHD as WT ILC2s do using an established mouse model of aGVHD. RESULTS: bone marrow transplant was performed by irradiating BALB/c strain of recipient mice and transplanting with bone marrow and T cells from the MHC-disparate C57BL/6 strain. We isolated ILC2s from Id1tg/tg and dKO mice and co-transplanted them to study their effects. Our results confirm that activated ILC2s have a protective role in aGVHD, but the effects varied depending on the origin of ILC2s. Co-transplantation of ILC2s from Id1tg/tg mice were beneficial in aGVHD and are especially helpful in ameliorating the skin manifestations of aGVHD. However, ILC2s from dKO mice were less effective at the protection and behaved differently depending on if the cells were isolated from dKO mice were pre-treated with IL-25 in vivo. CONCLUSION: These findings support the notion that thymus-derived ILC2s from Id1tg/tg mice are protective against aGVHD, with a significant improvement of skin lesions and they behave differently from dKO mice in the setting of aGVHD.

Hemophagocytic Lymphohistiocytosis Secondary to Ehrlichia Chaffeensis in Adults: A Case Series From Oklahoma.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation that occurs as either a familial disorder or as a sporadic condition in association with a variety of triggers. Infections are the most common cause of HLH in adults and should be searched for as early treatment usually results in a favorable outcome. Human monocytotropic ehrlichiosis (HME) is a very rare cause of HLH. Failure to consider ehrlichiosis can result in misdiagnosis and an increased length of hospitalization and healthcare cost as described in our report. Treatment for secondary HLH is aimed at reducing hypercytokinemia and eradicating inflammatory and infected cells. It is important to promptly initiate doxycycline when tick-borne diseases are being entertained as a possible trigger, as the antibiotic is effective, safe and inexpensive.

Changes in the neurotransmitter profile in the central nervous system of marine medaka (Oryzias melastigma) after exposure to brevetoxin PbTx-1 - A multivariate approach to establish exposure biomarkers.

A strategy to construct multivariate biomarkers for exposure to algal neurotoxins via correlating changes to the profiles of a series of neurotransmitters and their metabolites in the central nervous system (CNS) of exposed test organism is reported. 3-Month-old marine medaka (Oryzais melastigma) were exposed to waterborne brevetoxin PbTx-1 at two sub-lethal dose levels (0.5 and 2.5 µg-PbTx-1 L-1) for a duration of 12 h before quantification of 43 selected neurotransmitters and metabolites in their CNS were measured via dansyl chloride derivatization and LC-MS/MS determination. The profiling data were analyzed by multivariate statistical analyses, including principle component analysis (PCA), projection on latent structure-discriminate analysis (PLS-DA) and orthogonal projection on latent structure-discriminate analysis (OPLS-DA). Neurotransmitters and metabolites related to activation of voltage-gated sodium channels (VGSCs), N-methyl-D-aspartic acid receptors (NMDARs) and cholinergic neurotransmission were found to contribute significantly to class separation in the corresponding OPLS-DA models. Those models obtained from different exposure dosages were correlated by the Shared and Unique Structures Plot (SUS-plot) to identify appropriate variables for the construction of exposure biomarkers in the form of multivariate predictive scores. The established biomarkers for male and female medaka fish were able to predict acute sub-lethal exposure to PbTx-1 with good sensitivity and specificity (male fish: sensitivity 94.7%, specificity 80.0%; female fish: sensitivity 91.4%, specificity 83.3%). Neurotransmitter profiles in the CNS of medaka fish that should have recovered from exposure to PbTx-1 have also been determined to reveal long-term impacts to the CNS of the affected organism even after the exposure has been interrupted.

Toward eliminating HLA class I expression to generate universal cells from allogeneic donors.

Long-term engraftment of allogeneic cells necessitates eluding immune-mediated rejection, which is currently achieved by matching for human leukocyte antigen (HLA) expression, immunosuppression, and/or delivery of donor-derived cells to sanctuary sites. Genetic engineering provides an alternative approach to avoid clearance of cells that are recognized as "non-self" by the recipient. To this end, we developed designer zinc finger nucleases and employed a "hit-and-run" approach to genetic editing for selective elimination of HLA expression. Electro-transfer of mRNA species coding for these engineered nucleases completely disrupted expression of HLA-A on human T cells, including CD19-specific T cells. The HLA-A(neg) T-cell pools can be enriched and evade lysis by HLA-restricted cytotoxic T-cell clones. Recognition by natural killer cells of cells that had lost HLA expression was circumvented by enforced expression of nonclassical HLA molecules. Furthermore, we demonstrate that zinc finger nucleases can eliminate HLA-A expression from embryonic stem cells, which broadens the applicability of this strategy beyond infusing HLA-disparate immune cells. These findings establish that clinically appealing cell types derived from donors with disparate HLA expression can be genetically edited to evade an immune response and provide a foundation whereby cells from a single donor can be administered to multiple recipients.

Liposarcoma in children and young adults: a multi-institutional experience.

BACKGROUND: There are limited data regarding the differences in clinical presentation and outcome of liposarcomas between adult and pediatric patients. The role of adjuvant radiotherapy in the treatment of childhood liposarcoma is unclear. PROCEDURE: A multi-institutional retrospective analysis of medical records was performed for patients ≤ 21 years of age presenting with a verified histologic diagnosis of liposarcoma. RESULTS: Thirty-three patients were evaluable for this study, 23 of whom were male. Median age was 17.2 years. Twenty-four cases were myxoid subtype and 7 were pleomorphic subtype. In myxoid cases, 17 (71%) presented with extremity tumors; none had metastases. Eleven of these patients with myxoid subtype were treated with surgery only, seven with surgery + radiation, three with surgery + radiation + chemotherapy. Median radiation therapy dose for patients with myxoid tumors was 60 Gy. At median follow-up of 4.2 years (range 0.1-32.2 years), two patients relapsed with one death from progressive disease. In seven pleomorphic cases, four patients had primary tumors at central axial sites. Six patients (86%) received multimodal therapy, but six patients experienced relapse of disease. Four patients died from progressive disease. CONCLUSIONS: Pediatric liposarcoma has a different spectrum of presentation compared to adult cases. Myxoid liposarcoma is the more common subtype, usually occurs in extremities, and has an excellent prognosis. Pleomorphic liposarcoma occurs in axial sites, and despite multimodal therapy, outcome is poor. Further study is needed to identify the optimal therapy for pediatric liposarcoma.

A high throughput microelectroporation device to introduce a chimeric antigen receptor to redirect the specificity of human T cells.

It has been demonstrated that a chimeric antigen receptor (CAR) can directly recognize the CD19 molecule expressed on the cell surface of B-cell malignancies independent of major histocompatibility complex (MHC). Although T-cell therapy of tumors using CD19-specific CAR is promising, this approach relies on using expression vectors that stably integrate the CAR into T-cell chromosomes. To circumvent the potential genotoxicity that may occur from expressing integrating transgenes, we have expressed the CD19-specific CAR transgene from mRNA using a high throughput microelectroporation device. This research was accomplished using a microelectroporator to achieve efficient and high throughput non-viral gene transfer of in vitro transcribed CAR mRNA into human T cells that had been numerically expanded ex vivo. Electro-transfer of mRNA avoids the potential genotoxicity associated with vector and transgene integration and the high throughput capacity overcomes the expected transient CAR expression, as repeated rounds of electroporation can replace T cells that have lost transgene expression. We fabricated and tested a high throughput microelectroporator that can electroporate a stream of 2 x 10(8) primary T cells within 10 min. After electroporation, up to 80% of the passaged T cells expressed the CD19-specific CAR. Video time-lapse microscopy (VTLM) demonstrated the redirected effector function of the genetically manipulated T cells to specifically lyse CD19+ tumor cells. Our biomedical microdevice, in which T cells are transiently and safely modified to be tumor-specific and then can be re-infused, offers a method for redirecting T-cell specificity, that has implications for the development of adoptive immunotherapy.

Absolute lymphocyte count is a novel prognostic indicator in ALL and AML: implications for risk stratification and future studies.

BACKGROUND: Leukemia is the leading cause of disease-related death in children, despite significant improvement in survival and modern risk stratification. The prognostic significance of absolute lymphocyte counts (ALC) was evaluated in young patients with acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL). METHODS: In all, 171 consecutive de novo cases of AML and ALL, age 350 cells/microL carries an excellent prognosis, with a 5-year overall survival (OS) of 85% (HR 0.2, P= .012). Similarly in ALL, an ALC-15 <350 cells/microL predicts poor survival, with a 6-year RFS of 43% (HR 4.5, P= .002), whereas an ALC-15 >350 cells/microL predicts excellent outcome, with a 6-year OS of 87% (HR 0.2, P= .018). Importantly, ALC remains a strong predictor in multivariate analysis with known prognostic factors. CONCLUSIONS: ALC is a simple, statistically powerful measurement for patients with de novo AML and ALL. The results, when combined with previous studies, demonstrate that ALC is a powerful new prognostic factor for a range of malignancies. These findings suggest a need for further exploration of postchemotherapy immune status and immune-modulating cancer therapies.