Complete response to donor lymphocyte infusion for primary hemophagocytic lymphohistiocytosis relapse after allogeneic hematopoietic cell transplantation.

Primary hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory disorder characterized by dysregulation of inflammatory cells and cytokine signalling. Although first-line treatment consisting of immunosuppressive therapy and allogeneic hematopoietic cell transplantation (HCT) is often curative, it remains unknown whether any effective therapies exist for disease relapse/progression after HCT. Here we present a case of a 29-year-old male with primary HLH that relapsed after HCT and subsequently achieved durable long disease-free survival following a donor-lymphocyte infusion (DLI). To our knowledge, this represents the first case demonstrating the efficacy of DLI for relapsed primary HLH.

Impact of FLT3 internal tandem duplication and NPM1 mutations in acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation.

BACKGROUND AIMS: The internal tandem duplication of FLT3 (FLT3ITD) and NPM1 mutations (NPM1mut) are well-established prognostic factors in cytogenetically intermediate-risk acute myeloid leukemia (AML) when treated with chemotherapy alone. However, their prognostic value in the setting of allogeneic hematopoietic cell transplantation (HCT) is controversial. METHODS: FLT3 and NPM1 mutational status was determined at diagnosis using single-gene polymerase chain reaction or next-generation sequencing in 247 adult patients with cytogenetically intermediate-risk AML who underwent myeloablative HCT. Multivariate Fine-Gray and Cox regression was used to analyze the cumulative incidence of relapse (CIR), relapse-free survival (RFS) and overall survival (OS). RESULTS: FLT3ITD and NPM1mut were present in 74 of 247 (30%) and 79 of 247 (32%) patients, respectively. There was no significant difference between patients without a FLT3ITD or NPM1mut (FLT3NONITD/NPM1WT) and patients with a FLT3ITD mutation alone (FLT3ITD/NPM1WT) with regard to CIR (P = 0.60), RFS (P = 0.91) or OS (P = 0.66). Similarly, there was no significant difference between FLT3NONITD/NPM1WT and FLT3NONITD/NPM1mut patients with regard to CIR (P = 0.70), RFS (P = 0.75) or OS (P = 0.95). The presence of a concurrent mutation in NPM1 did not appear to modify the impact of having a FLT3ITD mutation. CONCLUSIONS: In contrast to chemotherapy-only treatment, FLT3 and NPM1 mutational status does not appear to predict outcomes in patients with cytogenetically intermediate-risk AML following HCT. These results suggest that HCT may ameliorate the poor prognostic effect of FLT3ITD mutation and that HCT should be considered over chemotherapy-only treatment in FLT3ITD-mutated AML.

Incomplete chimerism following myeloablative and anti-thymocyte globulin-conditioned hematopoietic cell transplantation is a risk factor for relapse and chronic graft-versus-host disease.

BACKGROUND AIMS: The value of routine chimerism determination after myeloablative hematopoietic cell transplantation (HCT) is unclear, particularly in the setting of anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis. METHODS: Blood samples were collected at 3 months post-HCT from 558 patients who received myeloablative conditioning and ATG-based GVHD prophylaxis. Chimerism was assessed using multiplex polymerase chain reaction of short tandem repeats in sorted T cells (CD3+) and leukemia lineage cells (CD13+CD33+ for myeloid malignancies and CD19+ for B-lymphoid malignancies). ATG exposure was determined using a flow cytometry-based assay. The primary outcomes of interest were relapse and chronic GVHD (cGVHD). RESULTS: Incomplete (<95%) T-cell chimerism and leukemia lineage chimerism were present in 17% and 4% of patients, respectively. Patients with incomplete T-cell chimerism had a significantly greater incidence of relapse (36% versus 22%, subhazard ratio [SHR] = 2.03, P = 0.001) and lower incidence of cGVHD (8% versus 25%, SHR = 0.29, P < 0.001) compared with patients with complete chimerism. In multivariate modeling, patients with high post-transplant ATG area under the curve and any cytomegalovirus (CMV) serostatus other than donor/recipient seropositivity (non-D+R+) had an increased likelihood of incomplete T-cell chimerism. Patients with incomplete leukemia lineage chimerism had a significantly greater incidence of relapse (50% versus 23%, SHR = 2.70, P = 0.011) and, surprisingly, a greater incidence of cGVHD (45% versus 20%, SHR = 2.64, P = 0.003). CONCLUSIONS: High post-transplant ATG exposure and non-D+R+ CMV serostatus predispose patients to incomplete T-cell chimerism, which is associated with an increased risk of relapse. The increased risk of cGVHD with incomplete B-cell/myeloid chimerism is a novel finding that suggests an important role for recipient antigen-presenting cells in cGVHD pathogenesis.

Donor Genetic Predisposition to High Interleukin-10 Production Appears Protective against Acute Graft-Versus-Host Disease.

The persistence of graft-versus-host disease (GVHD) as the principal complication of allogeneic hematopoietic cell transplantation (HCT) demonstrates that HLA matching alone is insufficient to prevent alloreactivity. We performed molecular and functional characterization of 22 candidate cytokine genes for their potential to improve matching in 315 myeloablative, 10/10 HLA-matched donor−recipient pairs. Recipients of a graft carrying the -1082GG IL10 gene promoter region variant had a three-fold lower incidence of grade II−IV acute GVHD compared to IL10-1082AA graft recipients (SHR = 0.25, p = 0.005). This was most evident in matched unrelated donor (MUD) transplants, where the greatest alloreactivity is expected. IL10-1082GG transplants did not experience an increased incidence of relapse, and, consequently, overall survival was two-fold higher in IL10-1082GG MUD transplants (HR = 0.17, p = 0.023). Longitudinal post-transplant measurements demonstrated that -1082GG is a high-IL10-producing and -expressing genotype with attenuated CD8+ T-cell reconstitution. High post-transplant donor chimerism in T- and myeloid-cells (>95%) confirmed a predominant donor, rather than recipient, genotype effect on immune function and aGVHD. To date, this is the first study to report corroborating genome-to-cellular evidence for a non-HLA donor immunogenetic variant that appears to be protective against GVHD. The incorporation of IL10 variants in donor selection criteria and clinical-management decisions has the potential to improve patient outcomes.

A biomarker-guided, prospective, phase 2 trial of pre-emptive graft-versus-host disease therapy using anti-thymocyte globulin.

BACKGROUND AIMS: Intensified immunosuppressive prophylaxis for graft-versus-host disease (GVHD) may be toxic and therefore warranted only in patients at high risk of developing GVHD. In patients who underwent allogeneic hematopoietic cell transplant at the authors' center, high serum soluble IL-2 receptor alpha (sIL-2Rα) and low IL-15 levels on day 7 post-transplant were found to predict a high risk of developing clinically significant GVHD (sGVHD), defined as grade 2-4 acute GVHD or moderate to severe chronic GVHD. METHODS: This was a prospective, phase 2 trial in which high-risk patients (serum sIL-2Rα >4500 ng/L or IL-15 <31 ng/L) received rabbit anti-thymocyte globulin (ATG) 3 mg/kg on day 8 post-transplant. Controls consisted of patients who had their sIL-2Rα/IL-15 levels measured but did not participate in the trial. A total of 68 trial patients and 143 controls were accrued to this study. The primary endpoint was incidence of sGVHD. RESULTS: There was a reduction in sGVHD in high-risk trial patients (received day 8 ATG) compared with high-risk controls (did not receive day 8 ATG) (sub-hazard ratio [SHR] = 0.48, P < 0.05). There was no significant difference between the groups in overall survival or relapse; however, there was a greater incidence of non-GVHD-associated non-relapse mortality in high-risk trial patients (SHR = 3.73, P < 0.05), mostly related to infections. This may be due in part to the biomarkers ineffectively stratifying GVHD risk. CONCLUSIONS: Pre-emptive ATG therapy is both feasible and effective at reducing sGVHD without increasing relapse. Further mitigation strategies are needed to reduce the risk of infection associated with intensified GVHD prophylaxis. This study was registered at ClinicalTrials.gov (NCT01994824).

Targeting Oral Squamous Cell Carcinoma with Combined Polo-Like-Kinase-1 Inhibitors and γ-Radiation Therapy.

Polo-like-kinase-1 (PLK-1) is a serine/threonine kinase that regulates the cell cycle and acts as an oncogene in multiple cancers, including oral squamous cell carcinoma (OSCC). The loss of PLK-1 can inhibit growth and induce apoptosis, making it an attractive therapeutic target in OSCC. We evaluated the efficacy of PLK-1 inhibitors as novel, targeted therapeutics in OSCC. PLK-1 inhibition using BI6727 (volasertib) was found to affect cell death at low nanomolar concentrations in most tested OSCC cell lines, but not in normal oral keratinocytes. In cell lines resistant to volasertib alone, pre-treatment with radiotherapy followed by volasertib reduced cell viability and induced apoptosis. The combinatorial efficacy of volasertib and radiotherapy was replicated in xenograft mouse models. These findings highlight the potential of adding PLK-1 inhibitors to adjuvant therapy regimens in OSCC.

Rituximab Toxicity after Preemptive or Therapeutic Administration for Post-Transplant Lymphoproliferative Disorder.

Rituximab is commonly used as prevention, preemption, or therapeutically for post-transplant lymphoproliferative disorder (PTLD) after hematopoietic cell transplantation (HCT). Although it is generally assumed that rituximab toxicity (ie, infections resulting from hypogammaglobulinemia and neutropenia) is negligible in relation to mortality due to PTLD, limited evidence supports the validity of this assumption. We sought to determine the impact of rituximab on immunoglobulin levels, neutrophil count, infection density, and mortality outcomes. This study retrospectively analyzed 349 HCT recipients, 289 of whom did not receive rituximab and 60 of whom received rituximab preemptively or therapeutically at a median of 55 days post-transplantation. IgM, IgG, and IgA levels at 6 months and 12 months post-transplantation were lower in patients who received rituximab compared with those who did not (significant at P < .05 for IgM and IgA at 6 months and for IgM and IgG at 12 months). Rituximab recipients also had a higher incidence of severe neutropenia (<.5/nl) between 3 and 24 months (subhazard ratio [SHR], 2.3; P = .020). Regarding non-Epstein-Barr viral infections/PTLD, the rituximab group had a higher infection density between 3 and 24 months compared with the no-rituximab group (3.8 versus 1.6 infections per 365 days at risk; incidence rate ratio, 2.2; P < .001). The rituximab group also had a higher incidence of fatal infections (SHR, 3.1; P = .026), higher nonrelapse mortality (SHR, 2.4; P = .006), and higher overall mortality (hazard ratio, 1.7; P = .033). There were no significant between-group differences in the incidence of clinically significant graft-versus-host disease, graft failure, or relapse. Based on this study, rituximab given for PTLD is associated with substantial morbidity and mortality. Whether the benefit of preemptive rituximab outweighs the risk remains to be determined. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Indications for additional volume studies for gland volume estimation in prostate cancer brachytherapy.

An estimated gland volume of > 60 cc is a relative contraindication to brachytherapy for prostate cancer. As volume estimation using biopsy ultrasound (Bx-US) alone may be inaccurate, many centers perform additional volume assessments prior to the brachytherapy procedure. At the study institution, computed tomography (CT) based volume assessments were routinely performed on all patients to determine brachytherapy eligibility. This study aimed to determine whether this CT imaging could be omitted for certain Bx-US based gland volume estimates. To investigate this, 1576 consecutive patients that received ultrasound based intraoperatively planned brachytherapy at a single comprehensive cancer center between 2003 and 2021 were reviewed. Gland volume as estimated by Bx-US, CT and magnetic resonance (MR) imaging were compared to intraoperatively contoured gland volume (ICGV) or the larger contoured gland volume on CT for any patients receiving neo-adjuvant androgen deprivation therapy (ADT) for gland downsizing (IM-US-corr). There was a significant difference between IM-US-corr and estimated gland volume for Bx-US (P < 0.001) and MR (P < 0.001), but not CT (P = 0.160). Bx-US and MR tended to underrepresent the IM-US-corr, with a > 20% difference from actual volume in 31% and 59% of cases, respectively. When Bx-US volume was estimated to be < 40 cc, < 50 cc and < 60 cc, an IM-US-corr > 60 cc was encountered in 2%, 5% and 7% of cases, respectively. In contrast, IM-US-corr > 60 cc was encountered in 0.2%, 1% and 2% of cases for CT estimates of < 40 cc, < 50 cc and < 60 cc. In patients with an estimated gland volume of < 50 cc by Bx-US, dedicated pre-operative volume studies are unlikely to alter management. However, patients above this cut-off stand to benefit from the use of additional volume assessment to better delineate gland volume and determine eligibility for brachytherapy.

Emerging evidence for non-pharmacologic interventions in reducing the burden of respiratory illnesses.

The global pandemic caused by SARS-CoV-2 (COVID-19) has led to significant morbidity and mortality, and unprecedented economic and health system disruption. Non-pharmacologic interventions (NPIs) such as masking and physical distancing have formed the underpinnings of COVID-19 infection control strategies. Concomitantly, numerous jurisdictions have seen a decrease in hospitalizations for non-COVID-19 respiratory illnesses (NCRIs) such as asthma, community-acquired pneumonia, influenza, and chronic obstructive pulmonary disease relative to pre-pandemic levels. These associations give rise to a number of testable hypotheses regarding the efficacy of NPIs in reducing the substantial burden of NCRIs. Here, we review emerging perspectives on the role of NPIs in NCRI prevention with the ultimate goal of informing future research and public policy development as we move into what may be the endemic phase of the COVID-19 pandemic.

Clinical Outcomes from Dose-Reduced Radiotherapy to the Prostate in Elderly Patients with Localized Prostate Cancer.

Radical treatment of localized prostate cancer in elderly patients may lead to unacceptable treatment-associated toxicities that adversely impact quality of life without improving survival outcomes. This study reports on a cohort of 54 elderly (>70 years) patients that received 4000-5000 cGy of palliative external beam radiotherapy (EBRT) as an alternative to androgen deprivation therapy (ADT). The primary outcome of interest was the period of ADT-free survival, and secondary outcomes included overall survival (OS) and metastases-free survival (MFS). Kaplan-Meier regression was used to estimate survival outcomes. Thirty-six (67%) patients achieved a break in ADT post-radiotherapy, with a median time to ADT reinitiation of 20 months. Common Terminology Criteria for Adverse Events (CTCAE) were limited to low-grade gastrointestinal (GI) or genitourinary (GU) toxicities, with no skin toxicities observed. Grade 1 GI toxicity was observed in 9 (17%) patients, and grades 1 and 2 GU toxicities were observed in 13 (24%) and 3 (6%) patients, respectively, with no higher-grade toxicities reported. Five-year MFS and OS were 56% and 78%, respectively. In summary, the treatment regimen was well-tolerated and achieved durable ADT-free survival in most patients. Dose-reduced EBRT appears to be a viable alternative to ADT in elderly patients with localized prostate cancer.

Excessive waitlists and delays to treatment with low-dose-rate brachytherapy predict an increased risk of recurrence and metastases in intermediate-risk prostatic carcinoma.

PURPOSE: It has previously been shown that increased wait times for prostatectomy are associated with poorer outcomes in intermediate-risk prostatic carcinoma (PCa). However, the impact of wait times on PCa outcomes following low-dose-rate brachytherapy (LDR-BT) are unknown. METHODS AND MATERIALS: We retrospectively reviewed 466 intermediate-risk PCa patients that underwent LDR-BT at a single comprehensive cancer center between 2003 and 2016. Wait times were defined as the time from biopsy to LDR-BT. The association of wait times with outcomes was evaluated using Cox and Fine-Gray regression in both univariate and multivariate models. RESULTS: Median (interquartile range) follow-up and wait time for all patients were 8.1 (6.3-10.4) years and 5.1 (3.9-6.9) months, respectively. Among NCCN unfavourable intermediate-risk (UIR) patients (n = 170; 36%), increased wait times predicted both a greater cumulative incidence of recurrence [MHR = 1.01/month of wait time (95% CI: 1.00-1.03); P = 0.044] and metastases [MHR = 1.04/month of wait time (95% CI: 1.02-1.06); P < 0.001] in multivariate modeling. In NCCN favourable intermediate-risk (FIR) patients, there was no significant association between wait time and recurrence or metastases risk. Among all intermediate-risk patients, wait time was associated with an increase in the incidence of metastases [MHR = 1.03/month of wait time (95% CI: 1.02-1.05); P < 0.001], but not recurrence in multivariate models. There was no association between wait time and overall survival in the UIR, FIR, or all intermediate-risk cohorts. CONCLUSIONS: Resource constraints within this center's public healthcare system have contributed to waitlists exceeding 5-months in length. This study finds that patients with UIR PCa experience a 1% increase in the risk of recurrence and 4% increase in the risk of metastases with each additional month of delay in definitive disease management. Preventing such extended management delays in LDR-BT may improve disease-related outcomes in patients with PCa.

Ecological Succession of Polymicrobial Communities in the Cystic Fibrosis Airways.

Antimicrobial therapies against cystic fibrosis (CF) lung infections are largely aimed at the traditional, well-studied CF pathogens such as Pseudomonas aeruginosa and Burkholderia cepacia complex, despite the fact that the CF lung harbors a complex and dynamic polymicrobial community. A clinical focus on the dominant pathogens ignores potentially important community-level interactions in disease pathology, perhaps explaining why these treatments are often less effective than predicted based on in vitro testing. A better understanding of the ecological dynamics of this ecosystem may enable clinicians to harness these interactions and thereby improve treatment outcomes. Like all ecosystems, the CF lung microbial community develops through a series of stages, each of which may present with distinct microbial communities that generate unique host-microbe and microbe-microbe interactions, metabolic profiles, and clinical phenotypes. While insightful models have been developed to explain some of these stages and interactions, there is no unifying model to describe how these infections develop and persist. Here, we review current perspectives on the ecology of the CF airway and present the CF Ecological Succession (CFES) model that aims to capture the spatial and temporal complexity of CF lung infection, address current challenges in disease management, and inform the development of ecologically driven therapeutic strategies.