Anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation in patients with high-risk CD30+ lymphoma: a phase 1 study.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the safety of anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation (HSCT) in patients with CD30+ lymphoma at high risk of relapse. METHODS: This phase 1 dose-escalation study was performed at two sites in the USA. Patients aged 3 years and older, with classical Hodgkin lymphoma or non-Hodgkin lymphoma with CD30+ disease documented by immunohistochemistry, and a Karnofsky performance score of more than 60% planned for autologous HSCT were eligible if they were considered high risk for relapse as defined by primary refractory disease or relapse within 12 months of initial therapy or extranodal involvement at the start of pre-transplantation salvage therapy. Patients received a single infusion of CAR T cells (2 × 107 CAR T cells per m2, 1 × 108 CAR T cells per m2, or 2 × 108 CAR T cells per m2) as consolidation after trilineage haematopoietic engraftment (defined as absolute neutrophil count ≥500 cells per µL for 3 days, platelet count ≥25 × 109 platelets per L without transfusion for 5 days, and haemoglobin ≥8 g/dL without transfusion for 5 days) following carmustine, etoposide, cytarabine, and melphalan (BEAM) and HSCT. The primary endpoint was the determination of the maximum tolerated dose, which was based on the rate of dose-limiting toxicity in patients who received CAR T-cell infusion. This study is registered with ClinicalTrials.gov (NCT02663297) and enrolment is complete. FINDINGS: Between June 7, 2016, and Nov 30, 2020, 21 patients were enrolled and 18 patients (11 with Hodgkin lymphoma, six with T-cell lymphoma, one with grey zone lymphoma) were infused with anti-CD30 CAR T cells at a median of 22 days (range 16-44) after autologous HSCT. There were no dose-limiting toxicities observed, so the highest dose tested, 2 × 108 CAR T cells per m2, was determined to be the maximum tolerated dose. One patient had grade 1 cytokine release syndrome. The most common grade 3-4 adverse events were lymphopenia (two [11%] of 18) and leukopenia (two [11%] of 18). There were no treatment-related deaths. Two patients developed secondary malignancies approximately 2 years and 2·5 years following treatment (one stage 4 non-small cell lung cancer and one testicular cancer), but these were judged unrelated to treatment. At a median follow-up of 48·2 months (IQR 27·5-60·7) post-infusion, the median progression-free survival for all treated patients (n=18) was 32·3 months (95% CI 4·6 months to not estimable) and the median progression-free survival for treated patients with Hodgkin lymphoma (n=11) has not been reached. The median overall survival for all treated patients has not been reached. INTERPRETATION: Anti-CD30 CAR T-cell infusion as consolidation after BEAM and autologous HSCT is safe, with low rates of toxicity and encouraging preliminary activity in patients with Hodgkin lymphoma at high risk of relapse, highlighting the need for larger studies to confirm these findings. FUNDING: National Heart Lung and Blood Institute, University Cancer Research Fund at the Lineberger Comprehensive Cancer Center.

A prospective cohort study identifies two types of HIV+ Kaposi Sarcoma lesions: proliferative and inflammatory.

Kaposi sarcoma (KS) is the most common cancer in people living with HIV (PLWH) in many countries where KS-associated herpesvirus is endemic. Treatment has changed little in 20 years, but the disease presentation has. This prospective cohort study enrolled 122 human immunodeficiency virus (HIV) positive KS patients between 2017 and 2019 in Malawi. Participants were treated with bleomycin, vincristine and combination antiretroviral therapy, the local standard of care. One-year overall survival was 61%, and progression-free survival was 58%. The 48-week complete response rate was 35%. RNAseq (n = 78) differentiated two types of KS lesions, those with marked endothelial characteristics and those enriched in inflammatory transcripts. This suggests that different KS lesions are in different disease states consistent with the known heterogeneous clinical response to treatment. In contrast to earlier cohorts, the plasma HIV viral load of KS patients in our study was highly variable. A total of 25% of participants had no detectable HIV; all had detectable KSHV viral load. Our study affirms that many KS cases today develop in PLWH with well-controlled HIV infection and that different KS lesions have differing molecular compositions. Further studies are needed to develop predictive biomarkers for this disease.

Postoperative Serum Cortisol and Cushing Disease Recurrence in Patients With Corticotroph Adenomas.

CONTEXT: In Cushing disease, the association between the rate of serum cortisol decline and recurrent disease after corticotroph adenoma removal has not been adequately characterized. OBJECTIVE: To analyze postoperative serum cortisol and recurrence rates in Cushing disease. METHODS: Patients with Cushing disease and pathology-confirmed corticotroph adenoma were retrospectively studied. Cortisol halving time was estimated using exponential decay modeling. Halving time, first postoperative cortisol, and nadir cortisol values were collected using immediate postoperative inpatient laboratory data. Recurrence and time-to-recurrence were estimated and compared among cortisol variables. RESULTS: A total of 320 patients met inclusion/exclusion criteria for final analysis, and 26 of those patients developed recurrent disease. Median follow-up time was 25 months (95% CI, 19-28 months), and 62 patients had ≥ 5 years follow-up time. Higher first postoperative cortisol and higher nadir were associated with increased risk of recurrence. Patients who had a first postoperative cortisol ≥ 50 µg/dL were 4.1 times more likely to recur than those with a first postoperative cortisol < 50 µg/dL (HR 4.1, 1.8-9.2; P = .0003). Halving time was not associated with recurrence (HR 1.7, 0.8-3.8, P = .18). Patients with a nadir cortisol ≥2 µg/dL were 6.6 times more likely to recur than those with a nadir cortisol of < 2 µg/dL (HR 6.6, 2.6-16.6, P < .0001). CONCLUSION: Postoperative nadir serum cortisol is the most important cortisol variable associated with recurrence and time-to-recurrence. Compared to first postoperative cortisol and cortisol halving time, a nadir < 2 µg/dL showed the strongest association with long-term remission and typically occurs within the first 24 to 48 hours after surgery.

Utility of Urine Cultures During Febrile Neutropenia Workup in Hematopoietic Stem Cell Transplantation Recipients Without Urinary Symptoms.

The utility of obtaining screening urine cultures for febrile neutropenia (FN) during hematopoietic stem cell transplant (HCT) is unknown. In 667 adult HCT patients with FN, only 40 (6%) were found with bacteriuria. Antibiotics were modified in 3 patients (0.4%) based on urine cultures and none developed urinary-associated infectious complications.

Efficacy of a Dual-Epitope Dendritic Cell Vaccine as Part of Combined Immunotherapy for HER2-Expressing Breast Tumors.

Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2) epitopes. In addition, preclinical work has shown that this T cell response can be augmented by Ag-directed mAb therapy. This study evaluated the activity and safety of a combination of dendritic cell (DC) vaccination given with mAb and cytotoxic therapy. We performed a phase I/II study using autologous DCs pulsed with two different HER2 peptides given with trastuzumab and vinorelbine to a study cohort of patients with HER2-overexpressing and a second with HER2 nonoverexpressing metastatic breast cancer. Seventeen patients with HER2-overexpressing and seven with nonoverexpressing disease were treated. Treatment was well tolerated, with one patient removed from therapy because of toxicity and no deaths. Forty-six percent of patients had stable disease after therapy, with 4% achieving a partial response and no complete responses. Immune responses were generated in the majority of patients but did not correlate with clinical response. However, in one patient, who has survived >14 y since treatment in the trial, a robust immune response was demonstrated, with 25% of her T cells specific to one of the peptides in the vaccine at the peak of her response. These data suggest that autologous DC vaccination when given with anti-HER2-directed mAb therapy and vinorelbine is safe and can induce immune responses, including significant T cell clonal expansion, in a subset of patients.

Neonatologists' Perspectives on Exploring Parental Spirituality in Prenatal Consultations.

Background and Objectives: Values of religion, spirituality, and faith (RSF) are central to decision making for many parents facing extremely preterm labor or prenatal diagnoses of potentially life-limiting congenital anomalies. Neonatologists' opinions and comfort with discussing parental RSF are not well known. We sought to understand neonatologists' current practices and perceptions of exploring parental RSF in prenatal consultations. Methods: A retrospective chart review was performed at a single U.S. academic institution to evaluate the inclusion of spiritual terminology in documentation. All mothers who were admitted with anticipated extremely preterm delivery as well as those with prenatal diagnoses of potentially life-limiting congenital anomalies were included in analysis. After chart review, an anonymous survey was distributed to neonatology attendings and fellows to examine perspectives on exploring parental RSF. Results: The chart review indicated that RSF terminology was absent from the documentation of all prenatal consultations performed by neonatology. Sixty-five percent of survey respondents considered RSF important in their personal lives and 47% considered RSF important in clinical practice. The three most significant barriers to exploring RSF were lack of training or education in spiritual care, differences between physicians' and patients' personal beliefs, and insufficient time. Conclusions: Our study highlights a gap between the goal for prenatal counseling in cases of extreme prematurity and potentially life-limiting congenital anomalies and current practices that frequently exclude the values most important to many parents. Lack of training in spiritual care is a significant barrier to neonatologists exploring parental RSF.

Timing of Pediatric Palliative Care Consults in Hospitalized Patients with Heart Disease.

Pediatric palliative care (PPC) provides an extra layer of support for families caring for a child with complex heart disease as these patients often experience lifelong morbidities with frequent hospitalizations and risk of early mortality. PPC referral at the time of heart disease diagnosis provides early involvement in the disease trajectory, allowing PPC teams to longitudinally support patients and families with symptom management, complex medical decision-making, and advanced care planning. We analyzed 113 hospitalized pediatric patients with a primary diagnosis of heart disease and a PPC consult to identify timing of first PPC consultation in relation to diagnosis, complex chronic conditions (CCC), and death. The median age of heart disease diagnosis was 0 days with a median of two CCCs while PPC consultation did not occur until a median age of 77 days with a median of four CCCs. Median time between PPC consult and death was 33 days (interquartile range: 7-128). Death often occurred in the intensive care unit ( n = 36, 67%), and the most common mode was withdrawal of life-sustaining therapies ( n = 31, 57%). PPC referral often occurred in the context of medical complexity and prolonged hospitalization. Referral close to the time of heart disease diagnosis would allow patients and families to fully utilize PPC benefits that exist outside of end-of-life care and may influence the mode and location of death. PPC consultation should be considered at the time of heart disease diagnosis, especially in neonates and infants with CCCs.

Palliative Care Needs Assessment for Pediatric Complex Care Providers.

CONTEXT: Children with medical complexity (CMC) are often cared for by both complex care and palliative care pediatric teams. No prior research has investigated the relationship between these two disciplines. OBJECTIVES: The purpose of this article is to investigate challenges that complex care programs face in caring for children with medical complexity (CMC), as well as to explore whether identified challenges could be met through collaboration with pediatric palliative care or additional training for complex care teams. METHODS: Medical providers who self-identified as providing clinical care to children with medical complexity were asked to complete an online anonymous survey. Subjects were recruited through a Complex Care listerv. Data were analyzed using descriptive statistics. RESULTS: 85 subjects completed the survey, of whom 87.1% (n=74) were physicians, and 12.0% (n=11) were nurse practitioners. Subjects reported several challenges in caring for CMC, including symptom management, establishing goals of care, advance care planning, and coordination of care. A majority of subjects reported benefitting from palliative care consultative assistance in each subject area. Most subjects described their relationship with palliative care as a close partnership with frequent overlap. CONCLUSIONS: The evolving field of pediatric complex care is associated with an array of challenges in caring for CMC. Many of these challenges include competency areas where palliative care providers receive concerted training. Our research suggests greater palliative care involvement in the CMC population can benefit complex care teams and patients, given the expertise palliative providers can bring to the population and the discipline of complex care.

Correlation of Engraftment and Time from Melphalan Administration to Stem Cell Infusion.

Single-agent, high-dose melphalan continues to be the most commonly used conditioning regimen for transplantation-eligible patients with multiple myeloma undergoing autologous stem cell transplantation. The timing of melphalan administration with respect to stem cell infusion has not been clearly defined. Many institutions require a minimum of 24 hours between melphalan administration and stem cell infusion; however, some institutions have adopted shorter intervals based on melphalan's short half-life. Some studies have suggested that shortening the interval between melphalan administration and stem cell infusion may contribute to delays in engraftment, but this correlation has not been clearly evaluated or defined. This multicenter retrospective cohort study evaluated the times to neutrophil and platelet engraftment in patients who received stem cells at least 24 hours after melphalan (≥24 hours cohort) compared with those who received stem cells within 24 hours of melphalan (<24 hours cohort. The study included a total of 723 adult patients, 502 patients in the ≥24 hours cohort and 221 in the <24 hours cohort, treated at 3 transplantation centers between January 1, 2016, and September 30, 2019. Patient characteristics were summarized using descriptive statistics. The Fisher exact test was used to compare nominal categorical variables between the 2 cohorts, and the nonparametric van der Waerden test or Mood median test was used to compare ordinal or continuous variables. The median time to neutrophil engraftment was 12 days for both the ≥24 hours cohort (interquartile range [IQR], 11 to 12 days) and the <24 hours cohort (IQR, 11 to 13 days) (P = .07). The median time to platelet engraftment was 19 days for both the ≥24 hours cohort (IQR, 17 to 22 days) and <24 hours cohort (IQR, 17 to 20 days) (P = .25). The median time between melphalan administration and stem cell infusion in the <24 hours cohort was 18 hours, with a minimum time of 12 hours. The existing literature has not clearly defined the impact of the timing between melphalan administration and stem cell infusion on engraftment in autologous transplantation. The ability to safely shorten the interval between chemotherapy and transplantation could increase logistical flexibility and/or decrease the length of hospital stay. This large multicenter retrospective study did not identify a statistical or clinical impact on engraftment when melphalan was infused <24 hours or ≥24 hours before autologous stem cell infusion.

Extracorporeal membrane oxygenation and paediatric palliative care in an ICU.

OBJECTIVES: Compare rates, clinical characteristics, and outcomes of paediatric palliative care consultation in children supported on extracorporeal membrane oxygenation admitted to a single-centre 16-bed cardiac or a 28-bed paediatric ICU. METHODS: Retrospective review of clinical characteristics and outcomes of children (aged 0-21 years) supported on extracorporeal membrane oxygenation between January, 2017 and December, 2019 compared by palliative care consultation. MEASUREMENTS AND RESULTS: One hundred children (N = 100) were supported with extracorporeal membrane oxygenation; 19% received a palliative care consult. Compared to non-consulted children, consulted children had higher disease severity measured by higher complex chronic conditions at the end of extracorporeal membrane oxygenation hospitalisation (5 versus. 3; p < 0.001), longer hospital length of stay (92 days versus 19 days; p < 0.001), and higher use of life-sustaining therapies after decannulation (79% versus 23%; p < 0.001). Consultations occurred mainly for longitudinal psychosocial-spiritual support after patient survived device deployment with a median of 27 days after cannulation. Most children died in the ICU after withdrawal of life-sustaining therapies regardless of consultation status. Over two-thirds of the 44 deaths (84%; n = 37) occurred during extracorporeal membrane oxygenation hospitalisation. CONCLUSIONS: Palliative care consultation was rare showing that palliative care consultation was not viewed as an acute need and only considered when the clinical course became protracted. As a result, there are missed opportunities to involve palliative care earlier and more frequently in the care of extracorporeal membrane survivors and non-survivors and their families.

Phase II Single-Arm Study of Palbociclib and Cetuximab Rechallenge in Patients with KRAS/NRAS/BRAF Wild-Type Colorectal Cancer.

BACKGROUND: Cetuximab is often administered to patients with KRAS wild-type (KRAS-WT) metastatic colorectal cancer (mCRC), although resistance inevitably develops. We hypothesized that co-inhibition of the epidermal growth factor receptor (EGFR) with cetuximab and downstream cyclin-dependent kinases (CDK) 4/6 with palbociclib would be effective for anti-EGFR rechallenge in KRAS-WT mCRC. METHODS: We designed a single-arm, Simon's 2-stage, phase II trial of cetuximab and palbociclib in KRAS-WT mCRC treated with ≥2 prior lines of therapy. We report here on cohort B rechallenging patients with anti-EGFR-based therapy who had disease control of at least 4 months on prior anti-EGFR therapy. Primary endpoint was disease control rate (DCR) at 4 months. RESULTS: Ten evaluable patients were enrolled in this cohort. The 4-month DCR was 20%, which did not fulfill the prespecified 4-month DCR rate to continue. Median progression-free survival was 1.8 months and median overall survival was 6.6 months. Three patients had stable disease, although overall response rate was 0%. Most common treatment-related grades 3-4 adverse events were lymphopenia and leukopenia. CONCLUSION: Selection of patients for anti-EGFR rechallenge using clinical criteria alone was insufficient to identify response to palbociclib + cetuximab. Additional biomarkers are needed to select anti-EGFR rechallenge and circulating tumor DNA (ctDNA) analysis is planned for samples collected in this study. (ClinicalTrials.gov Identifier: NCT03446157).

An Automatic Pediatric Palliative Care Consultation for Children Supported on Extracorporeal Membrane Oxygenation: A Survey of Perceived Benefits and Barriers.

Background: Pediatric palliative care (PPC) consultation is infrequent among children on extracorporeal membrane oxygenation (ECMO). Objective: Investigate intensive care unit (ICU) team members' perceptions of automatic PPC consultation for children on ECMO in an ICU in the United States. Methods: Cross-sectional survey assessing benefits, barriers to PPC, and consultation processes. Results: Of 291 eligible respondents, 48% (n = 140) completed the survey and 16% (n = 47) answered an open-ended question. Benefits included support in decision-making (n = 98; 70%) and identification of goals of care (n = 89; 64%). Barriers included perception of giving up on families (n = 59; 42%) and poor acceptability by other team members (n = 58; 41%). Respondents endorsed communication with the primary ICU team before (n = 122; 87%) and after (n = 129; 92%) consultation. Open-ended responses showed more positive (79% vs. 13%) than negative statements. Positive statements reflected on expanding PPC to other critically-ill children where negative statements revealed unrecognized value in PPC. Conclusions: Results demonstrate opportunities for education about the scope of PPC and improvements in PPC delivery.

Evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer.

PURPOSE: Triple negative breast cancer (TNBC) is characterized by the presence of immune cells in the tumor microenvironment, however, the response to single-agent immune checkpoint inhibitor (ICI) therapy is modest. Preclinical models have demonstrated that intratumoral regulatory T cells (Tregs) dampen the antitumor response to ICI. We performed a single-arm phase II trial to evaluate the efficacy of a single low dose of cyclophosphamide (Cy) to deplete Tregs administered before initiating pembrolizumab. PATIENTS AND METHODS: 40 patients with pretreated metastatic TNBC were enrolled. The primary endpoints were progression-free survival (PFS) and change in peripheral blood Tregs after Cy. Secondary endpoints included overall response rate (ORR), duration of response, overall survival, treatment-related adverse events (AEs), and correlative evaluations. RESULTS: Median PFS was 1.8 months, and the ORR was 21%. Tregs were not significantly decreased after Cy prior to ICI (-3.3%, p=0.19), and increased significantly after the first cycle of therapy (+21% between cycles 1 and 2, p=0.005). Immune-related AEs were similar to historical pembrolizumab monotherapy, and were associated with response to therapy (p=0.02). Patients with pretreatment tumors harboring increased expression of B cell metagene signatures and increased circulating B cell receptor repertoire diversity were associated with clinical response and immune-related toxicity (IRT). CONCLUSIONS: Among patients with heavily pretreated TNBC, Cy prior to pembrolizumab did not significantly deplete Tregs, and in those with decreased numbers there was rapid recovery following therapy. Increased B cell gene expression in baseline samples was associated with clinical response and IRT.

A phase I evaluation of the effect of curcumin on dose-limiting toxicity and pharmacokinetics of irinotecan in participants with solid tumors.

Curcumin inhibits UDP-glucuronyltransferases, a primary metabolic pathway for cancer chemotherapeutic agents like irinotecan. Concurrent administration of both agents may exacerbate irinotecan toxicity. We conducted this phase I study to determine the safety of concurrent curcumin and irinotecan administration. Ten participants with advanced solid tumors received one of four doses (1, 2, 3, and 4 g) of a curcumin phosphatidylcholine complex (PC) orally daily, and 200 mg/m2 of i.v. infusion irinotecan on days 1 and 15 of a 28-day cycle, to determine the maximum tolerated dose (MTD) of PC. Thirteen participants received 4 g of PC (MTD) to assess the effect on the pharmacokinetic (PK) properties of irinotecan and its metabolites, SN-38 and SN-38G. Irinotecan, SN-38, and SN-38G exposure equivalence with and without curcumin was assessed using area under the plasma concentration-time curves from 0 to 6 h (AUC0-6h ). Safety assessments and disease responses were also evaluated. The combination of irinotecan and PC was well-tolerated. Because there was no dose limiting toxicity, the maximum dose administered (4 g) was defined as the recommended phase II dose of PC. PC did not significantly alter the plasma exposure and other PK properties of irinotecan and its metabolites. There was no apparent increase in the incidence of irinotecan-associated toxicities. The objective response rate was 3/19 (22%, 95% confidence interval [CI]: 5-39%), median progression free survival and overall survival (n = 23) were 4 months (95% CI: 2.9-8.9 months) and 8.4 months (95% CI: 3.7 - not evaluable [NE]), respectively. Future studies are required to evaluate the efficacy of this combination.

'I'm praying for a miracle': characteristics of spiritual statements in paediatric intensive care unit care conferences.

CONTEXT: Supporting spiritual needs is a well-established aspect of palliative care, but no data exist regarding how physicians engage with patients and families around spirituality during care conferences in paediatric intensive care units (PICU). OBJECTIVES: To assess the frequency and characteristics of family and physician spiritual statements in PICU care conferences. METHODS: We performed qualitative analysis of 71 transcripts from PICU conferences, audio-recorded at an urban, quaternary medical centre. Transcripts were derived from a single-centre, cross-sectional, qualitative study. RESULTS: We identified spiritual language in 46% (33/71) of PICU care conferences. Spiritual statements were divided relatively evenly between family member (51%, 67/131) and physician statements (49%, 64/131). Physician responses to families' spiritual statements were coded as supportive (46%, 31/67), deferred (30%, 20/67), indifferent (24%, 16/67) or exploratory (0/67). CONCLUSIONS: In this single-centre PICU, spiritual statements were present 46% of the time during high stakes decision-making conferences, but there was little evidence of spiritual care best practices, such as offering chaplain support and performing open-ended spiritual assessments. PICU clinicians should expect spiritual statements in care conferences and be prepared to respond.

Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia.

Immune suppression, exhaustion, and senescence are frequently seen throughout disease progression in acute myeloid leukemia (AML). We conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg i.v. on day 14 to examine whether PD-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to 2 years. Among 37 patients enrolled, the overall response rate, composite complete remission (CRc) rate (primary endpoint), and median overall survival (OS) were 46%, 38%, and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS, 13.2 and 11.3 months, respectively). Grade ≥3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T cells expressing TCF-1 in the bone marrow prior to treatment. A multifaceted correlative approach of genomic, transcriptomic, and immunophenotypic profiling offers insights on molecular correlates of response and resistance to pembrolizumab. SIGNIFICANCE: Immune-checkpoint blockade with pembrolizumab was tolerable and feasible after high-dose cytarabine in R/R AML, with encouraging clinical activity, particularly in refractory AML and those receiving treatment as first salvage regimen. Further study of pembrolizumab and other immune-checkpoint blockade strategies after cytotoxic chemotherapy is warranted in AML.See related commentary by Wei et al., p. 551. This article is highlighted in the In This Issue feature, p. 549.

Safety and Efficacy of Pembrolizumab Prior to Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia.

Programmed death 1 (PD-1) is an integral component of acute myelogenous leukemia (AML) immune evasion, chemotherapy resistance, and disease progression. PD-1 inhibitors are being investigated as treatment for AML in combination with hypomethylating agents and cytotoxic chemotherapy with encouraging findings. Although allogeneic stem cell transplantation (alloSCT) remains the most established curative treatment for patients with relapsed and refractory AML in complete remission, there are limited data on the clinical outcomes and safety of immune checkpoint inhibitors (ICIs) prior to alloSCT in AML. In the present study, we compared clinical outcomes of 9 patients with AML receiving high-dose cytarabine followed by pembrolizumab in a phase II clinical trial (NCT02768792) prior to alloSCT versus a historical control group of 18 AML patients who underwent alloSCT without prior ICI exposure. The nonparametric Jonckheere-Terpstra test was used to test for a difference in the ordered severity categories of acute graft-versus-host disease (GVHD) within 100 days of transplantation. Time-to-event estimates for overall survival and relapse-free survival were calculated using the Kaplan-Meier method and compared using a log-rank test. One-year survival was not significantly different between the treatment groups (67% versus 78%; P = .34). 100-day mortality was 0% in the ICI group versus 17% in the control group, and there was no increase in grade III-IV acute GVHD in patients treated with pembrolizumab prior to alloSCT. No chronic GVHD was seen in patients treated with pembrolizumab prior to alloSCT and who received post-transplantation cyclophosphamide (PTCy) as part of their conditioning regimen. These findings reinforce the safety and feasibility of ICI therapy prior to alloSCT in patients with AML, and suggest that PTCy may abrogate GVHD risk and severity in patients who receive ICI prior to undergoing alloSCT for AML.

Pediatric Palliative Care.

OBJECTIVE/METHODS: Pediatric Palliative Care (PPC) is a multidisciplinary medical subspecialty focused on the care of children with serious illnesses and terminal diagnoses. Providers impact the care of children from the perinatal stage through adolescence/young adulthood and help patients and families face diagnoses such as complex chronic disease and malignancy. This article describes these unique populations and distinct areas of current PPC research. RESULTS: Unique aspects of PPC include a high level of prognostic uncertainty, symptom burden, pediatric, and surrogate advance care planning, hope in the face of prognostic challenges, care of children at end of life, concurrent care, staff support, sibling support, and bereavement. CONCLUSION: PPC's evolution from an extension of hospice into a continuum of support for families and staff caring for children with serious illnesses is exemplified in both qualitative and quantitative research. The literature proves the value that PPC can provide to families, hospitals, and communities. PPC is evolving from a supportive service into a uniquely beneficial, collaborative, educational, and interdisciplinary specialty that improves outcomes for all involved.Plain Language Summary (PLS)Pediatric Palliative Care (PPC) is a service provided to all children with serious illness as a way of addressing suffering. Populations served by PPC range from those not yet born to patients preparing for adulthood. The serious illnesses they face range from chronic disease to cancer. Over the last 20 years research has explored the unique aspects of the pediatric experience of serious illness, including prognostic uncertainty, concurrent care, symptom management, advance care planning, hope, family experience of illness, care at the end of life, staff support, and bereavement.As the number of patients who would benefit from PPC services rapidly expands nationally and worldwide, PPC teams provide education and skills training for their colleagues in primary and subspecialty fields. Hospitals benefit from PPC through improved patient experience, family-centered care, and staff support. Communities are served by PPC that occurs in and out of the hospital.Research in PPC provides guidance for challenging questions in care and has resulted in an increasingly robust body of work. PPC providers have skills of advanced communication training, hope in the face of uncertainty, targeted and personalized symptom management, and a diverse understanding of quality of life. These skills help support decision-making and establish strong connections between providers and families.The field of PPC has a distinct skillset to support families who face serious illness. This article helps medical and psychosocial providers visualize how PPC is evolving from what has often been explained to families as an added layer of support into a uniquely beneficial, collaborative, and interdisciplinary service.

Phase 1 trial of adavosertib (AZD1775) in combination with concurrent radiation and cisplatin for intermediate-risk and high-risk head and neck squamous cell carcinoma.

BACKGROUND: Adavosertib (AZD1775) is an inhibitor of the Wee1 kinase. The authors conducted a phase 1b trial to evaluate the safety of adavosertib in combination with definitive chemoradiotherapy for patients with newly diagnosed, intermediate-risk/high-risk, locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Twelve patients with intermediate-risk/high-risk HNSCC were enrolled, including those with p16-negative tumors of the oropharynx, p16-positive tumors of the oropharynx with ≥10 tobacco pack-years, and tumors of the larynx/hypopharynx regardless of p16 status. All patients were treated with an 8-week course of concurrent intensity-modulated radiotherapy at 70 grays (Gy) (2 Gy daily in weeks 1-7), cisplatin 30 mg/m2 weekly (in weeks 1-7), and adavosertib (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8). The primary objective was to determine the maximum tolerated dose and the recommended phase 2 dose of adavosertib given concurrently with radiation and cisplatin. Secondary objectives were to determine the 12-week objective response rate and progression-free and overall survival. RESULTS: Three patients (25%) experienced a dose-limiting toxicity, including febrile neutropenia (n = 2) and grade 4 thromboembolism (n = 1). Two dose-limiting toxicities occurred with adavosertib at 150 mg. The median follow-up was 14.7 months. The 12-week posttreatment objective response rate determined by positron emission tomography/computed tomography was 100%. The 1-year progression-free and overall survival rates were both 90%. The maximum tolerated dose of adavosertib was 100 mg. CONCLUSIONS: Adavosertib 100 mg (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8), in combination with 70 Gy of intensity-modulated radiotherapy and cisplatin 30 mg/m2 , is the recommended phase 2 dose for patients with HNSCC.

The impact of pathologic staging of the hilar/mediastinal nodes on outcomes in patients with early-stage NSCLC receiving stereotactic body radiotherapy.

BACKGROUND: The importance of invasive mediastinal nodal staging in early-stage non-small cell lung cancer (NSCLC) in the PET/CT era is dependent on tumor factors that increase risk of nodal metastasis. At our institution, patients undergo biopsy via either CT-guidance (without nodal staging) or navigational bronchoscopy with endobronchial ultrasound transbronchial needle aspiration for nodal staging. This study aims to compare outcomes after stereotactic body radiotherapy (SBRT) stratified by receipt of invasive mediastinal nodal staging. METHODS: In this retrospective study, records of all consecutive patients undergoing SBRT for early-stage NSCLC between 2010 and 2017 were analyzed. The association between time-to event outcomes (recurrence and survival) were evaluated with covariates of interest including tumor size, location, histology, smoking history, prior lung cancer history, radiation dose and receipt of nodal staging. Both univariable and multivariable analyses were used to examine these comparisons. RESULTS: Overall, 158 patients were treated with SBRT. One hundred forty-nine out of one hundred fifty-eight patients (94%) underwent PET/CT staging, and all patients underwent tumor-directed biopsy. Seventy-nine patients underwent navigational bronchoscopy with nodal staging and 79 patients underwent CT-guided biopsy without nodal staging. Receipt of nodal staging was not associated with tumor size (P=0.35), yet was associated with central tumor location (P<0.001). There was no statistically significant association between receipt of nodal staging and time-to-event recurrence or survival outcomes; for example 3-year overall survival (OS) was 65% vs. 67% (P=0.65) and 3-year freedom from nodal failure was 84% vs. 69% (P=0.1) for those with and without nodal staging, respectively. CONCLUSIONS: Similar recurrence and survival outcomes were observed after SBRT regardless of receipt of invasive mediastinal nodal staging. Further prospective evaluation can help identify which patients might derive greatest benefit from invasive staging of the mediastinum in the PET/CT era.