ZNF683 marks a CD8+ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome.

Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyze single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 patients with RS. Response is associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells. This signature overlaps with that of tumor-infiltrating populations from anti-PD-1 responsive solid tumors. ZNF683 is found to directly target key T cell genes (TCF7, LMO2, CD69) and impact pathways of T cell cytotoxicity and activation. Analysis of pre-treatment peripheral blood from 10 independent patients with RS treated with anti-PD-1, as well as patients with solid tumors treated with anti-PD-1, supports an association of ZNF683high T cells with response.

Sensitivity of treatment-free survival to subgroup analyses in patients with advanced melanoma treated with immune checkpoint inhibitors.

Patients with advanced melanoma treated with immune checkpoint inhibitors can experience ongoing disease control after treatment discontinuation without subsequent systemic anticancer therapy. We previously defined a novel outcome, treatment-free survival (TFS), as the time between protocol therapy cessation and subsequent therapy initiation/death. We assessed the effect of established prognostic variables [lactate dehydrogenase (LDH), programmed death ligand 1 status, BRAF mutation status, performance status, and sex] on TFS in different treatment scenarios: treatment until toxicity/progression with frequent early cessation (nivolumab plus ipilimumab), treatment until toxicity/progression with a well-tolerated regimen (nivolumab), and treatment for a short fixed duration (ipilimumab). Data were pooled from 1077 patients with advanced melanoma treated in the CheckMate 069 and 067 trials. TFS was defined as the area between the Kaplan-Meier curves for time to therapy cessation and time to subsequent therapy initiation/death. TFS was estimated by restricted mean (r-mean) survival time at 36 months since randomization. Clinically meaningful TFS (r-mean TFS 3.7-12.7 months) was observed across all patient subgroups. TFS was longest in patients treated with nivolumab plus ipilimumab. The largest differences in r-mean TFS were observed with LDH in the nivolumab plus ipilimumab and ipilimumab treatment groups (TFS difference 4.7 and 4.9 months, respectively). In the nivolumab group, there was little difference in TFS across subgroups (r-mean TFS 3.7-5.5 months). TFS was sensitive to prognostic subgroup differences; however, duration of treatment affected the sensitivity of TFS. These results provide further support for TFS as a clinical outcome measure.

Association of clonal hematopoiesis with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association of CHIP with COPD remains unclear. We analyzed whole-genome sequencing and whole-exome sequencing data to detect CHIP in 48 835 patients, of whom 8444 had moderate to very severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In the COPDGene cohort, individuals with CHIP had risks of moderate-to-severe, severe, or very severe COPD that were 1.6 (adjusted 95% confidence interval [CI], 1.1-2.2) and 2.2 (adjusted 95% CI, 1.5-3.2) times greater than those for noncarriers. These findings were consistently observed in three additional cohorts and meta-analyses of all patients. CHIP was also associated with decreased FEV1% predicted in the COPDGene cohort (mean between-group differences, -5.7%; adjusted 95% CI, -8.8% to -2.6%), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (odds ratio, 1.03 per 10 pack-years; 95% CI, 1.01-1.05 per 10 pack-years) in the meta-analysis of all patients. Inactivation of Tet2 in mouse hematopoietic cells exacerbated the development of emphysema and inflammation in models of cigarette smoke exposure. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.

Genomic profiling of a randomized trial of interferon-α vs hydroxyurea in MPN reveals mutation-specific responses.

Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPNs), little is known about their impact on molecular response to cytoreductive treatment. We performed targeted next-generation sequencing (NGS) on 202 pretreatment samples obtained from patients with MPN enrolled in the DALIAH trial (A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms; #NCT01387763), a randomized controlled phase 3 clinical trial, and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNα) or hydroxyurea. The primary aim was to evaluate the association between complete clinicohematologic response (CHR) at 24 months and molecular response through sequential assessment of 120 genes using NGS. Among JAK2-mutated patients treated with IFNα, those with CHR had a greater reduction in the JAK2 variant allele frequency (median, 0.29 to 0.07; P < .0001) compared with those not achieving CHR (median, 0.27 to 0.14; P < .0001). In contrast, the CALR variant allele frequency did not significantly decline in those achieving CHR or in those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNα compared with hydroxyurea (P = .04). Furthermore, treatment-emergent DNMT3A mutations were significantly enriched in IFNα-treated patients not attaining CHR (P = .02). A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted odds ratio, 5.29; 95% confidence interval, 1.59-17.54; P = .007), as was a mutation in TET2 alone (age-adjusted odds ratio, 3.03; 95% confidence interval, 1.03-9.01; P = .044). At 24 months, we found mutation-specific response patterns to IFNα: (1) JAK2- and CALR-mutated MPN exhibited distinct molecular responses; and (2) DNMT3A-mutated clones/subclones emerged on treatment.

Treatment-free Survival after Immune Checkpoint Inhibitor Therapy versus Targeted Therapy for Advanced Renal Cell Carcinoma: 42-Month Results of the CheckMate 214 Trial.

PURPOSE: Patients discontinuing immuno-oncology regimens may experience periods of disease control without need for ongoing anticancer therapy, but toxicity may persist. We describe treatment-free survival (TFS), with and without toxicity. PATIENTS AND METHODS: Data were analyzed from the randomized phase III CheckMate 214 trial of nivolumab plus ipilimumab (n = 550) versus sunitinib (n = 546) for treatment-naïve, advanced renal cell carcinoma (aRCC). TFS was estimated by the 42-month restricted mean times defined by the area between Kaplan-Meier curves for two time-to-event endpoints defined from randomization: time to protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was subdivided as TFS with and without toxicity by counting days with ≥1 grade ≥3 treatment-related adverse event (TRAE). RESULTS: At 42 months since randomization, 52% of nivolumab plus ipilimumab and 39% of sunitinib intermediate/poor-risk patients were alive; 18% and 5% surviving treatment-free, respectively. Among favorable-risk patients, 70% and 73% of nivolumab plus ipilimumab and sunitinib patients were alive; 20% and 9% treatment-free. Over the 42-month period, mean TFS was over twice as long after nivolumab plus ipilimumab than sunitinib for intermediate/poor-risk (6.9 vs. 3.1 months) and three times as long for favorable-risk patients (11.0 vs. 3.7 months). Mean TFS with grade ≥3 TRAEs was a small proportion of time for both treatments (0.6 vs. 0.3 months after nivolumab plus ipilimumab vs. sunitinib for intermediate/poor-risk, and 0.9 vs. 0.3 months for favorable-risk patients). CONCLUSIONS: Patients initiating first-line nivolumab plus ipilimumab for aRCC spent more survival time treatment-free without toxicity versus those on sunitinib, regardless of risk group.

Treatment-free survival over extended follow-up of patients with advanced melanoma treated with immune checkpoint inhibitors in CheckMate 067.

BACKGROUND: Treatment-free survival (TFS) characterizes disease control after discontinuation of immune checkpoint inhibitors (ICIs) until subsequent therapy or death. We previously evaluated TFS in a pooled analysis of the CheckMate 067 and CheckMate 069 trials of the ICIs nivolumab and ipilimumab, alone or in combination, in patients with advanced melanoma after minimum follow-up of 36 months. This analysis investigated TFS differences between treatments in CheckMate 067 after a minimum follow-up of 60 months, and their relation to overall survival (OS) differences. METHODS: Data were from 937 patients who initiated treatment (nivolumab plus ipilimumab, nivolumab, or ipilimumab) in CheckMate 067 (NCT01844505). TFS was defined as the area between the Kaplan-Meier curves for time to protocol therapy cessation and time to subsequent systemic therapy initiation or death, each measured from randomization. TFS was partitioned as time with and without toxicity. Toxicity included persistent and late-onset grade ≥2 select treatment-related adverse events (ie, those of potential immunologic etiology). The area between Kaplan-Meier curves was estimated by the difference in 60-month restricted-mean times of the endpoints. Between-group differences were estimated with bootstrapped 95% CIs. RESULTS: At 60 months from randomization, 39%, 24%, and 11% of patients assigned to treatment with nivolumab plus ipilimumab, nivolumab, and ipilimumab, respectively, had survived and were treatment-free. The 60-month mean TFS was approximately twice as long with the combination (19.7 months) than with nivolumab (9.9 months; absolute difference, 9.8 (95% CI 6.7 to 12.8)) or ipilimumab (11.9 months; absolute difference, 7.8 (95% CI 4.6 to 11.0)). In the respective groups, mean TFS represented 33% (8% with and 25% without toxicity), 17% (2% and 14%), and 20% (3% and 17%) of the 60-month period. Compared with 36-month estimates, mean TFS over the 60-month period represented slightly greater percentages of time in the nivolumab-containing regimen groups and a lesser percentage in the ipilimumab group. TFS differences between the combination and either monotherapy increased with longer follow-up. CONCLUSIONS: Along with improved long-term OS with the nivolumab-containing regimens versus ipilimumab, TFS without toxicity was sustained with nivolumab plus ipilimumab versus either monotherapy, demonstrating larger between-group differences with extended follow-up.

Phase II Multicenter Study of Enzalutamide in Metastatic Castration-Resistant Prostate Cancer to Identify Mechanisms Driving Resistance.

PURPOSE: Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase II multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance. PATIENTS AND METHODS: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole-exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing. RESULTS: A total of 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in AR (mutations, amplifications) and tumor suppression genes (PTEN, RB1, and TP53), which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased AR amplifications (64.7% at progression vs. 53.9% at baseline) and BRCA2 alterations (64.7% at progression vs. 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR-regulated genes, and neuroendocrine markers at progression. CONCLUSIONS: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of BRCA2 alterations post-enzalutamide, highlighting the importance of serial tumor sampling in CRPC.

Sequencing of PD-1/L1 Inhibitors and Carboplatin Based Chemotherapy for Cisplatin Ineligible Metastatic Urothelial Carcinoma.

PURPOSE: Current first line treatment options in patients with metastatic urothelial carcinoma unfit to receive cisplatin containing chemotherapy include PD-1/L1 inhibitors and carboplatin containing chemotherapy. However, the optimal sequencing of these therapies remains unclear. MATERIALS AND METHODS: We conducted a multicenter retrospective analysis. Consecutive cisplatin ineligible patients with metastatic urothelial carcinoma treated with first line carboplatin containing chemotherapy followed sequentially by second line PD-1/L1 inhibitor, or the reverse order, were included. Patient demographics, objective response, time to treatment failure for first line and second line therapy, interval between end of first line and initiation of second line treatment (Interval1L-2L) and overall survival were collected. Multivariate analysis was conducted to examine the association of sequencing on overall survival. RESULTS: In this multicenter retrospective study we identified 146 cisplatin ineligible patients with metastatic urothelial carcinoma treated with first line PD-1/L1 inhibitor therapy followed by second line carboplatin containing chemotherapy (group 1, 43) or the reverse sequence (group 2, 103). In the overall cohort median age was 72, 76% were men and 18% had liver metastasis. In both groups objective response rates were higher with carboplatin containing chemotherapy (45.6% first line, 44.2% second line) compared to PD-1/L1 inhibitors (9.3% first line, 21.3% second line). On multivariate analysis treatment sequence was not associated with overall survival (HR 1.05, p=0.85). Site of metastasis was the only factor significantly associated with overall survival (p=0.002). CONCLUSIONS: In this biomarker unselected cohort of cisplatin ineligible patients with metastatic urothelial carcinoma, PD-1/L1 inhibitor followed by carboplatin containing chemotherapy and the reverse sequence had comparable overall survival.

Association between CD8 and PD-L1 expression and outcomes after radical prostatectomy for localized prostate cancer.

BACKGROUND: Characterization of markers of both immune suppression and activation may provide more prognostic information than assessment of single markers in localized prostate cancer. We therefore sought to determine the association between CD8 and PD-L1 expression in localized prostate tumors and biochemical recurrence (BCR) and metastasis-free survival (MFS). METHODS: Tissue microarrays were constructed on 109 men undergoing radical prostatectomy (RP) for localized prostate cancer at Dana-Farber Cancer Institute between 1991 and 2008. Fluorescence immunohistochemistry was used to evaluate the expression of six immune markers (CD3, CD4, CD8, PD-1, PD-L1, FOXP3). Quantitative multispectral imaging analysis was used to calculate the density of each marker, which was dichotomized by the median as "high" or "low." Cox proportional hazards regression models and Kaplan-Meier analyses were used to analyze associations between immune marker densities and time to BCR and MFS. RESULTS: Over a median follow-up of 8.1 years, 55 (51%) and 39 (36%) men developed BCR and metastases, respectively. Median time to BCR was shorter in men with low CD8 (hazard ratio [HR] = 2.27 [1.27-4.08]) and high PD-L1 expression (HR = 2.03 [1.17-3.53]). While neither low CD8 or high PD-L1 alone were independent predictors of BCR or MFS on multivariable analysis, men with low CD8 and/or high PD-L1 had a significantly shorter time to BCR (median 3.5 years vs. NR) and MFS (median 10.8 vs. 18.4 years) compared to those with high CD8 and low PD-L1 expression. The main limitation is the retrospective and singe-center nature of the study. CONCLUSION: The presence of higher CD8 and lower PD-L1 expression in prostatectomy specimens was associated a low risk of biochemical relapse and metastatic disease. These findings are hypothesis-generating and further study is needed.

Transcriptomic analysis of micropapillary high grade T1 urothelial bladder cancer.

No consensus currently exist on the optimal treatment of patients with high-risk nonmuscle invasive (HGT1) micropapillary variant of bladder cancer (MPBC). Transcripsome analysis may allow stratification of MPBC-HGT1 enabling prediction of recurrence and guide therapeutic management for individual patients. Whole transcriptome RNA-Sequencing of tumors from 23 patients with MPBC-HGT1 and 64 conventional urothelial carcinomas (cUC) (reference set) was performed. Differentially expressed genes between MPBC-HGT1 and cUC-HGT1 were explored. Cox proportional hazard models and Kapplan-Meier methods were used to assess the relation between time to progression (TTP) and individual gene expression adjusting for clinical covariates. Over 3000 genes were differentially expressed in MPBC-HGT1 as compared with cUC-HGT1 and a 26-gene signature is characteristic of MPBC within HGT1. A set of three genes; CD36, FAPB3 and RAETE1; were significantly associated with TTP. High expression of FABP3 and CD36 were associated with shorter TTP (p = 0.045 and p = 0.08) as was low expression of RAET1E (p = 0.01). Our study suggest that a 26-gene signature can define MPBC-HGT1 within conventional urothelial carcinomas. A prognostic risk index of three genes (FABP3, CD36 and RAET1E) was found to be associated with shorter TTP and may help classify a group of patients with MPBC-HGT1 with high-risk of early progression. These observations might have implications in terms of radical cystectomy recommendation in MPBC patients.

Incidence, Patterns, and Outcomes with Adjuvant Chemotherapy for Residual Disease After Neoadjuvant Chemotherapy in Muscle-invasive Urinary Tract Cancers.

BACKGROUND: Patients with residual muscle-invasive urinary tract cancer after neoadjuvant chemotherapy (NAC) have a high risk of recurrence. OBJECTIVE: To retrospectively evaluate whether additional adjuvant chemotherapy (AC) improves outcomes compared with surveillance in patients with significant residual disease despite NAC. DESIGN, SETTING, AND PARTICIPANTS: We identified 474 patients who received NAC from the Retrospective International Study of Cancers of the Urothelium database, of whom 129 had adverse residual disease (≥ypT3 and/or ypN+). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to relapse (TTR) was the primary endpoint assessed starting from 2mo after surgery to minimize immortal time bias. Secondary endpoints included overall survival (OS), incidence of AC use, and chemotherapy patterns. Kaplan-Meier and Cox regression models estimated TTR, OS, and associations with AC, adjusting for the type of NAC, age, and pathological stage in multivariable analyses. RESULTS AND LIMITATIONS: A total of 106 patients underwent surveillance, while 23 received AC. Gemcitabine-cisplatin was the most frequent regimen employed in both settings (30.4%), and the majority (82.6%) of the patients switched to a different regimen. Median follow-up was 30mo. Over 50% of patients developed a recurrence. Median TTR was 16mo (range: <1-108mo). Longer median TTR was observed with AC compared with surveillance (18 vs 10mo, p=0.06). Risk of relapse significantly decreased with AC when adjusted in multivariable analyses (p=0.01). The subgroup analyses of ypT4b/ypN+ patients (AC: 19; surveillance: 50) who received AC had significantly greater median TTR (20 vs 9mo; hazard ratio 0.43; 95% confidence interval: 0.21-0.89). No difference in OS was found. Limitations include the retrospective design. CONCLUSIONS: The utilization of AC after NAC in patients with high-risk residual disease is not frequent in clinical practice but might reduce the risk of recurrence. Further investigation is needed in this high-risk population to identify optimal therapy and to improve clinical outcomes such as the ongoing adjuvant immunotherapy trials. PATIENT SUMMARY: We found that administering additional chemotherapy in patients who had significant residual disease despite preoperative chemotherapy is not frequent in clinical practice. While it might reduce the risk of recurrence, it did not clearly increase overall survival. We encourage participation in the ongoing immunotherapy trials to see whether we can improve outcomes using a different type of therapy that stimulates the immune system.

Results of a Multicenter Phase II Study of Atezolizumab and Bevacizumab for Patients With Metastatic Renal Cell Carcinoma With Variant Histology and/or Sarcomatoid Features.

PURPOSE: In this multicenter phase II trial, we evaluated atezolizumab combined with bevacizumab in patients with advanced renal cell carcinoma (RCC) with variant histology or any RCC histology with ≥ 20% sarcomatoid differentiation. PATIENTS AND METHODS: Eligible patients may have received previous systemic therapy, excluding prior bevacizumab or checkpoint inhibitors. Patients underwent a baseline biopsy and received atezolizumab 1,200 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. The primary end point was overall response rate (ORR) by RECIST version 1.1. Additional end points were progression-free survival (PFS), toxicity, biomarkers of response as determined by programmed death-ligand 1 (PD-L1) status, and on-therapy quality-of-life (QOL) metrics using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 and the Brief Fatigue Inventory. RESULTS: Sixty patients received at least 1 dose of either study agent; the majority (65%) were treatment naïve. The ORR for the overall population was 33% and 50% in patients with clear cell RCC with sarcomatoid differentiation and 26% in patients with variant histology RCC. Median PFS was 8.3 months (95% CI, 5.7 to 10.9 months). PD-L1 status was available for 36 patients; 15 (42%) had ≥ 1% expression on tumor cells. ORR in PD-L1-positive patients was 60% (n = 9) v 19% (n = 4) in PD-L1-negative patients. Eight patients (13%) developed treatment-related grade 3 toxicities. There were no treatment-related grade 4-5 toxicities. QOL was maintained throughout therapy. CONCLUSION: In this study, atezolizumab and bevacizumab demonstrated safety and resulted in objective responses in patients with variant histology RCC or RCC with ≥ 20% sarcomatoid differentiation. This regimen warrants additional exploration in patients with rare RCC, particularly those with PD-L1-positive tumors.

Rate of differentiation syndrome in patients based on timing of initial all-trans retinoic acid administration.

All-trans-retinoic acid (ATRA) is the standard of care for the management of acute promyelocytic leukemia (APL), but can be associated with differentiation syndrome (DS). Over a seven-year period, we sought to determine the impact of ATRA initiation time on the development of DS. ATRA administration time had no impact on DS occurrence (p = =0.13), APL risk (p = =0.28) or regimen received (p = =0.1). Patients with higher mean body mass index (BMI) were more likely to develop moderate or severe DS (p = =0.02). Early treatment of APL is essential and maybe strongly considered in patients with elevated BMI.

Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition-A Pooled Analysis of Patients With Advanced Melanoma.

PURPOSE: Outcome measures that comprehensively capture attributes of immuno-oncology agents, including prolonged treatment-free time and persistent treatment-related adverse events (TRAEs), are needed to complement conventional survival end points. METHODS: We pooled data from the CheckMate 067 and 069 clinical trials of nivolumab and ipilimumab, as monotherapies or in combination, for patients with advanced melanoma. Treatment-free survival (TFS) was defined as the area between Kaplan-Meier curves for two conventional time-to-event end points, each defined from random assignment: time to immune checkpoint inhibitor (ICI) protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was partitioned as time with and without toxicity by a third end point, time to cessation of both ICI therapy and toxicity. Toxicity included persistent and late-onset grade 3 or higher TRAEs. The area under each Kaplan-Meier curve was estimated by the 36-month restricted mean time. RESULTS: At 36 months, many of the 1,077 patients who initiated ICI therapy were surviving free of subsequent therapy initiation (47% nivolumab plus ipilimumab, 37% nivolumab, 15% ipilimumab). The restricted mean TFS was longer for nivolumab plus ipilimumab (11.1 months) compared with nivolumab (4.6 months; difference, 6.5 months; 95% CI, 5.0 to 8.0 months) or ipilimumab (8.7 months; difference, 2.4 months; 95% CI, 0.8 to 4.1 months); restricted mean TFS represented 31% (3% with and 28% without toxicity), 13% (1% and 11%), and 24% (less than 1% and 23%) of the 36-month period, respectively, in the three treatment groups. TFS without toxicity was longer for nivolumab plus ipilimumab than nivolumab (difference, 6.0 months) or ipilimumab (difference, 1.7 months). CONCLUSION: The analysis of TFS between ICI cessation and subsequent therapy initiation revealed longer TFS without toxicity for patients with advanced melanoma who received nivolumab plus ipilimumab compared with nivolumab or ipilimumab. Regardless of treatment, a small proportion of the TFS involved grade 3 or higher TRAEs.

Evaluating a Video-Based, Personalized Webpage in Genitourinary Oncology Clinical Trials: A Phase 2 Randomized Trial.

BACKGROUND: The pace of drug discovery and approvals has led to expanding treatments for cancer patients. Although extensive research exists regarding barriers to enrollment in oncology clinical trials, there are limited studies evaluating processes to optimize patient education, oral anticancer therapy administration, and adherence for patients enrolled in clinical trials. In this study, we assess the feasibility of a video-based, personalized webpage for patients enrolled in genitourinary oncology clinical trials involving 1 or more oral anticancer therapy. OBJECTIVE: The primary objective of this trial was to assess the differences in the number of patient-initiated violations in the intervention arm compared with a control arm over 4 treatment cycles. Secondary objectives included patient satisfaction, frequently asked questions by patients on the intervention arm, patient-initiated calls to study team members, and patient-reported stress levels. METHODS: Eligible patients enrolling on a therapeutic clinical trial for a genitourinary malignancy were randomized 2:1 to the intervention arm or control arm. Patients randomized to the intervention arm received access to a video-based, personalized webpage, which included videos of patients' own clinic encounters with their providers, instructional videos on medication administration and side effects, and electronic versions of educational documents. RESULTS: A total of 99 patients were enrolled (89 were evaluable; 66 completed 4 cycles). In total, 71% (40/56) of patients in the intervention arm had 1 or more patient-initiated violation compared with 70% (23/33) in the control arm. There was no difference in the total number of violations across 4 cycles between the 2 arms (estimate=-0.0939, 95% CI-0.6295 to 0.4418, P value=.73). Median baseline satisfaction scores for the intervention and control arms were 72 and 73, respectively, indicating high levels of patient satisfaction in both arms. Median baseline patient-reported stress levels were 10 and 13 for the intervention and control arms, respectively, indicating low stress levels in both arms at baseline. CONCLUSIONS: This study is among the first to evaluate a video-based, personalized webpage that provides patients with educational videos and video recordings of clinical trial appointments. Despite not meeting the primary endpoint of reduced patient-initiated violations, this study demonstrates the feasibility of a video-based, personalized webpage in clinical trials. Future research assessing this tool might be better suited for realms outside of clinical trials and might consider the use of an endpoint that assesses patient-reported outcomes directly. A major limitation of this study was the lack of prior data for estimating the null hypothesis in this population.

Phase 1 study of lenalidomide, bendamustine, and rituximab in previously untreated patients with chronic lymphocytic leukemia.

Bendamustine-rituximab (BR) is a standard therapy in CLL, and lenalidomide has single-agent activity. This phase 1 study evaluated lenalidomide-BR as initial CLL therapy. Thirteen patients were treated at three dose levels (DL), and an additional 10 were treated at the MTD. The MTD was DL3: lenalidomide 5 mg daily D8-21 of C1, then 10 mg D1-21 of C2-6. One DLT occurred at DL2 (pulmonary embolus). Grade ≥3 toxicities included neutropenia (52.2%), rash (26.1%), anemia (21.7%), thrombocytopenia (21.7%), and febrile neutropenia (13.0%). Of 13, 9 treated at the MTD required dose modification, most for neutropenia (5). OR and CR rates were 87% and 39%, respectively. Lenalidomide-BR could be safely administered and was active as initial CLL therapy, although frequent dose modification at the MTD suggests that lenalidomide 10 mg is too high for most patients. Given the current treatment landscape, lenalidomide combinations warrant evaluation in CLL patients who are chemonaïve but have been failed by the approved targeted therapies.

Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma.

NKG2D ligands are widely expressed in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. We conducted a phase I dose-escalation study to evaluate the safety and feasibility of a single infusion of NKG2D-chimeric antigen receptor (CAR) T cells, without lymphodepleting conditioning in subjects with acute myeloid leukemia/myelodysplastic syndrome or relapsed/refractory multiple myeloma. Autologous T cells were transfected with a γ-retroviral vector encoding a CAR fusing human NKG2D with the CD3ζ signaling domain. Four dose levels (1 × 106-3 × 107 total viable T cells) were evaluated. Twelve subjects were infused [7 acute myeloid leukemia (AML) and 5 multiple myeloma]. NKG2D-CAR products demonstrated a median 75% vector-driven NKG2D expression on CD3+ T cells. No dose-limiting toxicities, cytokine release syndrome, or CAR T cell-related neurotoxicity was observed. No significant autoimmune reactions were noted, and none of the ≥ grade 3 adverse events were attributable to NKG2D-CAR T cells. At the single injection of low cell doses used in this trial, no objective tumor responses were observed. However, hematologic parameters transiently improved in one subject with AML at the highest dose, and cases of disease stability without further therapy or on subsequent treatments were noted. At 24 hours, the cytokine RANTES increased a median of 1.9-fold among all subjects and 5.8-fold among six AML patients. Consistent with preclinical studies, NKG2D-CAR T cell-expansion and persistence were limited. Manufactured NKG2D-CAR T cells exhibited functional activity against autologous tumor cells in vitro, but modifications to enhance CAR T-cell expansion and target density may be needed to boost clinical activity.

A phase 2 trial of abiraterone acetate without glucocorticoids for men with metastatic castration-resistant prostate cancer.

BACKGROUND: Abiraterone acetate suppresses adrenal androgens and glucocorticoids through the inhibition of CYP17; however, given the risk of mineralocorticoid excess, it is administered with glucocorticoids. Herein, the authors performed a phase 2, single-arm study that was designed to assess the safety of abiraterone acetate without steroids in patients with castration-resistant prostate cancer. METHODS: Eligible patients had castration-resistant prostate cancer with controlled blood pressure and normal potassium. Patients initially received abiraterone acetate at a dose of 1000 mg daily alone. Those with persistent or severe mineralocorticoid toxicity received treatment with prednisone initiated at a dose of 5 mg twice daily. Therapy was continued until radiographic progression, toxicity, or withdrawal. The primary objective of the current study was to determine the percentage of men requiring prednisone to manage mineralocorticoid toxicity. Toxicity was graded according to Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: A total of 58 patients received at least 1 dose of abiraterone acetate; the majority had metastases (53 patients; 91.4%). Sixteen patients (27.6%) received prior chemotherapy, 6 patients (10.3%) received prior enzalutamide, and 4 patients (7%) received prior ketoconazole. Grade 3 to 4 adverse events of interest included hypertension (9 patients; 15.5%) and hypokalemia (4 patients; 7%). There was no grade ≥3 edema. Seven patients (12%) initiated prednisone therapy for mineralocorticoid toxicity, 3 patients for hypertension (5%), and 4 patients for hypokalemia (7%). Two patients initiated prednisone therapy for fatigue (3%). Forty patients (68%) experienced a decline in prostate-specific antigen of ≥50% with the use of abiraterone acetate alone. Patients with lower baseline levels of androstenedione (P = .04), androsterone (P = .01), dehydroepiandrosterone (P = .03), and 17-hydroxyprogesterone (P = .03) were found to be more likely to develop mineralocorticoid toxicity. CONCLUSIONS: Treatment with abiraterone acetate without steroids is feasible, although clinically significant adverse events can occur in a minority of patients. The use of abiraterone acetate without prednisone should be balanced with the potential for toxicity and requires close monitoring.

Elevated Serum Cytokines and Trichomonas vaginalis Serology at Diagnosis Are Not Associated With Higher Gleason Grade or Lethal Prostate Cancer.

BACKGROUND: Inflammation and infections have been associated with prostate cancer progression. We assessed whether elevated serum cytokines or T. vaginalis seropositivity at the time of diagnosis was associated with higher grade or lethal prostate cancer. PATIENTS AND METHODS: Men with localized or metastatic prostate cancer were included in this study. Cytokine serum levels including interleukin (IL)-1α, IL-1ß, IL-2, IL-6, IL-8, monocyte chemotactic protein 1 (CCL-2), tumor necrosis factor α, and growth-regulated oncogene α (CXCL-1) using a multiplex enzyme-linked immunosorbent assay and T. vaginalis serology were measured in blood samples at diagnosis. RESULTS: A total of 324 patients were identified at time of localized disease and 118 at time of metastatic disease. Of the 189 patients with localized disease and clinical follow-up data (median, 73 months), 28 developed lethal disease. There was no association between circulating cytokine levels above median concentrations nor T. vaginalis seropositivity and risk of intermediate- to high-risk or lethal prostate cancer. CONCLUSION: Higher levels of serum cytokine levels and T. vaginalis seropositivity at diagnosis are not associated with high-grade or lethal prostate cancer and do not aid risk stratification of localized prostate cancer.