Chronic lymphocytic leukemia (CLL) is associated with perturbed immune function and increased risk for second primary malignancies (SPM). Ibrutinib and acalabrutinib (BTKi) are effective therapies ...for CLL resulting in partial restoration of immune function. The incidence of and risk factors for SPM in CLL patients receiving BTKi are not yet characterized. We retrospectively determined the incidence of SPM in CLL patients treated with ibrutinib or acalabrutinib at our institution between 2009 and 2017, assessed for association between baseline characteristics and SPM incidence, and compared the observed to expected cancer incidence among age, sex, and year matched controls without CLL. After a median of 44 months follow-up, 64/691 patients (9%) were diagnosed with SPM (excluding non-melanoma skin cancer NMSC). The 3-year cumulative incidence rate was 16% for NMSC and 7% for other SPM. On multivariable analysis, smoking was associated with increased SPM risk (HR 2.8 95% CI: 1.6-4.8) and higher baseline CD8 count was associated with lower SPM risk (HR 0.9 for 2-fold increase 95% CI: 0.8-0.9). The observed over expected rate of SPM was 2.2 95% CI: 1.7-2.9. CLL patients treated with BTKi remain at increased risk for SPM, and secondary cancer detection is an important consideration in this population.
Introduction:
Romidepsin is a novel histone deacetylase (HDAC) inhibitor, with a recent approval for treatment of cutaneous T-cell lymphoma (CTCL). HDAC inhibitors represent a novel approach to ...anti-tumor therapy. In contrast to traditional cytotoxic chemotherapy, HDAC inhibitors target underlying epigenetic changes leading to malignant transformation. Further study of romidepsin and similar agents in solid and hematologic malignancies is ongoing.
Areas covered:
This review discusses the development of romidepsin, its mechanism of action, pivotal clinical trials, drug toxicity and its recent approval for CTCL treatment. Key clinical trials covered include Phase I/II testing of romidepsin in solid and hematologic malignancies. In addition, the Phase II trial in CTCL leading to FDA approval of romidepsin is reviewed in detail. Literature search was performed using PubMed; keywords and concepts used included romidepsin, T-cell lymphoma and HDAC inhibitors.
Expert opinion:
Romidepsin is a potent HDAC inhibitor with demonstrable activity in T-cell lymphoma. In contrast to vorinostat, romidepsin is approved as second-line therapy. Current approval only includes CTCL; promising results have been demonstrated in Phase II testing of peripheral T-cell lymphoma subtypes. Future directions include expanded indications in T-cell lymphomas as well as novel combinations with other HDAC inhibitors and other therapeutic agents.
Background
The neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with advanced cancers treated with immune checkpoint inhibitors (ICI), but has generally been evaluated as a ...single threshold value at baseline. We evaluated NLR at baseline and within first month during treatment in patients who received ICI for advanced cancer to evaluate the prognostic value of baseline and of changes from baseline to on-treatment NLR.
Methods
A retrospective review of patients with advanced cancer treated with ICI from 2011 to 2017 at the Ohio State University was performed. NLR was calculated at the initiation of ICI and repeated at median of 21 days. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Significance of Cox proportional hazards models were evaluated by log-rank test. Calculations were performed using the survival and survminer packages in
R
, and SPSS.
Results
509 patients were identified and included in the analysis. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (
P
< 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with
P
< 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8–33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1–16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9–9.1).
Conclusions
We confirmed the prognostic value of NLR in patients with advanced cancer treated with ICIs. We found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. To our knowledge, this is the first study to demonstrate a non-linear change in NLR over time that correlates with survival.
Introduction
Immune checkpoint inhibitors (ICI) are associated with unique immune-related adverse events (irAEs). Immune-related thrombocytopenia (irTCP) is an understudied and poorly understood ...toxicity; little data are available regarding either risk of irTCP or the effect of irTCP on clinical outcomes of patients treated with ICI.
Methods
We conducted a retrospective review of sequential cancer patients treated with ICI between 2011 and 2017 at our institution. All patients who received ICI alone or in combination with other systemic therapy in any line of treatment were included; those with thrombocytopenia ≥ grade 3 at baseline were excluded. We calculated the incidence of ≥ grade 3 irTCP and overall survival (OS). Patient factors associated with irTCP were assessed.
Results
We identified 1,038 patients that met eligibility criteria. Overall, 89 (8.6%) patients developed grade ≥ 3 thrombocytopenia; eighteen were attributed to ICI (1.73% overall). Patients who developed grade ≥ 3 irTCP had worse overall survival compared to those whose thrombocytopenia was unrelated to ICI (4.17 vs. 10.8 month; HR. 1.94, 95% CI 1.13, 3.33; log-rank
p
= 0.0164). Patients with grade ≥ 3 irTCP also had worse survival compared to those without thrombocytopenia (4.17 vs. 13.31 months; HR 2.22, 95% CI 1.36, 3.62; log-rank
p
= 0.001). The incidence of irTCP appeared lowest among those treated with PD-1/L1 monotherapy (
p
= 0.059) and was not associated with cancer type, smoking status, age, gender, race, or line of therapy.
Conclusions
Unlike other irAEs, we found that irTCP was associated with worse overall survival. The incidence of irTCP appeared lowest among those treated with PD-1/L1 monotherapy.
Neuroendocrine tumors are a heterogeneous group of tumors originating in various anatomic locations. The management of this disease poses a significant challenge because of the heterogeneous clinical ...presentations and varying degrees of aggressiveness. The recent completion of several phase 3 trials, including those evaluating octreotide, sunitinib, and everolimus, demonstrate that rigorous evaluation of novel agents in this disease is possible and can lead to practice-changing outcomes. Nevertheless, there are many aspects to the treatment of neuroendocrine tumors that remain unclear and controversial. The North American Neuroendocrine Tumor Society published a set of consensus guidelines in 2010, which provided an overview for the treatment of patients with these malignancies. Here, we present a set of consensus tables intended to complement these guidelines and serve as a quick, accessible reference for the practicing physician.
The risk factors for immune-related adverse events (irAEs) remain undefined. Recently, a correlation between irAEs and clinical benefit was suggested. We examined the risk factors for irAEs and their ...effect on survival in patients with non–small-cell lung cancer (NSCLC) who had received immunotherapy.
We performed a retrospective review of patients with NSCLC treated with single-agent immunotherapy at our institution. irAEs were determined by treating physician diagnosis. A landmark analysis was performed at 3 months using log-rank tests and the Bonferroni method.
irAEs occurred in 27 of 91 patients (30%). The median overall survival (OS) for patients with irAEs was longer than that for patients without (24.3 vs. 5.3 months; hazard ratio, 2.75; 95% confidence interval, 1.54-4.92; P < .001). However, a landmark analysis of patients after 3 months of treatment revealed no difference in OS between patients with and without irAEs. No increased risk of pneumonitis was seen in patients with previous thoracic radiotherapy, although these patients had shorter survival (4.2 vs. 9.7 months; P = .004). Radiotherapy after the initiation of immunotherapy (n = 15) did not increase the risk of irAEs or pneumonitis; however, these patients had improved OS (17.3 vs. 6.0 months; P = .016).
The development of irAEs did not significantly correlate with survival when controlling for the duration of therapy in a landmark analysis. We found no increased risk of pneumonitis or irAEs in patients who had received radiotherapy. Radiotherapy before immunotherapy was associated with shorter survival, and radiotherapy after immunotherapy was associated with improved survival.
Immunotherapy is a mainstay of treatment for non–small-cell lung cancer. Serious immune-related adverse events (irAEs) occur; however, their effect on survival is unclear, and no defined risks factors have been elucidated. In the present study, we found no significant effect of irAE on survival in a landmark analysis, and no increased risk of pneumonitis in patients with previous radiation.
Epigenetic ("above genetics") modifications can alter the gene expression without altering the DNA sequence. Aberrant epigenetic regulations in cancer include DNA methylation, histone methylation, ...histone acetylation, non-coding RNA, and mRNA methylation. Epigenetic-targeted agents have demonstrated clinical activities in hematological malignancies and therapeutic potential in solid tumors. In this review, we describe mechanisms of various epigenetic modifications, discuss the Food and Drug Administration-approved epigenetic agents, and focus on the current clinical investigations of novel epigenetic monotherapies and combination therapies in solid tumors.
Alternative predictive end points for overall survival (OS), such as tumor response and progression-free survival (PFS), are useful in the early detection of drug efficacy; however, they have not ...been fully investigated in patients with advanced NSCLC treated with anti–programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies.
In a systematic review of the reported prospective clinical trials, data for response rate, median PFS, and median OS were extracted from 12 arms in 10 reported clinical trials using anti–PD-1/PD-L1 antibody, and their correlation was investigated. In a retrospective analysis at our institution, OS was compared according to tumor response on 5- to 9-week computed tomography scans and status of being progression-free at 8, 16, and 24 weeks by landmark analysis in 71 patients with advanced NSCLC treated with anti–PD-1/PD-L1 antibodies between 2013 and 2015.
In a systematic review, moderate correlations between median OS and median PFS (p = 0.120, r = 0.473) and between median OS and response rate (p = 0.141, r = 0.452) were identified using the Spearman correlation coefficient, although these correlations were not statistically significant. In a retrospective analysis of patients treated at our institution, disease control (partial response PR/stable disease versus progressive disease/not evaluable), and progression-free status at 8, 16, and 24 weeks significantly predicted OS (Cox proportional hazards model, PR/stable disease versus progressive disease/not evaluable, p = 0.0104, HR = 3.041; 8-week progression-free yes versus no, p = 0.0183, HR = 2.684; 16-week progression-free yes versus no, p = 0.0036, HR = 4.009; and 24-week progression-free yes versus no, p = 0.0002, HR = 12.726).
Both disease control (PR plus stable disease status) and landmark progression-free survival were correlated with OS, with the longer interval landmark PFS being the best predictor of survival in patients with NSCLC treated with anti–PD-1/PD-L1 antibodies.
Elderly patients account for the majority of lung cancer diagnoses but are poorly represented in clinical trials. We evaluated the overall survival (OS) of elderly patients with stage III NSCLC ...treated with definitive radiation compared with that of patients treated with definitive chemoradiation.
We conducted a comparative effectiveness study of radiation therapy versus chemoradiation in elderly (≥70 years old) patients with stage III NSCLC not treated surgically diagnosed from 2003 to 2014; the patients were identified by using the National Cancer Database. Two cohorts were evaluated: patients (n = 5023) treated with definitive radiation (≥59.4 Gy) and patients (n = 18,206) treated with definitive chemoradiation. Chemoradiation was further defined as concurrent (radiation and chemotherapy started within 30 days of each other) or sequential (radiation started >30 days after chemotherapy). We compared OS between the treatment groups by using the Kaplan-Meier method and Cox proportional hazards regression before and after propensity score matching (PSM).
Treatment with chemoradiation was associated with improved OS versus that with radiation both before PSM (hazard ratio HR = 0.66, 95% confidence interval CI: 0.64–0.68, p < 0.001) and after PSM (HR = 0.67, 95% CI: 0.64–0.70, p < 0.001). Relative to concurrent chemoradiation, sequential chemoradiation was associated with a 9% reduction in the risk for death (HR = 0.91, 95% CI: 0.85–0.96, p = 0.002).
We found that definitive chemoradiation resulted in a survival advantage compared with definitive radiation in elderly patients. Sequential chemotherapy and radiation was superior to concurrent chemoradiation. Although prospective trials are needed, this analysis suggests that chemoradiation should be strongly considered for elderly patients and the optimal sequencing of chemotherapy and radiation remains an unanswered question for this patient population.
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