Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy.

Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1-14. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies15-17 to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8+ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Seven decades of chemotherapy clinical trials: a pan-cancer social network analysis.

Clinical trials establish the standard of cancer care, yet the evolution and characteristics of the social dynamics between the people conducting this work remain understudied. We performed a social network analysis of authors publishing chemotherapy-based prospective trials from 1946 to 2018 to understand how social influences, including the role of gender, have influenced the growth and development of this network, which has expanded exponentially from fewer than 50 authors in 1946 to 29,197 in 2018. While 99.4% of authors were directly or indirectly connected by 2018, our results indicate a tendency to predominantly connect with others in the same or similar fields, as well as an increasing disparity in author impact and number of connections. Scale-free effects were evident, with small numbers of individuals having disproportionate impact. Women were under-represented and likelier to have lower impact, shorter productive periods (P < 0.001 for both comparisons), less centrality, and a greater proportion of co-authors in their same subspecialty. The past 30 years were characterized by a trend towards increased authorship by women, with new author parity anticipated in 2032. The network of cancer clinical trialists is best characterized as strategic or mixed-motive, with cooperative and competitive elements influencing its appearance. Network effects such as low centrality, which may limit access to high-profile individuals, likely contribute to the observed disparities.

Countering Opioid-induced Respiratory Depression in Male Rats with Nicotinic Acetylcholine Receptor Partial Agonists Varenicline and ABT 594.

BACKGROUND: Opioids can induce significant respiratory depression when administered as analgesics for the treatment of acute, postoperative, and chronic pain. There are currently no pharmacologic means of reversing opioid-induced respiratory depression without interfering with analgesia. Further, there is a growing epidemic of opioid overdose that could benefit from therapeutic advancements. The aim of this study was to test the ability of two partial agonists of α4ß2 nicotinic acetylcholine receptors, varenicline (used clinically for smoking cessation) and ABT 594 (tebanicline, developed as an analgesic), to reduce respiratory depression induced by fentanyl, remifentanil, morphine, and a combination of fentanyl and diazepam. METHODS: Whole body plethysmographic recordings, nociception testing, and righting reflex testing were used to examine ventilation, analgesia, and sedation in adult male Sprague-Dawley rats. RESULTS: Pre-, co-, or postadministration of varenicline or ABT 594 did not alter baseline breathing but markedly reduced opioid-induced respiratory depression. Varenicline had no effect on fentanyl-induced analgesia and ABT 594 potentiated fentanyl-induced analgesia. Specifically, 10-min administration of fentanyl induced a decrease in respiratory rate to 43 ± 32% of control in vehicle group, which was alleviated by preadministration of varenicline (85 ± 14% of control, n = 8, P < 0.001) or ABT 594 (81 ± 36% of control, n = 8, P = 0.001). ABT 594 or varenicline with a low dose of naloxone (1 µg/kg), but not varenicline alone, partially reversed fentanyl-induced lethal apnea, but neither compound provided the very rapid and complete reversal of apnea achieved with high doses of naloxone (0.03 to 1 mg/kg). Administration of varenicline (n = 4, P = 0.034) or ABT 594 (n = 4, P = 0.034) prevented lethal apneas induced by the combination of fentanyl and diazepam. CONCLUSIONS: Activation of α4ß2 nicotinic acetylcholine receptors by varenicline and ABT 594 counters opioid-induced respiratory depression without interfering with analgesia.

Late Rescue Therapy with Cord-Derived Mesenchymal Stromal Cells for Established Lung Injury in Experimental Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD), the main complication of extreme prematurity, has lifelong consequences for lung health. Mesenchymal stromal cells (MSCs) prevent lung injury in experimental BPD in newborn rodents when given in the immediate neonatal period. Whether MSC therapy can restore normal lung growth after established lung injury in adulthood is clinically relevant, but currently unknown. Experimental BPD was achieved by exposing newborn rats to 95% O2 from postnatal days 4-14. Human umbilical cord-derived MSCs were intratracheally administered to rats (1 × 106cells/kg body weight) as a single dose at 3 or 6 months of age followed by assessment at 5 or 8 months of age, respectively. Lung alveolar structure and vessel density were histologically analyzed. O2-exposed rats exhibited persistent lung injury characterized by arrested alveolar growth with airspace enlargement and a lower vessel density at both 5 and 8 months of age compared with controls. Single-dose MSC treatment at 3 months partially attenuated O2-induced alveolar injury and restored vessel density at 5 months. Treatment with a single dose at 6 months did not attenuate alveolar injury or vessel density at 8 months. However, treatment with multiple MSC doses at 6, 6.5, 7, and 7.5 months significantly attenuated alveolar injury and improved vessel density at 8 months of age. Treatment of the adult BPD lung with MSCs has the potential to improve lung injury if administered in multiple doses or at an early stage of adulthood.

Outcomes for Relapsed and Refractory Peripheral T-Cell Lymphoma Patients after Front-Line Therapy from the COMPLETE Registry.

BACKGROUND: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data. OBJECTIVES: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease. METHODS: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days. RESULTS: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months. CONCLUSIONS: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.

Blastic Transformation of a Mantle Cell Lymphoma Presenting as an Enlarging Unilateral Orbital Mass.

Mantle cell lymphoma (MCL) is an uncommon form of non-Hodgkin lymphoma predominantly affecting male individuals of advanced age. Approximately 1-9% of cases of lymphoma affecting the orbital and ocular adnexal regions are attributed to MCL. We describe the case of a 65-year-old man with a 24-year history of MCL with initial remission followed by multiple relapses who presented with acute-onset binocular diplopia and proptosis of the left eye. Subsequent imaging demonstrated a new left superior orbital mass. Biopsy of the mass revealed two clonally related, yet distinct cellular components demonstrating the classical mantle cell morphology and large cells that appeared to have transformed to the blastoid variant of MCL. Transformation of classical MCL to the blastoid variant of MCL is rare, with few reports in the literature. The blastoid variant of MCL tends to be aggressive and associated with a poor prognosis. The case we describe represents perhaps the first report of MCL transformation observed in the orbit.

Differential Interaction of Peripheral Blood Lymphocyte Counts (ALC) With Different in vivo Depletion Strategies in Predicting Outcomes of Allogeneic Transplant: An International 2 Center Experience.

Dosing regimens for antithymocyte globulin (ATG) and anti-CD52 antibody (alemtuzumab) for graft vs. host disease prophylaxis (GVHD) are empiric or weight-based, and do not account for individual patient factors. Recently, it has been shown that recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration interacts with the dose of ATG administered to predict transplantation outcome. Similarly, we wanted to analyze if the recipient ALC interacts with alemtuzumab dosing to predict outcomes. We retrospectively compared 364 patients, 124 patients receiving ATG (anti-thymocyte globulin) for GVHD prophylaxis, and undergoing unrelated first allogeneic transplant for myeloid and lymphoid malignancies (group 1) to 240 patients receiving alemtuzumab (group 2), in similar time period. There was no difference in survival or acute and chronic GVHD between 60 and 100 mg of alemtuzumab dosing. Unlike ATG (where the pre-transplant recipient ALC interacted with ATG dose on day of its administration (day 1) to predict OS and DFS (p = 0.05), within alemtuzumab group, the recipient ALC on second day of alemtuzumab administration (day 2) and its interaction with alemtuzumab dose strongly predicted OS, DFS and relapse (p = 0.05, HR-1.81, 1.1-3.3; p = 0.002, HR-2.41, CI, 1.3-4.2; and p = 0.003, HR-2.78, CI, 1.4-5.2), respectively. ALC (day 2) of 0.08 × 109/lit or higher, had a specificity of 96% in predicting inferior DFS. Like ATG, there is definite but differential interaction between the recipient peripheral blood ALC and alemtuzumab dose to predict OS, DFS, and relapses.

Clinicopathologic correlates of MYD88 L265P mutation and programmed cell death (PD-1) pathway in primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) patients have a poorer prognosis than systemic lymphoma. Gain-of-function MYD88 c.794T > C (p. L265P) mutation and programed cell death-1 (PD-1) pathway alterations are potential targetable pathways. Our study objective was to determine the clinicopathologic correlates of MYD88 mutation and PD-1 alterations in PCNSL and the impact of Epstein-Barr virus (EBV) infection. We studied 53 cases including 13 EBV-associated (EBVpos) PCNSL, 49% harbored MYD88 mutation, none seen in EBVpos PCNSL. MYD88 protein expression did not correlate with MYD88 mutation. T-cell and macrophage infiltration was common. All PD-L1-positive tumors were EBVpos. Two PD-L1 positive tumors showed 9p24.1/PD-L1 locus alterations by Fluorescence In Situ Hybridization. T cells and macrophages expressed PD-1 and/or PD-L1 in 98% and 83% cases, respectively. MYD88 mutation or protein expression and PD-1 or PD-L1 expression did not predict outcome. We hypothesize that EBVpos PCNSL has a distinct activation mechanism, independent of genetic alterations.

The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study.

BACKGROUND: The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1. METHODS: Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis. RESULTS: Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty-three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow-up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P = .06). ASCT was associated with superior survival for patients with advanced-stage disease or intermediate-to-high International Prognostic Index scores. ASCT significantly improved overall and progression-free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15-0.89). CONCLUSIONS: This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL.

Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial.

BACKGROUND: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma. METHODS: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805. FINDINGS: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p<0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related. INTERPRETATION: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma. FUNDING: Kyowa Kirin.

NCCN Guidelines Insights: T-Cell Lymphomas, Version 2.2018.

Natural killer (NK)/T-cell lymphomas are a rare and distinct subtype of non-Hodgkin's lymphomas. NK/T-cell lymphomas are predominantly extranodal and most of these are nasal type, often localized to the upper aerodigestive tract. Because extranodal NK/T-cell lymphomas (ENKL) are rare malignancies, randomized trials comparing different regimens have not been conducted to date and standard therapy has not yet been established for these patients. These NCCN Guidelines Insights discuss the recommendations for the diagnosis and management of patients with ENKL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Optimizing Antithymocyte Globulin Dosing for Unrelated Donor Allogeneic Hematopoietic Cell Transplantation Based on Recipient Absolute Lymphocyte Count.

Antithymocyte globulin (ATG) is used as prophylaxis against graft-versus-host disease (GVHD). Current dosing regimens for ATG are empiric and weight-based, and do not account for patient-specific factors. Furthermore, the target of ATG, recipient T cells post-cytotoxic chemotherapy, is not a function of recipient weight. We hypothesized the recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration would interact with the dose of ATG administered to predict transplantation outcomes. We retrospectively analyzed 135 patients who received ATG for GVHD prophylaxis for unrelated allogeneic hematopoietic cell transplantation at 3 different doses: 10 mg/kg, 7.5 mg/kg, and 5 mg/kg. There was no difference in 2-year overall survival (OS) among ATG dosing groups; however, deaths from infectious complications were significantly higher with higher doses of ATG (3.7% versus 19% versus 26.7%; P = .02). Severity of chronic GVHD was lower with higher doses of ATG (28% versus 24% versus 4%; P = .03). In multivariate analysis, the median peripheral blood ALC on day of ATG administration and the total amount of ATG interacted to predict OS (hazard ratio, .09; P = .03). For low recipient ALC (10th percentile, or .56 × 102/µL), a higher total ATG dose was associated with a greater risk of death, whereas for high recipient ALC (90th percentile, or 24.96 × 102/µL), a higher ATG dose was associated with a lower risk of death. Our findings suggest that the interaction between ATG and its target, the recipient lymphocyte, could represent a new paradigm for ATG dosing.

NCCN Guidelines Insights: Acute Lymphoblastic Leukemia, Version 1.2017.

The prognosis for patients with newly diagnosed acute lymphoblastic leukemia (ALL) has improved with the use of more intensive chemotherapy regimens, tyrosine kinase inhibitors, targeted agents, and allogeneic hematopoietic cell transplantation. However, the management of relapsed or refractory (R/R) ALL remains challenging and prognosis is poor. The NCCN Guidelines for ALL provide recommendations on standard treatment approaches based on current evidence. These NCCN Guidelines Insights summarize treatment recommendations for R/R ALL and highlight important updates, and provide a summary of the panel's discussion and underlying data supporting the most recent recommendations for R/R ALL management.

MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma.

Targeting somatically activated oncogenes has revolutionized the treatment of non-small cell lung cancer (NSCLC). Mutations in the gene mesenchymal-epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a hepatocyte growth factor-dependent manner. In addition, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. In addition, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed toward METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host. Cancer Res; 77(16); 4498-505. ©2017 AACR.

Analysis of Peripheral T-cell Lymphoma Diagnostic Workup in the United States.

BACKGROUND: With increased understanding of the unique entities, subtype-specific approaches for peripheral T-cell lymphoma (PTCL) are emerging, and more precise diagnoses are becoming increasingly important. PATIENTS AND METHODS: We analyzed the approach to the histopathologic diagnosis of PTCL using data from the comprehensive oncology measures of peripheral T-cell lymphoma (COMPLETE) study. The COMPLETE trial is a large prospective cohort study of patients with newly diagnosed PTCL in the United States. RESULTS: A total of 499 patients were enrolled from 40 academic and 15 community-based centers. Baseline assessment forms were collected for 493 patients, of which 435 (88%) were available for analysis. The most common diagnoses were PTCL, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, and angioimmunoblastic T-cell lymphoma (AITL). A mean of 10 markers (range, 0-21) was assessed per patient. CD30 was assessed frequently but not uniformly in cases that were not anaplastic large cell lymphoma. Only 17% of PTCL-NOS cases were assessed for PD1. CXCL13 was a relatively sensitive marker in AITL, expressed in 84% of tested cases; however, only 3% of PTCL-NOS cases were tested. T follicular helper cell marker assessment differed between academic and community practices, with PD1 more often evaluated by academic centers in cases of AITL (62% vs. 12%; P = .01). CONCLUSION: The diagnostic workup for PTCL in the United States varies widely and often lacks important phenotypic information to fully characterize the lymphoma. Gaps in testing of selected markers should be filled, given the impending revision to the World Health Organization classification. The accuracy of diagnosis will become increasingly important as we enter the era of targeted treatment for PTCL.

Thrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy.

BACKGROUND: Immune checkpoint inhibitors, including antibodies against programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), are being used with increasing frequency for the treatment of cancer. Immune-related adverse events (irAEs) including colitis, dermatitis, and pneumonitis are well described, but less frequent events are now emerging with larger numbers of patients treated. Herein we describe the incidence and spectrum of thrombocytopenia following immune checkpoint inhibitor therapy and two severe cases of idiopathic thrombocytopenic purpura (ITP). CASE PRESENTATIONS: A 47-year-old female with recurrent BRAF mutant positive melanoma received combination anti-PD-1 and anti-CTLA-4. Two weeks later, she presented with mucosal bleeding, petechiae, and thrombocytopenia and was treated with standard therapy for ITP with steroids and intravenous immunoglobulin (IVIG). Her diagnosis was confirmed with bone marrow biopsy, and given the lack of treatment response, she was treated with rituximab. She began to have recovery and stabilization of her platelet count that ultimately allowed her to be retreated with PD-1 inhibition with no further thrombocytopenia. A second patient, a 45-year-old female with a BRAF wild-type melanoma, received anti-PD-1 monotherapy and became thrombocytopenic 43 days later. Three weeks of steroid treatment improved her platelet count, but thrombocytopenia recurred and required additional steroids. She later received anti-CTLA-4 monotherapy and developed severe ITP with intracranial hemorrhage. Her ITP resolved after treatment of prednisone, IVIG, and rituximab and discontinuation of checkpoint inhibition. In a retrospective chart review of 2360 patients with melanoma treated with checkpoint inhibitor therapy, <1% experienced thrombocytopenia following immune checkpoint inhibition, and of these, most had spontaneous resolution and did not require treatment. CONCLUSIONS: Thrombocytopenia, especially ITP, induced by immune checkpoint inhibitors appears to be an uncommon irAE that is manageable with observation in mild cases and/or standard ITP treatment algorithms. In our series, the majority of patients had mild thrombocytopenia that resolved spontaneously or responded to standard corticosteroid regimens. However, in two severe cases, IVIG and rituximab, in addition to steroids, were required. Checkpoint inhibition was resumed successfully in the first patient but rechallenge was not tolerated by the second patient.

Differences in outcome of patients with syncytial variant Hodgkin lymphoma compared with typical nodular sclerosis Hodgkin lymphoma.

BACKGROUND: Nodular sclerosis Hodgkin lymphoma (NS-HL) is the most common subtype of HL and usually has a good prognosis. A variant of NS, the syncytial variant (SV) has well-established histopathologic features but little is known about its clinical behavior. Small case series have suggested that SV patients present with advanced disease and have a comparatively aggressive course. The objective of this study was to determine the clinical characteristics and outcome of SV patients. METHODS: A total of 167 adult patients with NS-HL including 43 patients with SV and 124 patients with typical NS (t-NS) were included in our analysis following institutional review board (IRB) approval. The Kaplan-Meier method was used to calculate the progression-free survival (PFS) and overall survival (OS). Log-rank test was used to determine the differences in survival. RESULTS: Of the 167 patients, 43 were confirmed as SV based on morphology and immunophenotype. Doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) was the most frequent induction regimen administered in 91% of all patients. The rate of complete response (CR) in the SV group was 74% versus 87% in the t-NS group (p = 0.05). At 49 months follow up, the PFS was 17 months in the SV group and not reached in the t-NS group [p < 0.0001; hazard ratio (HR) = 3.695; 95% confidence interval (CI) = 3.0, 11.07]. The median OS was not reached in both groups (p = 0.32). CONCLUSIONS: Our results show that SV histology represents a poor risk group with lower CR rate and shorter PFS and this should be considered in the risk stratification of classical HL patients.