Outcomes of patients with blastoid and pleomorphic variant mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.

Ibrutinib maintenance after frontline treatment in patients with mantle cell lymphoma.

Maintenance rituximab in mantle cell lymphoma (MCL) has improved survival and supports exploration of maintenance with novel agents. We evaluated the safety and efficacy of ibrutinib maintenance (I-M) after induction in patients with treatment-naive MCL. Patients with MCL with complete response (CR) or partial response to frontline chemoimmunotherapy ± autologous stem cell transplantation (auto-SCT) received I-M 560 mg daily for up to 4 years. Primary objective was 3-year progression-free survival (PFS) rate from initiation of I-M. Minimal residual disease (MRD) assessments by next-generation sequencing (NGS) on peripheral blood were measured before I-M initiation and at 1, 6, and 18 to 24 months after initiation. Among 36 patients, the median age was 60 years (range, 46-90). For frontline treatment, 18 patients (50%) had consolidation with auto-SCT in CR1 before I-M. At median follow-up of 55.7 months, 17 patients (47%) completed full course I-M (median, 37.5 cycles; range, 2-52). The 3-year PFS and overall survival (OS) rates were 94% and 97%, respectively. With prior auto-SCT, 3-year PFS and OS rates were both 100%. The most common treatment-related adverse event with I-M was infection (n = 31; 86%), typically low grade; the most common grade 3/4 toxicities were hematologic. In 22 patients with MRD assessments, all were MRD negative after induction. Six became MRD positive on I-M, with 2 reverting to MRD-negative status with continued I-M, and all maintain radiographic CR with the exception of 1 with disease progression. I-M is feasible in MCL after frontline chemoimmunotherapy with manageable toxicities although significant. Changes in NGS-MRD were noted in limited patients during maintenance with few progression and survival events. This trial was registered at www.clinicaltrials.gov as #NCT02242097.

Phase I study of novel SYK inhibitor TAK-659 (mivavotinib) in combination with R-CHOP for front-line treatment of high-risk diffuse large B-cell lymphoma.

Background: TAK-659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pretreated diffuse large B-cell lymphoma (DLBCL). We report results of a phase I single-institution escalation study of front-line treatment with R-CHOP and TAK-659 in treatment-naïve high-risk DLBCL. Methods: Patients with high-risk DLBCL were treated with R-CHOP for 1 cycle, followed by combined R-CHOP and TAK-659 for an additional five cycles, with TAK-659 dosing escalated from 60 mg, to 80 mg, to 100 mg daily, based on a 3 + 3 design. The primary objective was to determine the safety and establish the maximum tolerated dose (MTD) of TAK-659 in this setting. Results: Twelve patients were enrolled. Dose level 3 (100 mg) was established as the MTD. Dose level 1 (60 mg) maintained a similar area under the curve (AUC) to the MTD. With a median follow-up of 21 months, 92% of patients achieved complete response (CR). The most common treatment-emergent adverse events were lymphopenia (100%), infection (50%, n = 3 opportunistic), aspartate aminotransferase elevation (100%), and alanine aminotransferase elevation (83%). Conclusion: A TAK-659 dose of 60 mg was well tolerated, did not require dose modifications, and maintained a similar AUC to the MTD. The combination of R-CHOP and TAK-659 in patients with newly diagnosed high-risk DLBCL produces promising CR rates.

Spleen tyrosine kinase/FMS-like tyrosine kinase-3 inhibition in relapsed/refractory B-cell lymphoma, including diffuse large B-cell lymphoma: updated data with mivavotinib (TAK-659/CB-659).

We report an updated analysis from a phase I study of the spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 inhibitor mivavotinib, presenting data for the overall cohort of lymphoma patients, and the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; including an expanded cohort not included in the initial report). Patients with relapsed/refractory lymphoma for which no standard treatment was available received mivavotinib 60-120 mg once daily in 28-day cycles until disease progression/unacceptable toxicity. A total of 124 patients with lymphoma, including 89 with DLBCL, were enrolled. Overall response rates (ORR) in response-evaluable patients were 45% (43/95) and 38% (26/69), respectively. Median duration of response was 28.1 months overall and not reached in DLBCL responders. In subgroups with DLBCL of germinal center B-cell (GCB) and non-GCB origin, ORR was 28% (11/40) and 58% (7/12), respectively. Median progression free survival was 2.0 and 1.6 months in the lymphoma and DLBCL cohorts, respectively. Grade ≥3 treatment-emergent adverse events occurred in 96% of all lymphoma patients, many of which were limited to asymptomatic laboratory abnormalities; the most common were increased amylase (29%), neutropenia (27%), and hypophosphatemia (26%). These findings support SYK as a potential therapeutic target for the treatment of patients with B-cell lymphomas, including DLBCL. Trial registration: ClinicalTrials.gov number: NCT02000934.

A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia.

Mivavotinib (TAK-659) is an investigational type 1 tyrosine kinase inhibitor with dual activity against spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 (FLT3). We conducted a phase Ib study to investigate the safety, tolerability, and efficacy of mivavotinib in patients with refractory and/or relapsed (R/R) acute myeloid leukemia (AML). Both daily (QD) and twice daily (BID) dosing regimens were evaluated. A total of 43 patients were enrolled, and there were 5 complete responses (4 with incomplete count recovery). In the QD dosing regimen, the maximum tolerated dose (MTD) was not reached up to 160 mg QD per protocol; 140 mg QD was identified as the recommended phase II dose. In the BID dosing regimen, the MTD was 60 mg BID. Thirty patients (70%) experienced a bleeding event on study; the majority were grades 1 or 2, were resolved without mivavotinib modification, and were not considered related to study treatment. Eleven patients (26%) experienced grade ≥3 bleeding events, which were observed most frequently with the 80 mg BID dose. We conducted platelet aggregation studies to investigate the potential role of mivavotinib-mediated SYK inhibition on platelet function. The bleeding events observed may have been the result of several confounding factors, including AML disease status, associated thrombocytopenia, and high doses of mivavotinib. Overall, these findings indicate that the activity of mivavotinib in R/R AML is modest. Furthermore, any future clinical investigation of this agent should be undertaken with caution, particularly in thrombocytopenic patients, due to the potential bleeding risk of SYK inhibition. ClinicalTrials.gov: NCT02323113.

Phase Ib study of combinations of avadomide (CC-122), CC-223, CC-292, and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma.

There is a need for additional treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122), the selective, ATP-competitive mammalian target of rapamycin kinase inhibitor CC-223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC-292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC-122-DLBCL-001 study (NCT02031419), the dose-escalation portion explored combinations of CC-122, CC-223, and CC-292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose-limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24-84 years), and patients had a median of 3 (range 1-10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any-grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC-122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC-122 plus rituximab was considered suitable for dose expansion, whereas CC-223 and CC-292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC-122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi-arm dose-finding design.

Activity of the Gamma Secretase Inhibitor AL101 in Desmoid Tumors: A Case Report of 2 Adult Cases.

Desmoid tumors (aggressive fibromatosis) are soft tissue mesenchymal tumors that can be locally invasive and life-threatening. Depending on the location, these tumors are often unresectable or tend to recur after surgery. To date, there are no approved systemic therapies for desmoid tumors. These tumors typically harbor mutations in the ß-catenin oncogene CTNNB1 or the tumor suppressor gene adenomatous polyposis coli, resulting in constitutive activation of the WNT pathway. The Notch pathway is part of the underlying cause for desmoid tumor development, possibly due to crosstalk with the WNT pathway, providing a rationale for Notch inhibition as a therapeutic strategy. The gamma secretase activation of the Notch receptor can be targeted with investigational gamma secretase inhibitors. In this case report, we follow the course of 2 patients with desmoid tumors treated with the highly potent, parenterally administered investigational gamma secretase inhibitor AL101, resulting in long-lasting responses. Case 1 reports on a patient with a mesenteric desmoid tumor who participated in a phase 1 trial and then transitioned into a compassionate use program; Case 2 reports on a patient with recurrent pelvic tumors receiving AL101 through a compassionate use program. After tumor progression on other systemic therapies, Cases 1 and 2 had confirmed partial responses (41% and 60% maximal tumor size decrease from baseline) recorded after 1.0 and 1.6 years of treatment with AL101, with a duration of response of 8.6+ and 2.6+ years, respectively. Also, in a phase 1 study of AL102, a potent orally administered gamma secretase inhibitor that shares structural features with AL101, a patient with a desmoid tumor was noted to have tumor shrinkage. Formal clinical testing of AL102 for the treatment of patients with desmoid tumors that are not amenable to surgery or are refractory to/recurrent from other prior therapies is currently underway.

A phase I/II trial of brentuximab vedotin plus rituximab as frontline therapy for patients with immunosuppression-associated CD30+ and/or EBV + lymphomas.

Treatment strategies for post-transplant lymphoproliferative disorders (PTLD) consist of response-adapted risk-stratified methods using immunosuppression reduction, immunotherapy, and chemotherapy. We investigated the efficacy of Brentuximab vedotin given concurrently with Rituximab (BV + R) once weekly for four weeks, followed by optional consolidation, and up to one year of maintenance. Among 20 assessable patients, BV + R therapy resulted in an overall response rate of 75% (95% CI 51 to 91, p = 0.044) with 60% achieving a complete response. Median time to best response was 28 days. Two-year progression-free survival and overall survival rates were 75 and 90%, respectively. Most common severe grade 3/4 treatment-related toxicities included neutropenia (40%), hypertension (30%), infection (25%), and peripheral neuropathy (15%). BV + R is a novel and effective therapeutic strategy that achieved rapid and durable remissions in previously untreated PTLD patients; however, this treatment platform requires further modification due to the high rates of treatment-related toxicity.Key pointsBrentuximab vedotin + Rituximab showed ORR and CR rates of 75 and 60% in patients with immunosuppression-associated lymphoid malignanciesHigh rates of treatment delay were attributed to treatment-related toxicity; further dosing optimization of this regimen is required.

Preoperative Anticoagulation Management in Everyday Clinical Practice: An International Comparative Analysis of Work-as-Done Using the Functional Resonance Analysis Method.

OBJECTIVES: Preoperative anticoagulation management (PAM) is a complex, multidisciplinary process important to patient safety. The Functional Resonance Analysis Method (FRAM) is a novel method to study how complex processes usually go right at the frontline (labeled Safety-II) and how this relates to predefined procedures. This study aimed to assess PAM in everyday practice and explore the usability and utility of FRAM. METHODS: The study was conducted at an Australian and European Cardiothoracic Surgery Department. A FRAM model of work-as-imagined was developed using (inter)national guidelines. Semistructured interviews with 18 involved professionals were used to develop models reflecting work-as-done at both sites, which were presented to staff for validation. Workload in hours was estimated per process step. RESULTS: In both centers, work-as-done differed from work-as-imagined, such as in the division of tasks among disciplines (e.g., nurses/registrars rather than medical specialists), but control mechanisms had been developed locally to ensure safe care (e.g., crosschecking with other clinicians). Centers had organized the process differently, revealing opportunities for improvement regarding patient information and clustering of clinic visits. Presenting FRAM models to staff initiated discussion on improvement of functions in the model that are vital for success. Overall workload was estimated at 47 hours per site. CONCLUSIONS: This FRAM analysis provided insight into PAM from the perspective of frontline clinicians, revealing essential functions, interdependencies and variability, and the relation with guidelines. Future studies are warranted to study the potential of FRAM, such as for guiding improvements in complex systems.

Papillary fibroelastoma presenting with multi-organ symptoms.

Papillary fibroelastomas are a rare cardiac neoplasm typically found on the left side of the heart, and most commonly on the aortic valve, which can present with cardiac or neurologic symptoms. A 51-year-old woman with no cardiac history presented to a resident clinic with complaints of left-sided facial paresthesias and palpitations for 1 month. Echocardiographic imaging showed a mass on the aortic annulus, concerning for a cardiac tumor. Due to the risk of possible embolization, if the tumor was a myxoma, the patient required intrathoracic surgery. During the intrathoracic procedure the mass was confirmed to be a papillary fibroelastoma and the patient had the mass removed without any complications. Papillary fibroelastomas are found in less than 1% of the population but can present clinically with a wide variety of symptoms. Patients with this neoplasm are at risk for severe complications, due to embolization, potentially causing cerebrovascular accidents or myocardial infarctions. We present a case of a papillary fibroelastoma producing both cardiac and neurologic symptoms.

Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma.

PURPOSE: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. PATIENTS AND METHODS: Patients received continuous, once-daily oral TAK-659, 60-120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD. RESULTS: Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast (T max ∼2 hours) with a long terminal half-life (∼37 hours). Exposure generally increased with dose (60-120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). CONCLUSIONS: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.

Survival outcomes of diffuse large B-cell lymphoma by association with concurrent or antecedent follicular lymphoma and double hit status.

Diffuse large B-cell lymphoma (DLBCL) transformed from follicular lymphoma (FL) (tDLBCL) has been traditionally associated with an aggressive course, but more recent studies have shown longer survivals. The clinical significance of concurrent FL at the time of diagnosis of DLBCL (cDLBCL/FL) is less clear. We compared outcomes of tDLBCL, cDLBCL/FL, and de novo DLBCL (dDLBCL) and then evaluated the impact of double hit (DH) rearrangements (MYC with BCL2 and/or BCL6) in these subgroups' outcomes. The progression free survival (PFS) and overall survival (OS) were not significantly different among the three groups (dDLBCL, tDLBCL, and cDLBCL/FL). The effect of DH on survival was then analyzed in two subgroups: (1) dDLBCL and (2) tDLBCL + cDLBCL/FL. PFS and OS were significantly shorter in lymphomas with DH in each of these two subgroups. We conclude that DH status drives outcomes in all DLBCLs, regardless of their transformation status.

Multicentre retrospective study of intravascular large B-cell lymphoma treated at academic institutions within the United States.

Intravascular large B-cell lymphoma (IVLBCL) is a rare entity, with a generally aggressive course that may vary based on geographic presentation. While a United States (US) registry study showed relatively good outcomes with IVLBCL, clinicopathological and treatment data were unavailable. We performed a detailed retrospective review of cases identified at 8 US medical centres, to improve understanding of IVLBCL and inform management. We compiled data retrieved via an Institutional Review Board-approved review of IVLBCL cases identified from 1999 to 2015 at nine academic institutions across the US. We characterized the cohort's clinical status at time of diagnosis, presenting diagnostic and clinical features of the disease, treatment modalities used and overall prognostic data. Our cohort consisted of 54 patients with varying degrees of clinical features. Adjusting for age, better performance status at presentation was associated with increased survival time for the patients diagnosed in vivo (hazard ratio: 2·12, 95% confidence interval 1·28, 3·53). Based on the data we have collected, it would appear that the time interval to diagnosis is a significant contributor to outcomes of patients with IVLBCL.

Survival Outcomes of Younger Patients With Mantle Cell Lymphoma Treated in the Rituximab Era.

PURPOSE: Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger. PATIENTS AND METHODS: We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed. RESULTS: Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2). CONCLUSION: In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.

E. coli endocarditis of the tricuspid valve.

Infective endocarditis (IE) is a focus of infection which effects the endocardium, specifically the heart valves or intra-cardiac devices. A 64-year-old male with gastric carcinoma and no prior cardiac history presented to the emergency room with altered mental status. Initial investigations showed the patient had a leukocytosis with a left shift. Blood cultures taken upon arrival eventually grew Esherichia coli, thought to be from the urinary tract, although initial urinalysis was delayed until after initiation of antibiotics. Electrocardiogram showed sinus bradycardia with frequent premature atrial contractions. Chest X-Ray showed bilateral pleural effusions, which were eventually drained and found to be growing E. coli. Transthoracic echocardiogram was done which showed moderate-sized tricuspid valve vegetation with severe tricuspid regurgitation. IE has been increasing in incidence throughout the years. In prior decades IE was a disease primarily affecting patients with known rheumatic heart disease, prosthetic heart valves, and intravenous drug abusers however more commonly it is becoming healthcare acquired. E. coli is not often seen to be a culprit of IE. We present a rare case of E. coli endocarditis of a native tricuspid valve.

Hemophagocytic Lymphohistiocytosis in Cutaneous T-Cell Lymphoma.

Importance: Hemophagocytic lymphohistiocytosis (HLH) has been reported as a serious complication of cutaneous T-cell lymphoma (CTCL). Despite available diagnostic guidelines, it remains a diagnostic and therapeutic challenge in this patient population. Objectives: To examine the characteristics of CTCL associated with HLH and analyze the presenting signs and symptoms, therapeutic options, and outcome. Design, Setting, and Participants: In this case series, patients diagnosed with CTCL and HLH who were treated at a single institution from January 1, 2014, through December 31, 2017, were studied. Exposures: The HLH-2004 trial criteria, HScore, and various clinical and histopathologic variables were applied to and analyzed in the cohort. Main Outcomes and Measures: Subtype of CTCL, treatment administered for HLH, and patient outcome were assessed. Results: Seven patients (4 men and 3 women; median age, 50 years; range, 34-77 years) were identified from the database and included in the study. Cytotoxic subtypes of CTCL that involve the deep dermis and subcutaneous tissue were most commonly associated with HLH. Four patients met 5 or more HLH-2004 trial criteria, and 5 had an HScore probability greater than 85% at presentation. Common presenting HLH symptoms were fever and malaise. Cyclosporine, polychemotherapy, and systemic corticosteroids were the most common treatments. Patients receiving allogeneic stem cell transplants had the best outcomes, with all 3 of these patients alive and in complete remission. Conclusions and Relevance: Hemophagocytic lymphohistiocytosis is a life-threatening complication of CTCL associated with rare cytotoxic CTCL subtypes that primarily involve the subcutaneous tissue. Because these cases may resemble a granulomatous or infectious condition, the diagnosis and appropriate management are often delayed. The results of this study demonstrate the need for high awareness of HLH in patients with panniculitic lymphomas and indicate that allogeneic stem cell transplantation may be the best option for a sustained remission.

Systematic review and meta-analysis of selected toxicities of approved ALK inhibitors in metastatic non-small cell lung cancer.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the ALK gene or the ROS1 oncogenes. With the recent publication of pivotal trials leading to the approval of these compounds in different indications, their toxicity profile warrants an update. MATERIALS AND METHODS: A systematic literature search was performed in July 2017. Studies evaluating US FDA approved doses of one of the following ALK inhibitors: Crizotinib, Ceritinib, Alectinib or Brigatinib as monotherapy were included. Data were analyzed using random effects meta-analysis for absolute risks (AR), study heterogeneity, publication bias and differences among treatments. RESULTS: Fifteen trials with a total of 2,005 patients with evaluable toxicity data were included in this report. There was significant heterogeneity amongst different studies. The pooled AR of death and severe adverse events were 0.5% and 34.5%, respectively. Grade 3/4 nausea, vomiting, diarrhea, and constipation were uncommon: 2.6%, 2.5%, 2.7%, 1.2%, respectively. CONCLUSIONS: ALK inhibitors have an acceptable safety profile with a low risk of treatment-related deaths. Important differences in toxicity profile were detected amongst the different drugs.

An Extremely Rapid Case of Pneumonitis with the Use of Nivolumab for Pancreatic Adenocarcinoma.

Pancreatic cancer is the fourth most common cancer death in the United States despite comprising a small percentage of the total number of cancer cases. The estimated 5-year overall survival (OS) for patients with distant metastatic disease is approximately 3%. New treatment options are an unmet need and remain an area of active investigation. A 53-year-old male with metastatic pancreatic cancer presented to the hospital with acute-on-chronic respiratory failure approximately 24 hours after receiving a novel therapeutic combination. Chest imaging showed marked changes as concerning for pneumonitis. Infectious workup was negative. The patient had initial clinical improvement after receiving initial intravenous steroids and oxygen support but eventually deteriorated later opting for supportive measures only. With infection ruled out, drug-induced pneumonitis was felt to be the likely cause of the radiologic and clinical changes. The rapidity of onset of symptoms is the aspect being highlighted in this case.

Progression of undiagnosed cutaneous lymphoma after anti-tumor necrosis factor-alpha therapy.

BACKGROUND: Cutaneous lymphoma diagnosed after anti-tumor necrosis factor-α therapy (anti-TNF-α) has been reported in the literature, yet a clear link between both events remains elusive. OBJECTIVE: To review our experience with cutaneous lymphoma diagnosed during or after the use of anti-TNF-α therapies. METHODS: This is a multicenter retrospective study and a literature review. RESULTS: A total of 22 cases, including 20 cutaneous T-cell lymphomas (CTCLs) and 2 cutaneous B-cell lymphomas, were identified. In the CTCL group, 75% of the patients received an anti-TNF-α agent for a presumed inflammatory skin condition. Mycosis fungoides and Sézary syndrome were the most common subtypes of CTCL diagnosed. Advanced disease (stage IIB to IVA) was commonly seen at time of diagnosis and required aggressive therapy, including stem cell transplant in 3 patients; 2 patients in whom cutaneous B-cell lymphomas was diagnosed had an indolent course. A total of 31 cases were gathered from a literature search. LIMITATIONS: This is a retrospective study. CONCLUSIONS: Our findings suggest that the disease of most of the identified patients was misdiagnosed as psoriasis or eczema; therefore, a comprehensive morphologic and molecular review of skin biopsy specimens and peripheral blood samples should be considered before initiation of anti-TNF-α therapy in patients with poorly defined dermatitis or atypical presentations of psoriasis.

A Rare Case of Glioblastoma Multiforme with Osseous Metastases.

Glioblastoma multiforme is the most common malignant primary central nervous system neoplasm in adults. It has a very aggressive natural history with a median overall survival estimated at 14.6 months despite multimodality treatment. Extracranial metastases are very rare with few case reports published to date. We report the case of a 65-year-old male who underwent maximal safe resection for a newly diagnosed brain mass after presentation with new neurologic symptoms. He then received standard postsurgical adjuvant treatment for glioblastoma. Subsequently, he underwent another resection for early progressive disease. Several months later, he was hospitalized for new-onset musculoskeletal complaints. Additional investigation revealed new metastatic osseous lesions which were initially felt to be a new malignancy. The patient opted for supportive care and died 12 days later. Despite choosing no treatment, he elected to undergo a bone biopsy to understand the new underlying process. Results were that of metastatic GBM and were reported after the patient expired. Physicians caring for patients with GBM and new nonneurologic symptoms may contemplate body imaging.