Tandem high-dose influenza vaccination is associated with more durable serologic immunity in patients with plasma cell dyscrasias.

Patients with plasma cell dyscrasias (PCDs) experience an increased burden of influenza, and current practice of single-dose annual influenza vaccination yields suboptimal protective immunity in these patients. Strategies to improve immunity to influenza in these patients are clearly needed. We performed a randomized, double-blind, placebo-controlled clinical trial comparing tandem Fluzone High-Dose influenza vaccination with standard-of-care influenza vaccination. Standard-of-care vaccination was single-dose age-based vaccination (standard dose, <65 years; high dose, ≥65 years), and patients in this arm received a saline placebo injection at 30 days. A total of 122 PCD patients were enrolled; 47 received single-dose standard-of-care vaccination, and 75 received 2 doses of Fluzone High-Dose vaccine. Rates of hemagglutinin inhibition (HAI) titer seroprotection against all 3 strains (H1N1, H3N2, and influenza B) were significantly higher for patients after tandem high-dose vaccination vs control (87.3% vs 63.2%; P = .003) and led to higher seroprotection at the end of flu season (60.0% vs 31.6%; P = .04). These data demonstrate that tandem high-dose influenza vaccination separated by 30 days leads to higher serologic HAI titer responses and more durable influenza-specific immunity in PCD patients. Similar vaccine strategies may also be essential to achieve protective immunity against other emerging pathogens such as novel coronavirus in these patients. This trial was registered at www.clinicaltrials.gov as #NCT02566265.

Clinical and Serologic Responses After a Two-dose Series of High-dose Influenza Vaccine in Plasma Cell Disorders: A Prospective, Single-arm Trial.

BACKGROUND: Patients with multiple myeloma (MM) and other plasma cell disorders are highly susceptible to influenza infections, which are major causes of morbidity in this population, despite the routine administration of a seasonal influenza vaccination. Existing data are limited by small and retrospective studies, which suggest poor seroprotection rates of < 20% after standard influenza vaccination in patients with MM. PATIENTS AND METHODS: Patients with plasma cell dyscrasia (n = 51) were treated with a 2-dose series of high-dose inactivated trivalent influenza vaccine during the 2014 to 2015 influenza season. Laboratory-confirmed influenza infections were identified through seasonal surveillance, sera were collected for influenza hemagglutination antibody inhibition (HAI) titer assays, and logistic regression models were used to identify the clinical correlates to the HAI serologic responses. RESULTS: Influenza vaccine was well tolerated, without any vaccine-related grade ≥ 2 adverse events. Only 3 patients (6%) experienced laboratory-confirmed influenza. The rates of HAI seroprotection against all 3 vaccine strains (A/California/7/2009 [H1N1] pdm09-like virus; A/Texas/50/2012 [H3N2]-like virus; and a B/Massachusetts/2/2012-like virus) increased from 4% at baseline to 49% and 65% after 1 and 2 doses, respectively. The risk factors associated with a lower likelihood of HAI serologic response included plasma cell disorder requiring therapy, less than a partial response found on disease response assessment, and active conventional chemotherapy. Alternatively, active therapy with an immunomodulatory drug alone or with a proteasome inhibitor was associated with a greater likelihood of an HAI serologic response. CONCLUSION: These data have demonstrated that, in contrast to the historically poor results with standard influenza vaccination, this novel high-dose booster vaccination strategy leads to high rates of seroprotection. Randomized controlled studies are needed to compare this novel strategy to the standard vaccination strategy.

Clinical evaluation of compounds targeting PD-1/PD-L1 pathway for cancer immunotherapy.

Significant enthusiasm currently exists for new immunotherapeutic strategies: blocking the interaction between programmed death-1 receptor on T-cells and programmed death-ligand 1 on tumor cells to boost immune system stimulation to fight cancer. Immunomodulation with the antiprogrammed death-1/programmed death-ligand 1 monoclonal antibodies has shown to mediate tumor shrinkage and extend overall survival from several pivotal phase I/II studies in melanoma, renal cell carcinoma, and non-small cell lung cancer. This has prompted multiple large ongoing phase III trials with the expectation for fast-track FDA approvals to satisfy unmet medical needs. Compounds targeting the programmed death-1 pathway that are in clinical trials fall into two major categories, namely antiprogrammed death-1 antibodies: Nivolumab, MK-3475, and pidilizumab; and antiprogrammed death-ligand 1 antibodies: MPDL3280A, BMS-936559, MEDI4736, and MSB0010718C. We reviewed the clinical efficacy and safety of each compound based upon major registered clinical trials and published clinical data. Overall, response rate of more than 20% is consistently seen across all these trials, with maximal response of approximately 50% achieved by certain single antiprogrammed death-1 agents or when used in combination with cytotoxic T-lymphocyte antigen-4 blockade. The responses seen are early, durable, and have continued after treatment discontinuation. Immune-related adverse events are the most common side effects seen in these clinical trials. Overall, the skin and gastrointestinal tract are the most common organ systems affected by these compounds while hepatic, endocrine, and neurologic events are less frequent. These side effects are low grade, manageable, and typically resolve within a relatively short time frame with a predictable resolution pattern given proper management. We therefore propose detailed guidelines for management of major immune-related adverse events that are anticipated with antiprogrammed death-1/programmed death-ligand 1 therapies based on general experience with other monoclonal antibodies and the established management algorithms for immune-related adverse events for cytotoxic T-lymphocyte antigen-4 blockade with ipilimumab. We anticipate that the antiprogrammed death-1 strategy will become a viable and crucial clinical strategy for cancer therapy.

Successful desensitization to oxaliplatin with incorporation of calcium gluconate and magnesium sulfate.

Since the results of the MOSAIC trial demonstrated an improved disease-free survival in stage III colorectal patients treated with oxaliplatin combined with 5-fluorouracil and folinic acid when they were compared with those treated with 5-fluorouracil and folinic acid alone, the addition of this organoplatin to 5-fluorouracil and folinic acid has become first-line adjuvant treatment for stage III colorectal cancer. Unfortunately, there is a small population of patients who develop grade III/IV hypersensitivity reactions to oxaliplatin which, until recently, have interfered with further treatment with oxaliplatin-containing regimens. Successful oxaliplatin desensitization protocols for patients having severe oxaliplatin hypersensitivity reactions have been reported. However, none of these protocols, have incorporated magnesium and calcium salts. Retrospective data has suggested that pretreating colorectal cancer patients with magnesium sulfate and calcium gluconate before the administration of oxaliplatin may reduce the incidence of neurotoxicities induced by this drug. Therefore, we modified a previously published oxaliplatin-desensitization protocol by incorporating intravenous calcium gluconate and magnesium sulfate, and report a patient with stage IIIc colorectal cancer and prior severe hypersensitivity reactions to oxaliplatin who underwent successful oxaliplatin desensitization using this protocol.

Readministration of high-dose methotrexate in a patient with suspected immediate hypersensitivity and T-cell acute lymphoblastic lymphoma.

There is a paucity of literature addressing the management of methotrexate (MTX) hypersensitivity. We developed a high-dose MTX readministration protocol based on a modified, prolonged carboplatin desensitization protocol. Over 1.5 hours, 1/1000 of the total intravenous dose was administered followed by 1/100 over 1.5 hours, 1/10 over 6 hours, and the rest of the full dose over 24 hours. MTX readministration was successfully tolerated on three occasions in a 17-year-old male patient with T-cell acute lymphoblastic lymphoma and a history of urticarial reactions to MTX. This high-dose MTX readministration protocol may be valuable for treating patients with T-cell acute lymphoblastic lymphoma and suspected immediate MTX hypersensitivity.