A multicenter review of infusion-related reactions to daratumumab for relapsed multiple myeloma in the real world setting.

BACKGROUND: Daratumumab is used in the treatment of relapsed multiple myeloma. Daratumumab infusion-related reactions can occur with the highest incidence on the first infusion. METHODS: A retrospective review of all daratumumab infusions used as part of the DVd and DRd regimens for relapsed multiple myeloma was undertaken. The review of infusion-related reactions was conducted by reviewing the treatment room nursing note on the days that daratumumab was administered. If the patient experienced an infusion-related reaction, then the data captured included if the full dose was administered. RESULTS: Daratumumab infusion-related reactions occurred most frequently on the first dose. The rates of infusion-related reactions using a split dose approach for daratumumab administration were lower than that reported in clinical trials. All of the infusion-related reactions were managed with appropriate interventions in the outpatient setting. The adoption of rapid infusion daratumumab beginning with cycle 2 of DVd and DRd was well tolerated. CONCLUSIONS: Our experience of daratumumab infusions using a split dose approach was associated with an infusion-related reaction rate in 28% of patients on cycle 1, day 1 of DVd and DRd regimens. All patients were able to complete full doses of daratumumab by utilizing split dose. The rates of daratumumab infusion-related reactions are highest on the first infusion. In addition, our adoption of rapid infusion daratumumab was safe.

Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism.

BACKGROUND: Long-term low-molecular-weight heparin (LMWH) is the current standard for treatment of venous thromboembolism (VTE) in cancer patients. Whether treatment strategies should vary according to individual risk of VTE recurrence remains unknown. We performed a retrospective cohort study and a validation study in patients with cancer-associated VTE to derive a clinical prediction rule that stratifies VTE recurrence risk. METHODS AND RESULTS: The cohort study of 543 patients determined the model with the best classification performance included 4 independent predictors (sex, primary tumor site, stage, and prior VTE) with 100% sensitivity, a wide separation of recurrence rates, 98.1% negative predictive value, and a negative likelihood ratio of 0.16. In this model, the score sum ranged between -3 and 3 score points. Patients with a score ≤ 0 had low risk (≤ 4.5%) for recurrence and patients with a score >1 had a high risk (≥ 19%) for VTE recurrence. Subsequently, we applied and validated the rule in an independent set of 819 patients from 2 randomized, controlled trials comparing low-molecular-weight heparin to coumarin treatment in cancer patients. CONCLUSIONS: By identifying VTE recurrence risk in cancer patients with VTE, we may be able to tailor treatment, improving clinical outcomes while minimizing costs.

Risk of recurrent venous thromboembolism according to malignancy characteristics in patients with cancer-associated thrombosis: a systematic review of observational and intervention studies.

Patients with cancer-associated venous thromboembolism (VTE) should be treated with low molecular weight heparin. The ideal duration of anticoagulation in this population is unknown. It is important to evaluate whether there is variation in susceptibility for recurrent VTE according to malignancy characteristics. In this systematic review we sought to evaluate cancer characteristics that may influence the risk for VTE recurrence and the success of anticoagulation in patients with cancer-associated VTE. A systematic literature search strategy identified potential studies on MEDLINE, Embase, the Cochrane Register of Controlled Trials, MEDLINE In-Process and other nonindexed citations using the Ovid interface. There was no restriction to study design or language. No randomized controlled trials fulfilled our inclusion criteria. We included four retrospective and six prospective studies. VTE recurrence rate according to tumour stage suggested an increased risk for patients with metastatic malignancy compared with patients with localized disease (relative risk 1.36; 95% confidence interval 1.06-1.74, P = 0.01). We were unable to pool data to evaluate VTE recurrence according to tumour site and histology. The isolated evaluation of the included studies suggested that younger patients with adenocarcinoma, lung or gastrointestinal malignancy have the highest risk. There is paucity of data regarding detailed malignancy characteristics in patients with cancer-associated VTE. It appears that metastatic malignancy, or adenocarcinoma, or lung malignancy confers a higher risk of VTE recurrence than patients with localized malignancy, nonadenocarcinoma or breast cancer.

Cytotoxicity of enantiomers of gossypol Schiff's bases and optical stability of gossypolone.

Optical Schiff's bases of gossypol were prepared with chiral gossypol and ethylamine. As has been similarly observed among the gossypol enantiomers, the (-)-gossypol ethylimine was more active than either the (+)-gossypol ethylimine or the racemic gossypol ethylimine against KB and MCF7 cells. Gossypolone was also observed to be more toxic than gossypol against both cell lines. All of the gossypol products tested showed comparable toxicity toward MCF7/ADR (adriblastine-resistant) cells. Attempts at producing chiral gossypolone from chiral gossypol failed because of rapid racemization. In addition, the Schiff's base derivatives of gossypolone formed with R-(+)-2-amino-3-phenyl-1-propanol could only be separated at reduced temperature, indicating that gossypolone Schiff's bases are less optical stable than gossypol Schiff's bases.

New thioderivatives of gossypol and gossypolone, as prodrugs of cytotoxic agents.

New dithiane or dithiolane derivatives of gossypol and gossypolone were synthesized with dithiolethane or dithiolpropane in the presence of BF(3)/Et(2)O. These thioderivatives exhibited low toxicity on KB cells (human epidermoid carcinoma cells of the mouth). They react easily with electrophiles in aprotic solvents to regenerate gossypolone or to form dehydrogossypoldithianes and dehydrogossypoldithiolanes, which display higher toxicity on KB cells. In addition, the low toxicity of gossypol thioderivatives was reversed by nitric oxide donors in physiological media. These experiments suggest that gossypol and gossypolone dithianes and dithiolanes can be used as prodrugs that target tumor cells surrounded by high concentrations of nitric oxide.