Anca Prica

Safety and efficacy of thrombopoietin-receptor agonists in myelodysplastic syndromes: a systematic review and meta-analysis of randomized controlled trials

Thrombocytopenia is common (40–65%) and potentially serious in myelodysplastic syndromes (MDS). A systematic review was conducted to determine the safety and efficacy of adding a thrombopoietin‐receptor (THPO‐R) agonist to standard MDS treatment. MEDLINE, EMBASE and CENTRAL databases were searched. We included randomized controlled trials comparing a THPO‐R agonist to placebo. A meta‐analysis of the effects was performed. Endpoints included bleeding and platelet transfusion rates, risk of progression to acute myeloid leukaemia (AML) and mortality. Three hundred and eighty four patients from five trials were included, four using romiplostim and one using eltrombopag. Overall, the relative risk (RR) of bleeding with romiplostim versus placebo was 0·84 [95% confidence interval (CI): 0·57–1·24]. However, compared to placebo, romiplostim significantly decreased the exposure‐adjusted bleeding rate (RR 0·92; 95% CI: 0·86–0·99), as well as the exposure‐adjusted platelet transfusion rate (RR 0·69; 95% CI: 0·53–0·88). The RR of AML progression with romiplostim was 1·36 (95% CI: 0·54–3·40), however the outcome data were judged as higher risk of bias. Romiplostim is promising in its ability to decrease patient‐important outcomes: bleeding and platelet transfusion need. Although the risk of AML progression was not increased, due to unclear risk of bias in the data, this safety concern is difficult to assess. Therefore, romiplostim cannot yet be routinely recommended. Early eltrombopag data is promising.

Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1–2 trial

BACKGROUND Brentuximab vedotin is currently approved for patients with relapsed or refractory Hodgkins lymphoma who previously received an autologous stem cell transplant or two previous multiagent chemotherapy regimens, and for patients with relapsed or refractory systemic anaplastic large-T-cell lymphoma who previously received at least one chemotherapy regimen. A high proportion of patients with CD30-expressing relapsed or refractory lymphomas have durable responses to single-agent brentuximab vedotin and show longer progression-free survival than do patients treated with chemotherapy. In patients with Hodgkins lymphoma and peripheral T-cell lymphoma, treatment with bendamustine alone only achieves modest improvements in progression-free survival compared with that for chemotherapy. The objective of this study was to explore the safety and clinical activity of the combination of brentuximab vedotin plus bendamustine in heavily pretreated patients with relapsed or refractory Hodgkins lymphoma and anaplastic large-T-cell lymphoma. METHODS In this international, multicentre, single-arm, phase 1-2 trial, eligible patients were aged 18 years or older, had histologically confirmed relapsed or refractory Hodgkins lymphoma or anaplastic large-T-cell lymphoma, had biopsy-proven CD30-positive tumours, had an Eastern Cooperative Oncology Group performance status of 2 or less, and received at least one previous multiagent chemotherapy regimen. In phase 1, patients were assigned following a 3+3 dose-escalation design to one of four cohorts to receive one dose of either 1·2 mg/kg or 1·8 mg/kg of brentuximab vedotin intravenously on day 1 of a 21 day cycle, plus one dose of bendamustine (70 mg/m2, 80 mg/m2, or 90 mg/m2) on days 1 and 2 of the treatment cycle. In phase 2, all patients were assigned to receive brentuximab vedotin plus bendamustine at the recommended phase 2 dose from phase 1. The primary endpoints were maximum tolerated dose and dose-limiting toxicity for phase 1, and the proportion of patients achieving an overall response in phase 2. For both phases 1 and 2, all patients receiving at least one dose of study drug were evaluable for toxicity and all patients completing at least one cycle of therapy were evaluable for response. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01657331. FINDINGS Between July 26, 2012, and May 31, 2017, we enrolled and assigned 65 patients to treatment (64 [98%] with Hodgkins lymphoma and one [2%] with anaplastic large-T-cell lymphoma; 28 [43%] during phase 1 and 37 [57%] during phase 2). In the phase 1 part, the maximum tolerated dose of the combination was not reached. Dose-limiting toxicities were observed in three (11%) of 28 patients, including grade 4 neutropenia at 1·8 mg/kg brentuximab vedotin plus 80 mg/m2 of bendamustine in two (7%) patients and diffuse rash at 1·2 mg/kg brentuximab vedotin plus 70 mg/m2 of bendamustine in one (4%) patient. The recommended phase 2 dose was deemed to be 1·8 mg/kg of brentuximab vedotin and 90 mg/m2 of bendamustine, which are the standard doses of the drugs when given as single agents. In the phase 2 part, an overall response was achieved in 29 (78% [95% CI 62-91]) of 37 patients. Serious adverse events included grade 3 lung infection in five (14%) of 37 patients in the phase 2, and grade 3-4 neutropenia in 16 (25%) of 65 patients across phases 1 and 2. There were no treatment-related deaths. INTERPRETATION This study shows that brentuximab vedotin plus bendamustine, with a favourable safety profile, is an active salvage regimen for heavily pretreated patients with relapsed or refractory Hodgkins lymphoma. This salvage regimen can potentially serve as an efficacious and safe alternative to platinum-based chemotherapy before autologous stem cell transplant. FUNDING Seattle Genetics, Lymphoma Research Fund of Columbia University and National Center for Advancing Translational Sciences, and National Institutes of Health.

Frontline rituximab monotherapy induction versus a watch and wait approach for asymptomatic advanced-stage follicular lymphoma: A cost-effectiveness analysis.

A watch and wait (WW) strategy is the standard of care for patients with asymptomatic advanced‐stage follicular lymphoma. Recent data have demonstrated an improvement in the time to progression with rituximab induction (RI) with or without rituximab maintenance (RM) in comparison with a WW strategy wait in such patients. It remains unclear whether this is a cost‐effective strategy.

Pyoderma gangrenosum secondary to azacitidine in myelodysplastic syndrome.

A 66-year-old female was diagnosed with myelodysplastic syndrome (MDS), specifically refractory cytopenia with multilineage dysplasia. Her bone marrow demonstrated 3% blasts with a complex karyotype and she had transfusion-dependent anaemia and thrombocytopenia. She was started on azacitidine for very high-risk MDS, as determined by her Revised International Prognostic Scoring System score. The first cycle of azacitidine was well tolerated. Three days into her second cycle, multiple erythematous, painful pustular plaques with a violaceous border and central haemorrhagic crusting appeared on her lips, inner nose and upper arms (top). Empirical ciprofloxacin and clindamycin had no clinical benefit and the lesions then progressed to involve her forearms, with three dominant lesions 3–4 cm in diameter. A skin biopsy demonstrated a neutrophilic infiltrate with marked acute inflammation and reactive changes (bottom); microbiological studies were negative. The clinical and pathological presentation was in keeping with pyoderma gangrenosum (PG). She was treated with prednisone and colchicine, and the azacitidine was withheld for 2 months with subsequent healing of the lesions. The forearm lesions recurred when re-challenged with azacitidine, but promptly responded to a second course of prednisone. Neutrophilic dermatoses, including Sweet syndrome and PG, are uncommon but well-documented dermatological sequalae of MDS. However, given the recurrence of skin lesions with therapy, the clinical and pathological picture was most in keeping with PG secondary to azacitidine, rather than to the underlying disease. PG in MDS has also been linked to the administration of granulocyte colony-stimulating factor. While our patient’s skin lesions were controlled with concurrent colchicine and corticosteroids, her MDS did not improve with azacitidine and as a result, this drug was stopped after five cycles. Eric Tseng, Raed Alhusayen, Shachar Sade, Rena Buckstein and Anca Prica Sunnybrook Health Sciences Centre, University of Toronto, and Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. E-mail: anca.prica@uhn.ca images in haematology

Emerging therapies for the treatment of relapsed or refractory follicular lymphoma

With no treatment standard having been established for relapsed and refractory follicular lymphoma, a number of therapeutic approaches are used in Canada. In patients who relapse early or who eventually become resistant to subsequent treatment, prognosis is poor, and new approaches are needed. A number of novel therapies are being examined in this setting, including monoclonal antibodies, immunoconjugates, immunomodulatory agents, and signal transduction inhibitors. With the body of evidence for those emerging therapies accumulating and the standard upfront treatment changing from rituximab and chop (cyclophosphamide-doxorubicin-vincristine-prednisone) or rituximab and cvp (cyclophosphamide-vincristine-prednisone) to bendamustine and rituximab, treatment decisions in the relapsed and refractory setting have become more complex. The choice of subsequent treatment must consider type of upfront treatment; duration of remission; and patient-related factors such as age, comorbidities, and treatment preferences. This paper summarizes the evidence for novel therapies and proposes recommendations for subsequent treatment options by remission duration after induction and maintenance.

Financial Impact of Cancer Drug Wastage and Potential Cost Savings From Mitigation Strategies

PURPOSE Cancer drug wastage occurs when a parenteral drug within a fixed vial is not administered fully to a patient. This study investigated the extent of drug wastage, the financial impact on the hospital budget, and the cost savings associated with current mitigation strategies. METHODS We conducted a cross-sectional study in three University of Toronto-affiliated hospitals of various sizes. We recorded the actual amount of drug wasted over a 2-week period while using current mitigation strategies. Single-dose vial cancer drugs with the highest wastage potentials were identified (14 drugs). To calculate the hypothetical drug wastage with no mitigation strategies, we determined how many vials of drugs would be needed to fill a single prescription. RESULTS The total drug costs over the 2 weeks ranged from

Rapidity and quality of response to steroid-based induction therapy, without the addition of novel agents, does not affect post transplant outcomes in multiple myeloma.

50,257 to

Significance of treatment response when managing patients with primary central nervous system lymphoma

716,983 in the three institutions. With existing mitigation strategies, the actual drug wastage over the 2 weeks ranged from

Single-center Experience in Treating Patients With t(4;14) Multiple Myeloma With and Without Planned Frontline Autologous Stem Cell Transplantation

928 to

Fertility preservation in post-pubescent female cancer patients: A practical guideline for clinicians

5,472, which was approximately 1% to 2% of the total drug costs. In the hypothetical model with no mitigation strategies implemented, the projected drug cost wastage would have been