Frontline brentuximab vedotin in combination with dacarbazine or bendamustine in patients aged ≥60 years with HL.

Patients aged ≥60 years with treatment-naive Hodgkin lymphoma (HL) have few treatment options and inferior survival due to treatment-related toxicities and comorbidities. This phase 2, nonrandomized, open-label study evaluated brentuximab vedotin (BV) monotherapy (results previously reported), BV plus dacarbazine (DTIC), and BV plus bendamustine. Patients had classical HL and were ineligible for or declined frontline chemotherapy. Twenty-two patients received 1.8 mg/kg BV and 375 mg/m2 DTIC for up to 12 cycles, and 20 more patients received 1.8 mg/kg BV plus 90 or 70 mg/m2 bendamustine for up to 6 cycles (dose reduced due to toxicity). Subsequent BV monotherapy was allowed. Approximately 30 patients were to receive BV plus bendamustine; however, the incidence of serious adverse events (65%) and 2 deaths on study led to discontinuation of bendamustine and cessation of enrollment. Most patients had stage III/IV disease, and approximately half had ≥3 comorbidities or were impaired in ≥1 aspect that significantly interfered with quality of life. For BV plus DTIC, the objective response rate (ORR) was 100% and the complete remission (CR) rate was 62%. To date, the median progression-free survival (PFS) is 17.9 months. For BV plus bendamustine, the ORR was 100% and the CR rate was 88%. Neither the median PFS nor overall survival was reached. For elderly patients with HL, BV plus DTIC may be a frontline option based on tolerability and response duration. Despite activity, BV plus bendamustine is not a tolerable regimen in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older.

Outcomes in older patients with Hodgkin lymphoma (HL) tend to be poor following conventional chemotherapy regimens. Treatment-related toxicity is significant and comorbidities often limit therapeutic options. This phase 2, open-label study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, as frontline therapy in 27 HL patients aged ≥60 years. The objective response rate (ORR) was 92%, with 73% achieving complete remission. All patients achieved stable disease or better, and had decreased tumor volume following treatment. At the time of this analysis, the median duration of objective response for efficacy-evaluable patients (N = 26) was 9.1 months (range, 2.8 to 20.9+ months), median progression-free survival was 10.5 months (range, 2.6+ to 22.3+ months), and median overall survival had not been reached (range, 4.6+ to 24.9+ months). The observed adverse events (AEs) were generally consistent with the known safety profile of brentuximab vedotin. The most common AEs were peripheral sensory neuropathy (78%), fatigue (44%), and nausea (44%), and were ≤ grade 2 for most patients. The incidence of grade 3 peripheral neuropathy events was relatively high (30% overall), particularly among patients with the known risk factors of diabetes and/or hypothyroidism (46% vs 14% for those without). However, these risk factors were not associated with delayed time to resolution/improvement of peripheral neuropathy. Preliminary data showed no substantial age-related changes in brentuximab vedotin pharmacokinetics. Brentuximab vedotin monotherapy may provide a frontline treatment option for older patients who cannot tolerate conventional combination chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

Phase I/IIa study of sequential chemotherapy regimen of bendamustine/irinotecan followed by etoposide/carboplatin in untreated patients with extensive disease small cell lung cancer (EDSCLC).

PURPOSE: The sequence bendamustine (B) + Irinotecan (I) followed by etoposide (E) + carboplatin (C) was hypothesized to increase progression-free survival (PFS) and overall survival (OS) in untreated extensive-disease small cell lung cancer (EDSCLC) patients compared to historical controls by exploiting mitotic catastrophe. Absent expression of ERCC-1 and expression of topoisomerases were hypothesized to be predictive for PFS and OS. METHODS: This was a phase I/IIa trial in 30 patients to determine the maximum tolerated dose (MTD) of B + I and the PFS of B + I E + C with secondary end points including overall response rate (ORR) and OS. Biomarkers measured by immunohistochemistry (IHC) obtained from diagnostic specimens were correlated with outcome. RESULTS: The MTD of B + I was not reached. During treatment with B + I, there were two grade 5 toxicities from neutropenic sepsis and metabolic encephalopathy. Other toxicities included fatigue, nausea/vomiting, diarrhea, and weight loss. For the sequence, the PFS and OS were 6.0 months and 10 months, respectively. The ORR for B + I and the sequence were 82% and 83%, respectively. Topoisomerase-2 expression was predictive for TTP and OS, but absent ERCC-1 expression was not, contrary to our hypothesis. CONCLUSIONS: B + I is an active regimen in EDSCLC. Toxicities included two grade 5 events but were otherwise manageable. The novel sequence B + I E + C increased PFS and OS compared to historical controls. Correlative studies are conflicting regarding the mechanism of action of this novel sequence.

Cushing's syndrome due to ectopic adrenocorticotrophic hormone production by olfactory neuroblastoma.

OBJECTIVE: To review a case of olfactory neuroblastoma (ON) with Cushing's syndrome (CS) due to ectopic production of adrenocorticotrophic hormone (ACTH) and compare the histopathologic diagnosis, treatment modality, and prognostic factors with the literature. METHODS: We report the clinical presentation, biochemistry, imaging, histopathology, treatment, and outcome of a patient with ON. We conducted an English language literature review of CS due to ectopic ACTH production and ON. RESULTS: CS due to ectopic ACTH production is uncommon, and CS due to ON is extremely rare. A 19-year-old Hispanic man presented with right nasal obstruction, involuntary weight gain, and intensely pruritic skin rash. Examination revealed large, wide purple striae on both arms and the abdomen. Head magnetic resonance imaging (MRI) revealed a right ethmoid sinus enhancing mass extending into the orbit, nasal cavity, and maxillary and sphenoid sinuses. Laboratory results showed a pm cortisol level of 26 mcg/dL, a 24-hour urinary free cortisol level of 7,507 mcg, an ACTH level of 83 pg/mL, and nonsuppression of cortisol with an overnight dexamethasone suppression test (1 and 8 mg). A biopsy revealed ON, and immunohistochemistry (IHC) was positive for ACTH. He underwent chemotherapy followed by surgical debulking and adjuvant radiation therapy, with no disease recurrence through the last follow-up in February 2012. Plasma and urinary cortisol levels normalized following surgery. CONCLUSION: This is the first case reported of a Hispanic male with an uncommon tumor (ON) and an even more uncommon presentation, ectopic ACTH production causing CS. The extremely high ACTH levels and plasma and urine cortisol levels dramatically dropped following multimodality management. So far, he has had 2.5 years of disease-free survival.

Hematologic outcomes of myelodysplastic syndromes treatment with hypomethylating agents in community practice.

INTRODUCTION: Hypomethylating agents (HMAs) treat myelodysplastic syndromes (MDS) through suppression of abnormal clones that may cause low hemoglobin (Hgb), platelet (PLT) deficiencies, and reduced absolute neutrophil count (ANC). Our study examined hematologic outcomes in MDS among patients treated with HMAs in a large community hematology-oncology practice. MATERIALS AND METHODS: A retrospective study using electronic medical record data studied patients who received at least one cycle of a single HMA (decitabine [DAC] or azacitidine [AZA]) for MDS from June 1, 2006, to May 31, 2009, who had pretreatment and end-of-treatment Hgb, PLT counts, and ANC available. Multivariate logistic regression assessed predictors of end-of-treatment response (Hgb ≥ 11 g/dL without transfusion or erythrocyte stimulating agent; PLT ≥ 100,000 cells/µL without transfusion; ANC ≥ 1000 cells/mm(3) without colony stimulating factor) adjusting for baseline laboratory values, age, gender, and comorbidities. HMA choice was studied as a predictor of outcome. RESULTS: A total of 137 patients (mean age, 72.2 years; 57% male) met full inclusion criteria (DAC = 84, AZA = 53). Mean number of cycles was four (range, 1-16 cycles) for DAC and five (range, 1-23 cycles) for AZA. Total number of cycles significantly predicted Hgb, PLT, and ANC response (odds ratio [OR] 1.19, P = .029; OR 1.15, P = .031; OR 1.16, P = .047, respectively). Growth factor use at any point during HMA treatment was negatively associated with Hgb and ANC response (OR 0.85, P = .007; OR 0.96, P = .046). There was no difference between treatments in likelihood of PLT or ANC response. CONCLUSIONS: Patients treated with HMAs for MDS are more likely to achieve hematologic response when treated with a greater number of cycles.