Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome.

Treatment results of AML in elderly patients are unsatisfactory. In an open label randomized phase II study, we investigated whether addition of the XPO1 inhibitor selinexor to intensive chemotherapy would improve outcome in this population. 102 AML patients > 65 years of age (median 69 (65-80)) were randomly assigned to standard chemotherapy (3 + 7) with or without oral selinexor 60 mg twice weekly (both arms n = 51), days 1-24. In the second cycle, cytarabine 1000 mg/m2 twice daily, days 1-6 with or without selinexor was given. CR/CRi rates were significantly higher in the control arm than in the investigational arm (80% (95% C.I. 69-91%) vs. 59% (45-72%; p = 0.018), respectively). At 18 months, event-free survival was 45% for the control arm versus 26% for the investigational arm (Cox-p = 0.012) and overall survival 58% vs. 33%, respectively (p = 0.009). AML and infectious complications accounted for an increased death rate in the investigational arm. Irrespective of treatment, MRD status after two cycles appeared to be correlated with survival. We conclude that the addition of selinexor to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients. (Netherlands Trial Registry number NL5748 (NTR5902), www.trialregister.nl ).

Capecitabine, epirubicin and cisplatin in the treatment of oesophagogastric adenocarcinoma.

BACKGROUND: Inoperable or metastatic oesophagogastric adenocarcinoma has a poor prognosis. From the many different chemotherapeutic regimens used in the past, a combination of epirubicin, cisplatin and continuous 5-fluorouracil infusion (ECF) showed a consistent response rate of +/- 50% with acceptable toxicity. Continuous 5-FU infusion may be replaced by oral fluoropyrimidines. Here we evaluate treatment with epirubicin and cisplatin combined with oral capecitabine (ECC), replacing intravenous 5-FU infusion. METHODS: Retrospectively, we analysed 23 consecutive patients who were treated with epirubicin, cisplatin and oral capecitabine for inoperable or metastatic oesophagogastric adenocarcinoma during 2002 and 2003. RESULTS: The overall response rate was 57%; another 26% achieved stable disease and only 17% had progressive disease. The median duration of response was 6.4 months; the median survival was 9.0 months. Previously treated patients (n=10) had a significantly worse overall response rate (20%) compared with previously untreated patients (85%). A nonsignificant difference in median survival was found between these groups (3.9 vs 9.8 months in previously treated vs untreated patients). An acceptable incidence of grade 3 and 4 toxicity was found. CONCLUSION: Capecitabine in combination with epirubicin and cisplatin is an effective and safe alternative to ECF, without the risks of a continuous venous access.

Successful treatment of fulminant postoperative bleeding due to acquired haemophilia.

Acquired haemophilia is a rare but life-threatening phenomenon in patients who have undergone surgical treatment. We describe a patient with a history of pancreatic cancer and a conventional pancreaticoduodenectomy, who underwent elective resection of an enterocutaneous fistula, complicated by fulminant haemorrhagic shock, caused by acquired haemophilia A. Eventually, the bleeding was controlled by a combination of aggressive haemostatic and immunosuppressive therapy. Prompt diagnosis of acquired haemophilia is crucial to allow early and appropriate haemostatic treatment and reduce the period of increased bleeding risk by eradicating the inhibitor with immunosuppressive therapy.

Intensified chemotherapy inspired by a pediatric regimen combined with allogeneic transplantation in adult patients with acute lymphoblastic leukemia up to the age of 40.

Event-free survival (EFS) at 5 years in pediatric acute lymphoblastic leukemia (ALL) is >80%. Outcome in adult ALL is still unsatisfactory, which is due to less cumulative dosing of chemotherapy and less strict adherence to timing of successive cycles. In the present phase II trial, we evaluated a pediatric regimen in adult patients with ALL under the age of 40. Treatment was according to the pediatric FRALLE approach for high-risk ALL patients and characterized by increased dosages of asparaginase, steroids, methotrexate and vincristin. However, allogeneic stem cell transplantation was offered to standard risk patients with a sibling donor and to all high-risk patients in contrast to the pediatric protocol. Feasibility was defined by achieving complete remission (CR) and completion of treatment within a strict timeframe in at least 60% of patients. In all, 54 patients were included with a median age of 26. CR was achieved in 49 patients (91%), of whom 33 completed treatment as scheduled (61%). Side effects primarily consisted of infections and occurred in 40% of patients. With a median follow-up of 32 months, EFS estimated 66% at 24 months and overall survival 72%. These data show that a dose-intensive pediatric regimen is feasible in adult ALL patients up to the age of 40.