Summary Background Cord-blood transplants are associated with delayed or failed engraftment in about 20% of adult patients. The aim of this phase I/II study was to establish the safety and efficacy ...of a new administration route (intrabone) for cord-blood cells, measured by the donor-derived neutrophil and platelet engraftment. Methods Adult patients with acute leukaemia, for whom an unrelated stem-cell transplantation was indicated and no suitable unrelated human leucocyte antigen (HLA)-matched donor had been identified, were included in the study and underwent a cord-blood transplant in San Martino Hospital, Genoa, Italy. Eight patients were in first complete remission, ten in second complete remission, and 14 had advanced-stage, refractory disease. HLA matching was 5/6, 4/6, and 3/6 for 9, 22, and one patient, respectively. Cord-blood cells were concentrated in four 5-mL syringes, and were infused in the superior-posterior iliac crest under rapid general anaesthesia. Median transplanted cell dose was 2·6×107 /kg (range 1·4–4·2). The primary endpoint was the probability of neutrophil and platelet recovery after intrabone cord-blood transplantantion. Secondary endpoints included the incidence of acute graft-versus-host disease, relapse, and overall survival. This trial is registered on the ClinicalTrials.gov website, number NCT 00696046. Findings Between March 31, 2006, and Jan 25, 2008, 32 consecutive patients with acute myeloid leukaemia (n=20) or acute lymphoblastic leukaemia (n=12) underwent a cord-blood transplant (median age 36 years range 18–66). No complications occurred during or after the intrabone infusion of cells. Four patients with advanced-stage disease died within 12 days of the procedure. Median time to recovery of neutrophils in 28 patients (≥0·5×109 /L) was 23 days (range 14–44) and median time to recovery of platelets in 27 patients (≥20×109 /L) was 36 days (range 16–64). All patients were fully chimeric from 30 days after transplantation to the last follow-up visit, suggesting an early complete donor engraftment. No patient developed grade III–IV acute graft-versus-host disease. Causes of death were transplant related (n=5), infection (n=7), and relapse (n=4). 16 patients were alive and in haematological remission at a median follow-up of 13 months (range 3–23). Interpretation Our preliminary data suggest that direct intrabone cord-blood transplantation overcomes the problem of graft failure even when low numbers of HLA-mismatched cord-blood cells are transplanted, thus leading to the possibility of use of this technique in a large number of adult patients. Funding This work was supported by grants from the Associazione Italiana Ricerca contro il Cancro (FF), Compagnia di San Paolo Torino (FF), Progetto CARIGE Cellule Staminali (FF), the EUROCORD III (QLRT 2001-01918) (FF), Ministero della Salute (Ricerca Finalizzata Ministeriale 2005) (FF), and the Associazione Italiana Leucemie, Sezione Ligure.
Summary Background Follicular lymphoma is the most common form of lymphoma in Europe and the USA. In this prospective, single-arm, open-labelled, multicentre non-randomised phase II trial (FLUMIZ ...FLUdarabine, MItoxantrone, Zevalin trial) we aimed to assess the efficacy and safety of fludarabine and mitoxantrone plus radioimmunotherapy in untreated patients with follicular non-Hodgkin lymphoma (NHL). Methods Patients with stage III or IV untreated indolent follicular NHL were enrolled between June 1, 2004, and April 15, 2006, at 13 Italian institutions, and were treated with oral fludarabine (40 mg/m2 on days 1 to 3) and intravenous mitoxantrone (10 mg/m2 on day 1) every 28 days for six cycles. Patients who had at least a partial response (PR) with normal platelet counts (>100×109 /L) and granulocyte counts (1·5×109 /L), and bone-marrow infiltration less than 25% 4–6 weeks after completion of the sixth cycle of chemotherapy were deemed eligible for consolidation treatment 6–10 weeks after the sixth cycle with one course of yttrium-90 (90 Y)-labelled ibritumomab tiuxetan (Zevalin), which consisted of an initial infusion of intravenous rituximab (250 mg/m2 ) on day 1 followed by a second 250 mg/m2 infusion on day 7, 8, or 9. The second infusion was followed by a weight-based dose of90 Y-ibritumomab tiuxetan, administered as a slow intravenous push over 10 min. Primary endpoints were complete response (CR) and haematological toxic effects and secondary endpoints were overall survival and progression-free survival. Responses were classified according to the International Workshop for Response Criteria for non-Hodgkin's lymphomas. Analysis was per protocol. This trial is registered as a European Standard Controlled Trial on the EudraCT website http://oss-sper-clin.agenziafarmaco.it , number 2004-002211-92. Findings 61 patients were enrolled in the trial and received six cycles of fludarabine and mitoxantrone, after which an overall response was noted in 98% (60 of 61) of patients (43 of 61 patients had CR and 17 of 61 patients had PR). 57 patients (43 with CR and 14 with PR) were deemed eligible for subsequent90 Y-ibritumomab tiuxetan. Of the 14 patients who had PR after the initial treatment, 12 obtained CR after90 Y-ibritumomab tiuxetan. By the end of the entire treatment regimen 55 of 57 patients achieved CR. With a median follow-up of 30 months (range 21–48), 3-year progression-free survival was estimated to be 76% (95% CI 72·3–82·4) and 3-year overall survival 100%. 36 of 57 patients had grade 3 or 4 haematological toxic effects, and blood transfusions were given to 21 of 57 patients. Interpretation This trial has provided evidence for the feasibility, tolerability, and efficacy of fludarabine and mitoxantrone plus90 Y-ibritumomab tiuxetan in untreated patients with follicular NHL. Funding Italian Association for Leukaemias, Lymphomas, and Myeloma, Bologna, Italy.
Summary Background Creutzfeldt-Jakob disease (CJD) is a fatal, untreatable prion encephalopathy. Previous studies showed that doxycycline is effective in in-vitro and in-vivo models of disease, and ...patients with CJD who received compassionate treatment with doxycycline showed increased survival time compared with historical series. We therefore did a randomised, double-blind study of doxycycline versus placebo in CJD. Methods We recruited patients older than 18 years old who had a diagnosis of definite or probable sporadic CJD or genetic forms of the disease via Italian reference centres and the French national referral system. Patients were randomly assigned (ratio 1:1) to receive oral doxycycline (100 mg daily) or placebo under double-blind conditions from the day of randomisation to death. Centralised randomisation was done independently of enrolment or evaluation of patients using a minimisation method in Italy and a simple randomisation in France. Participants, caregivers, and clinicians were masked to group assignment. The primary efficacy variable was the survival time from randomisation. Interim analyses were planned to detect a significant effect of treatment as early as possible. This trial is registered with EudraCT, 2006-001858-27 for the Italian study and 2007-005553-34 for the French study. Findings From April 12, 2007, to Aug 19, 2010, in Italy, and from Jan 30, 2009, to Jan 10, 2012, in France, 121 patients with CJD were enrolled in the study, 62 of whom were randomly assigned to the treatment group and 59 to the placebo group. The first interim analysis showed absence of superiority of doxycycline compared with placebo, and the trial was stopped for futility. Efficacy analyses did not show significant differences between patients treated with doxycycline and placebo with regard to survival times (HR 1·1, 95% CI 0·8–1·7, p=0·50). Serious adverse events were judged not to be related to treatment, whereas a relation was deemed probable or possible for five non-serious adverse events that occurred in each treatment group. Interpretation Doxycycline at a dose of 100 mg per day was well tolerated but did not significantly affect the course of CJD, at variance with the results of previous observational studies. Our experience could be useful in the design of large multinational controlled trials of potential anti-prion molecules in this rare disease. Funding Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.
