No abstract

Brentuximab vedotin (BV) shows a high overall response rate (ORR) in relapsed/refractory (R/R) Hodgkin lymphoma (HL) after autologous transplant (ASCT). The aim of this multicenter study, conducted in nine Hematology Departments of Rete Ematologica Pugliese, was to retrospectively evaluate the efficacy and safety of BV as salvage therapy and as bridge regimen to ASCT or allogeneic transplant (alloSCT) in R/R HL patients. Seventy patients received BV. Forty-five patients (64%) were treated with BV as bridge to transplant:16 (23%) patients as bridge to ASCT and 29 (41%) as bridge to alloSCT. Twenty-five patients (36%), not eligible for transplant, received BV as salvage treatment. The ORR was 59% (CR 26%). The ORR in transplant naïve patients was 75% (CR 31%). In patients treated with BV as bridge to alloSCT, the ORR was 62% (CR 24%). In a multivariate analysis, the ORR was lower in refractory patients (p < 0.005). The 2y-OS was 70%. The median PFS was 17 months. Ten of the 16 (63%) naïve-transplant patients received ASCT, with 50% in CR before ASCT. In the 29 patients treated with BV as bridge to alloSCT, 28 (97%) proceeded to alloSCT with 25% in CR prior to alloSCT. The most common adverse events were peripheral neuropathy (50%), neutropenia (29%) and anemia (12%). These data suggest that BV is well tolerated and very effective in R/R HL, producing a substantial level of CR. BV may also be a key therapeutic agent to achieve good disease control before transplant, improving post- transplant outcomes, also in refractory and heavily pretreated patients, without significant overlapping toxicities with prior therapies.

Background Improving strategies for patients (pts) with relapsed/refractory (R/R) Hodgkin lymphoma (HL) who fail stem cell transplantation (SCT) or are unsuitable for the procedure remains an essential need. Lenalidomide and bendamustine are active and well tolerated as single agents in recurrent HL, with overall response rates (ORR) of 30% to 53% [Fenhinger, 2012; Corazzelli, 2012; Moskowitz, 2012].These agents independently frame different targets on tumor and microenvironment cells and may cooperate to override disturbed immunologic pathways and circumvent drug resistance in HL. In a Bayesian, multi-center, open label phase 1/2 study, we investigated for safety and efficacy the combination of continuous lenalidomide with weekly bendamustine (ClinicalTrials.gov # NTC01412307). Methods The study aimed at defining the optimal daily dose of continuous lenalidomide (10, 15, 20 or 25 mg) as combined, in a 28-day cycle, to weekly fixed-dose bendamustine (60 mg/m2; d 1, 8, 15). The dose-finding algorithm proceeded in cohorts of 3 pts, based on anticipated efficacy and toxicity pairs of probability (Thall & Cook, Biometrics 2004). Trade-offs between response [Cheson 2007 criteria] and dose-limiting toxicity [CTCv3.0 grade (G) >3 lasting >2 weeks] were assessed after 2 cycles (day +56) and pts were planned to receive up to 6 total courses, unless progression or unacceptable toxicity occurred. ORR and progression-free survival (PFS) were additional endpoints. Results Thirty-six pts (69% male) with a median age of 31 yrs (r 19-75) were enrolled. The median number of prior therapies was 4 (r 1-9) and the median time from upfront treatment was 24 mo.s (r 7-118). Twenty-six pts (72%) had primary refractory disease after ABVD, 16 pts (44%) failed prior SCT [single (n=7) or tandem (n=3) ASCT, tandem ASCT/alloSCT (n=6)]. Fifteen pts (42%) had previously received a median of 5 cycles (r 2-8) of brentuximab vedotin (BV) and 3 pts were already given bendamustine (>3 courses). Overall, 23 pts (64%) were refractory to most recent therapy. Eff/Tox trade-offs at cycle 2 showed that 73% of pts had response w/o toxicity, 19% had no response w/o toxicity, 6% had response with toxicity and 2% had no response with toxicity. With such Eff/Tox profiles, the study algorithm did not prompt any dose escalation for lenalidomide after the first 18 pts and the initial dose level (10 mg) was adopted for the expansion phase. A total of 156 LeBen cycles were administered, and pts received a median of 4 courses (r 1-6). Overall, 16 cycles were delayed due to G3/G4 thrombocytopenia (n=6), G4 neutropenia (n=3), G3 pneumonia (n=3), G3 respiratory infection (n=2), G2 phlebitis (n=1), G2 supraventricular arrhythmia (n=1). Two patients discontinued treatment, while in PR and CR after 4 courses, due to protracted (>2 weeks) thrombocytopenia. No G4 extra-hematological toxicity was observed. The complete response (CR) rate was 44% (16/36) with an ORR of 75% (27/36; 95% CI, 59-86). Notably, substantial CR and PR rates were achieved after LeBen regardless of primary refractoriness, SCT and BV failure (Table). Most CRs (14/16) were obtained within the first 4 cycles; 6 responders (4 CRs and 2 PRs) underwent SCT. Median PFS was 3.2 mo.s (r 1.5-5.4) for pts with progressive (PD) or stable disease (SD) and 11.4 mo.s (r 4-31) for those achieving CR/PR. Median overall survival for the entire cohort was 24 mo.s. Overall, complete responders (including 6 pts consolidated with SCT) had a 2-year disease-free survival of 41% (median, 14.3 mo.s). Conclusions The innovative schedule of the Leben combination is safe, yields high response rates in heavily pretreated and primary refractory HL pts, including SCT and BV failures, and steps over the 'single agent' activity of its components. Due to its immunomodulatory potential the Leben platform is amenable to further upgrading through lenalidomide maintenance, combination with immune checkpoint inhibitors and BV. Table 1. Efficacy results Responsesno. (%) All pts Refractory to upfront therapy Refractory to most recent therapy Failure after SCT Failure after ASCT Failure after AlloSCT Failure after BV Failure after SCT and BV Failure after bendamustine No BV (n=36) (n=26) (n=23) (n=16) (n=10) (n= 6) (n=15) (n=8) (n=3) (n=21) CR 16 (44) 11 (42) 8 (35) 8 (50) 6 (60) 2 (33) 5 (33) 3 (37) 0 11 PR 11 8 9 4 2 2 4 2 0 7 SD 2 2 2 1 0 1 1 1 1 1 PD 7 5 4 3 2 1 5 2 2 2 CR+PR 27 (75) 19 (73) 17 (74) 12 (75) 8 (80) 4 (66) 9 (60) 5 (62) 0 18 (86) Disclosures Pinto: Takeda, Celgene, Roche, TEVA: Honoraria; Takeda: Research Funding. Zinzani:Takeda: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

The authors have reported the first case of vaginal infection caused by Enterococcus raffinosus. The latter is a rarely identified species, but some of the infections described in the literature should direct some attention to this, often opportunistic pathogen, and its emerging multidrug resistance. Case reportDuring the second month of hospitalization by the Department of Haematology, a 50-year-old immunocompromised patient with acute leukaemia developed severe vulvovaginal itching and burning. At speculum examination, erythema and discharge were observed. Vaginal pH was 5.2, the amine test was negative and microscopy (Gram stain) showed the presence of numerous Gram-positive cocci and leukocytes. We obtained swab specimens from the middle third of the vagina and placed them on Sabouraud dextrose agar, sheep blood agar, MacConkey agar and Mannitol salt agar (all from Biolife). The plates were incubated in air. A second blood agar plate was inoculated and incubated anaerobically, whilst a third blood agar plate and a Thayer-Martin plate were inoculated and incubated in an atmosphere of 5 % CO 2 . All cultures were kept at 37 u C and examined after 24 and 48 h. After 24 h of incubation, smooth and a-haemolytic colonies (.150 c.f.u.), about 1 mm in diameter, were observed on all blood agar plates. The organism was found to be a Gram-positive coccus that formed pairs and short chains, and non-motile at 36 u C. None of Lancefield group A, B, C, D, F and G antisera produced a positive reaction (SLIDEX Strepto Plus; bioMérieux) (Facklam & Collins, 1989) and the catalase test was negative. No other organisms of known vaginal pathogenicity were isolated. The isolate was identified as Enterococcus raffinosus by using the VITEK 2 system (card GP; bioMérieux) with 99 % certainty, and the identification was confirmed by using the API system (Rapid ID 32 Strep; bioMérieux). Antibiotic susceptibility testing was performed with brain heart infusion agar (Biolife) using the disc diffusion method and was interpreted as per Clinical and Laboratory Standards Institute guidelines (Chirurgi et al., 1991; NCCLS, 2000;Prakash et al., 2005). The organism was found to be resistant to penicillin, ampicillin, amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, imipenem, meropenem, ciprofloxacin, clindamycin, erythromycin, cotrimoxazole, tetracycline, amikacin, gentamicin, netilmicin and tobramicin, and susceptible only to vancomycin, teicoplanin and rifampicin. Discs were provided by Oxoid.Pending the results from cultures, the patient was treated empirically and unsuccessfully with oral amoxicillin/clavulanate (1000 mg, every 12 h). Instead, the vaginal symptoms disappeared suddenly within the second day of teicoplanin therapy that the patient had received empirically because of the outbreak of a Gram-positive cocci bacteraemia (data not shown). One week after glycopeptide treatment, vaginal examination and cultures were repeated but they did not show signs of inflammation or E. raffinosus colonies, respectively. Fur...

Decitabine, a DNA hypomethylating agent, was approved for use in adults with acute myeloid leukemia (AML) not eligible for standard chemotherapy and is now widely accepted as standard treatment. Although a number of clinical trials demonstrated its benefits in elderly AML patients, older adults and patients with frequent comorbidities are typically under-represented in such settings. Thus, the aim of the present study is to evaluate, in a real-world setting, the effectiveness and toxicity of decitabine administered as a single agent in unselected previously untreated elderly AML patients not eligible for intensive chemotherapy. In nine hematological departments of the Apulian Hematological Network (REP), we enrolled 199 patients (median age: 75.4 years; range: 61–91) with de novo (n = 94) or secondary/therapy-related (n = 105) AML treated with decitabine 20 mg/m2 for five days every 4 weeks. Hazard ratios (HR) and their 95% confidence intervals (CI) were estimated using multivariate Cox regression. The average number of cycles administered per patient was 6.3 (SD: 6.0; median: 5 cycles). Complete response was achieved by 31 patients (15.6%) and partial response by 57 (28.6%), for a total of 88 responders overall (44.2%). After a median follow-up of 33.6 months, median OS was 8.7 months (95% CI: 7.4–10.3), and the 6-month, 1-year, and 3-year OS rates were 62.7%, 37.0%, and 7.1%, respectively. Mortality was increased in AML patients with ≥3 comorbidities (HR = 2.45; 95% CI: 1.18–5.08) vs. no comorbidities and in those with adverse karyotype (HR = 1.58; 95% CI: 1.05–2.38) vs. favourable or intermediate profile. Infection was the main registered adverse event (46.0%). In conclusion, this REP real-life study demonstrates, after a follow-up of almost 3 years, how decitabine administered to AML patients not suitable for intensive chemotherapy is effective and well tolerated, even in a population of truly elderly patients with frequent comorbidities.