Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial.

BACKGROUND: Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed. METHODS: Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR). RESULTS: A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49-0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors. CONCLUSIONS: Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients. TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.

Camrelizumab for relapsed or refractory classical Hodgkin lymphoma: Extended follow-up of the multicenter, single-arm, Phase 2 study.

Camrelizumab (a humanized high-affinity IgG4 mAb against programmed death-l) showed potent antitumor activity, well tolerance and controllable safety in patients with relapsed or refractory classical Hodgkin lymphoma (r/r cHL), based on the primary analysis of a Phase 2 study. Here, we present the extended follow-up outcomes. Seventy-five patients who had failed to achieve a remission or experienced progression after autologous stem cell transplantation or had received at least two lines of systemic chemotherapies were enrolled to receive camrelizumab 200 mg every 2 weeks. With a median follow-up of 36.2 months (range, 7.2-38.1), objective response rate per independent central review was 76.0% (95% confidence interval [CI], 64.7-85.1). Among the 57 responders, 31 (54.4%) had ongoing responses. Median duration of response was 31.7 months (95% CI, 16.7-not reached). Median progression-free survival was 22.5 months (95% CI, 14.7-not reached). Thirty-six-month overall survival rate was 82.7% (95% CI, 72.0-89.5). Reactive capillary endothelial proliferation (RCEP) occurred in 97.3% of patients (73/75), but all RCEP were Grade 1 or 2 in severity and 67.1% of these patients (49/73) achieved complete resolution. Occurrence of new RCEP lesions was rare (8/42 [19.0%] at 12 months; 2/32 [6.3%] at 24 months). No treatment-related deaths occurred, and no new toxicities were reported. With extended follow-up, camrelizumab monotherapy continues to provide a robust and durable response, long survival and manageable safety in r/r cHL patients.

Bendamustine versus chlorambucil in treatment of chronic lymphocytic leukaemia in China: a randomized, open-label, parallel-controlled, phase III clinical trial.

BACKGROUND: Chronic lymphoblastic leukemia (CLL) is the most common adult leukemia and mainly affects the elderly. Chemoimmunotherapy still has a role in the standard frontline therapy for specific population. However, the clinical activity of bendamustine has not been investigated in unfit Chinese patients with CLL. This study aimed to compare the efficacy and safety of bendamustine versus chlorambucil for untreated Chinese patients with Binet stage B/C CLL. METHODS: In this multi-center, randomized, open-label, parallel-controlled, phase III trial, patients with previously untreated CLL were enrolled and randomly assigned (1:1) to receive bendamustine or chlorambucil. The primary endpoint was the objective response rate. Secondary endpoints included progression-free survival, the duration of response, and overall survival. Adverse events were recorded to evaluate safety. RESULTS: Of 158 screened patients, 147 were enrolled and randomly allocated to receive bendamustine (n = 72) or chlorambucil (n = 75). After a median follow-up of 25.6 months (IQR 12.5-27.7), 69.0% (95% CI, 56.9-79.5) of bendamustine-treated patients achieved objective response and 37.0% (95% CI, 26.0-49.1) of chlorambucil with a difference of 32.0% (95%CI: 16.6-47.5), demonstrating the superiority of bendamustine to chlorambucil (p < 0.001). The median progression-free survival was longer for bendamustine (16.5 months; 95% CI, 11.3-24.7) versus chlorambucil (9.6 months; 95% CI, 8.7-11.8; p < 0.001). A longer median duration of response was seen in those receiving bendamustine (19.2 months; 95% CI, 11.8-29.1) than chlorambucil (10.7 months; 95% CI, 5.6-13.6; p = 0.0018). Median overall survival was not reached in either group. Overall survival at 18 months was 88% for bendamustine versus 85% for chlorambucil. Most common adverse events in both groups were neutropenia and thrombocytopenia. CONCLUSION: In untreated Chinese patients with Binet stage B/C CLL, bendamustine induced the better objective response and resulted in longer progression-free survival than chlorambucil. Overall, these results validate the role of bendamustine as an effective and safe first-line therapy in this population.

IgH translocation with undefined partners is associated with superior outcome in multiple myeloma patients.

BACKGROUND: In multiple myeloma (MM), impact of specific chromosomal translocations involving IgH (14q21 locus, including t(4;14), t(11;14), and t(14;16)) has been explored extensively. However, over 15% MM patients harboring IgH translocation with undefined partners have long been ignored. METHODS: A prospective non-randomized cohort study with a total of 715 newly-diagnosed MM cases was conducted, 13.6% of whom were t(14;undefined) positive. The whole cohort was divided into four groups: no IgH split (47.7%); t(14;undefined) (13.6%); t(11;14) (17.6%); and t(4;14) or t(14;16) group (21.1%). RESULTS: Median OS for the four groups was 84.2, not reached (NR), 58.7, and 44.2 months, respectively, with P values for t(14;undefined) vs no IgH split, t(11;14), and t(4;14)/t(14;16) groups of 0.197, 0.022, and 0.001, respectively. In bortezomib-based group, the survival advantage gained by t(14;undefined) group was much more significant compared to t(11;14) and t(4;14)/t(14;16) groups. Importantly, t(14;undefined) turned out to be an independent predictive factor for longer OS of MM patients in multivariate analysis, especially in the context of bortezomib treatment. Similar results were also observed in the PUMCH external validation cohort. CONCLUSION: Collectively, our data confirmed and externally validated the favorable prognosis of the t(14;undefined) groups, especially in the era of novel agents.

Treatment of Xanthelasma Palpebrarum With Intralesional Pingyangmycin.

BACKGROUND: Xanthelasma palpebrarum (xanthelasma) is the most common type of cutaneous xanthoma, and many patients tend to seek medical treatments for cosmetic reasons. Many methods treating xanthelasma have been proposed, but none of these options can be regarded as a perfect solution. OBJECTIVE: To study and evaluate the intralesional injection treatment of xanthelasma with pingyangmycin, which has been widely used as a broad-spectrum antitumor antibiotic. MATERIALS AND METHODS: 21 lesions in 12 patients were treated by intralesional pingyangmycin. Photographs were taken before and after each treatment session. Patients were followed up for 7 to 36 months. RESULTS: All patients except one received satisfactory results after up to 2 sessions. Only 1 patient had a local recurrence 1 year after the treatment. No severe complications such as infection, atrophy, ulceration, or scar were noticed. CONCLUSION: Intralesional pingyangmycin is a cheap, effective, and safe treatment for xanthelasma, which has been well accepted by patients.

Multiple myeloma patients with low proportion of circulating plasma cells had similar survival with primary plasma cell leukemia patients.

The common features shared by primary plasma cell leukemia (pPCL) and multiple myeloma (MM) with circulating plasma cells (CPCs) are peripheral blood invasion and expansion of plasma cells independent of the protective bone marrow (BM) microenvironment niche. However, few studies have addressed the relationship between pPCL and MM with CPCs. Here, we quantitated the number CPCs by conventional morphology in 767 patients with newly diagnosed MM; their clinic features were compared with those of 33 pPCL cases. When the presence of CPCs was defined as more than 2 % plasma cells per 100 nucleated cells on Wright-Giemsa stained peripheral blood smears, the incidence of MM with CPCs was 14.1 % in newly diagnosed MM. Patients with CPCs shared many clinical features with pPCL, especially clinical parameters related to tumor burden. However, no commonalities were found in immunophenotyping and cytogenetics. The prognosis of pPCL was poor, with a median progression free survival (PFS) of 12 months and an overall survival (OS) of 15 months. MM patients with CPCs had a clearly inferior PFS and OS as compared with the control cohort. Most interestingly, although the CPCs were not high enough to meet the diagnostic criteria for pPCL, the survival of MM patients with CPCs was comparable with that of pPCL, with a median PFS of 17 months and an OS of 25 months.

Is vaginal mucosal graft the excellent substitute material for urethral reconstruction in female-to-male transsexuals?

PURPOSE: Construction of a neourethra is always considered to be a difficult part in phalloplasty, especially for the female-to-male (FTM) transsexual patients. We report our experience with prefabricated pars pendulans urethrae using vaginal mucosal graft for phalloplasty in FTM transsexuals. MATERIALS AND METHODS: We retrospectively reviewed notes on the 22 FTM patients treated with pedicled-flap phalloplasty with prefabricated pars pendulans urethrae using vaginal mucosal graft between January 2008 and December 2012. Surgical outcome, urological function, and complications were recorded. Histological difference between normal mucosa and skin, and pathological changes of vaginal mucosal graft were also observed. RESULTS: All the reconstructive penis survived, and patients could void in a standing position finally at a median follow-up of 25.4 ± 6.0 months. Urethral fistula and urethral stricture rates were 31.8 % (7/22 patients) and 4.5 % (1/22 patients), respectively. The occurrence of the urethral stricture was remarkably low compared with previous reports. Our histological results also showed a pronounced similarity between vaginal and buccal mucosa. Morphologically, they resembled urethral epithelium more closely than the forearm skin. Following the free transfer, the vaginal mucosal graft also showed a good revascularization and the inflammatory reaction and the extent of fibrosis of the mucosa decreased to the normal level after a 6-month prefabrication. CONCLUSION: With prefabrication of vaginal mucosal graft, we reconstruct a competent phallic neourethra in these FTM transsexuals. According to its histological similarities and source character, the vaginal mucosa is the excellent substitute material for promising urethral reconstruction in FTM transsexuals.

Liver X receptor activation induces apoptosis of melanoma cell through caspase pathway.

Liver X receptors (LXRs) are nuclear receptors that function as ligand-activated transcription factors regulating lipid metabolism and inflammation. Recent discoveries found LXRs could regulate tumor growth in a variety of cancer cell lines. In this study, we investigated the effect of LXR activation on melanoma cell proliferation and apoptosis both in vitro and in vivo. Treatment of B16F10 and A-375 melanoma cells with synthetic LXR agonist T0901317 significantly inhibited the proliferation of melanoma cells in vitro. Meanwhile, T0901317 induced the apoptosis of B16F10 melanoma cells in a dose-dependent manner. Furthermore, western blot assay showed that the pro-apoptotic effect of T0901317 on B16F10 melanoma cells was mediated through caspase-3 pathway. Oral administration of T0901317 inhibited the growth of B16F10 melanoma in C56BL/6 mice. Altogether, this study demonstrates the critical role of LXRs in the regulation of melanoma growth and presents the LXR agonist T0901317 as a potential anti-melanoma agent.

A multicenter, open-label phase II study of recombinant CPT (Circularly Permuted TRAIL) plus thalidomide in patients with relapsed and refractory multiple myeloma.

Circularly permuted TRAIL (CPT), a recombinant mutant of human Apo2L/TRAIL, is a novel antitumor candidate for multiple myeloma (MM) and other hematologic malignancies. In this phase II study, the safety and efficacy of CPT plus thalidomide was investigated in thalidomide-resistant MM patients. A total of 43 patients were recruited into three CPT plus thalidomide cohorts based on CPT dosage in sequence: 5 mg/kg (n = 11), 8 mg/kg (n = 17), and 10 mg/kg (n = 15). CPT was administered via intravenous infusion on days 1-5, and thalidomide was given orally at 100 mg once daily in each 21-day cycle. The overall response rate (ORR) of 41 efficacy-evaluable patients was 22.0% (2 complete response, 3 near complete response, and 4 partial response). No significant difference in the ORR was observed among the three dose cohorts; however, the ORR tended to be higher with the higher-dose regimen. Median progression-free survival and median duration of response were 6.6 months and 6.1 months, respectively. The most common treatment-related adverse events (TRAEs) were neutropenia (46.5%), leukopenia (41.9%), fever (37.2%), elevated AST (32.6%), and elevated ALT (20.9%). TRAEs of Grade 3-4 were mainly neutropenia (18.6%), anemia (9.3%), elevated AST (7.0%), and leukopenia (4.7%). No significant differences were found in the incidence and severity of TRAEs among the three cohorts. In conclusion, CPT plus thalidomide was well tolerated with no occurrence of dose-limiting toxicities and demonstrated promising antitumor activity in RRMM patients. CPT at 10 mg/kg for 5 days in combination with thalidomide and dexamethason will be studied in the next clinical trial.

[Analysis of clinical characteristics for large granular lymphocytic leukemia].

OBJECTIVE: To explore the clinical and laboratory characteristics for large granular lymphocytic leukemia (LGL). METHODS: A total of 35 LGL patients were retrospectively analyzed from March 2004 to May 2013 at our department. RESULTS: Their median age of diagnosis was 51 years. The anemia-related symptoms included splenomegaly (n = 11, 31.4%). And one patient (2.8%) with a history of rheumatoid arthritis. Anemia was the most frequent hematological abnormality (n = 27, 77.1%). The range of LGL count in peripheral blood was (0.82-23.7) ×10(9)/L. Among them, 19 patients (54.2%) showed the CD3(+)CD57(+) CD56(-)indolent LGL phenotype. Two patients showed complex karyotype. T cell receptor ß chain variable region (TCRVß) analysis was positive in 8 patients. The median overall survival of aggressive LGL patients was significant shorter than that of indolent patient(16 months vs not reached, P = 0.000). Univariate analysis showed the median overall survival of patients with B symptom was significant shorter than that without B symptom (19 vs 45 months, P = 0.039); the median overall survival of patients with thrombocytopenia was significant shorter than that with platelet normal (16 vs 42 months, P = 0.000). Multivariate analysis showed B symptom (P = 0.736) and thrombocytopenia (P = 0.977) at diagnosis were not prognostic factors. CONCLUSIONS: Chinese LGL patient with rheumatoid arthritis is infrequent compared with foreign reports. TCRVß analysis is important for its diagnosis. The overall survival of aggressive LGL patients is significantly inferior to indolent patients, and need earlier intensive therapy in order to achieve longer survival.