KEYNOTE-434 part B: A phase 1 study evaluating the combination of epacadostat, pembrolizumab, and chemotherapy in Japanese patients with previously untreated advanced non-small-cell lung cancer.

BACKGROUND: Pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase-1 inhibitor) was well tolerated in Japanese patients with advanced solid tumors in part A of the nonrandomized, open-label, phase 1 KEYNOTE-434 study (NCT02862457). We report results from part B, which evaluated epacadostat plus pembrolizumab and chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Eligible patients aged ≥ 20 years had histologically or cytologically confirmed stage IIIB or IV NSCLC with no prior systemic therapy, and ECOG performance status of 0 or 1. Patients received epacadostat 100 mg orally twice-daily, pembrolizumab 200 mg intravenously every-3-weeks for ≤ 35 cycles, and 4 cycles of chemotherapy (cohort 1: cisplatin plus pemetrexed, non-squamous; cohort 2: carboplatin plus pemetrexed, non-squamous; cohort 3: carboplatin plus paclitaxel, squamous or non-squamous). Primary endpoint was incidence of dose-limiting toxicities (DLTs). Following unfavorable results from other studies, a protocol amendment removed epacadostat from the treatment combination. RESULTS: Of 19 patients, 7 were enrolled in cohort 1, and 6 each in cohorts 2 and 3. Median follow-up was 13.7 (range, 4.2-27.8) months. Five of 17 (29%) DLT-evaluable patients experienced ≥ 1 DLT (cohort 1, n = 1; cohorts 2 and 3, n = 2 each); most commonly maculopapular rash (grade 3, n = 3) and increased alanine aminotransferase (grade 2, n = 1; grade 3, n = 2). All patients experienced treatment-related adverse events (AEs); 58% experienced grade 3 or 4 treatment-related AEs. Objective response rate was 47%. CONCLUSION: The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02862457.

Pathological and Evolutive Correlations in Steroid Resistant Nephrotic Syndrome in Children.

Background: Nephrotic syndrome (NS) is the term used for the association of edema and massive proteinuria. From a therapeutic point of view, it is important to distinguish between primitive and secondary kidney damage. The clinical evolution, prognosis and therapeutic response in the NS in children are directly determined by the anatomopathological aspect. Steroid resistant nephrotic syndrome was diagnosed in patients with idiopathic NS based on lack of complete remission despite treatment with steroids. Purpose: To analyse the anatomopathological aspects of steroid resistant nephrotic syndrome (SRNS) and their correlation with evolution. Materials and Methods: We made a retrospective study with the aim to analyze the anatomo-pathological aspects and their correlations with evolution in 68 cases of steroid resistant nephrotic syndrome (SRNS) hospitalized in the Pediatric Nephrology Department in Iasi, Romania. We defined SRNS in all cases without response to corticosteroids after the first month of therapy. For all the cases selected, the period of follow-up was the minimal 6 months. Results and Discussions: A 36% case of nephrotic syndrome was corticoresistant, with the mean age at onset of patients with SRNS being 9.18 years, compared to KDIGO studies in which the corticosteroid resistance is 10-20%. Renal biopsy was performed in 80.88% children with SRNS and was allowed the evaluation of the activity and chronicity index. Total remission was obtained in 44.01% children with SRNS. The correlation of the anatomopathological aspects with the evolution is not statistically significant (p = 0.76), observing different therapeutic responses to all the analyzed histological types. Conclusion: Almost half of NS in children are cortico resistant. Remission was obtained in 44% of cases of SRNS. Predicting the response to long-term treatment in SRNS is difficult using only renal biopsy; it is necessary to introduce genetic molecular analyses to establish a judicious therapeutic attitude.

The safety and tolerability of epacadostat alone and in combination with pembrolizumab in patients with advanced solid tumors: results from a first-in-Japanese phase I study (KEYNOTE-434).

PURPOSE: Part A of the open-label, phase I KEYNOTE-434 study evaluated the safety and tolerability of epacadostat, an indoleamine 2,3-dioxygenase-1 inhibitor, alone and in combination with pembrolizumab in Japanese patients with advanced solid tumors. METHODS: Japanese patients with refractory/recurrent metastatic or locally advanced tumors were enrolled. Cohort 1 received oral epacadostat 25 mg or 100 mg twice daily (BID) and subsequently received epacadostat in combination with intravenous pembrolizumab 200 mg every 3 weeks. Cohort 2 received epacadostat 25 mg or 100 mg BID with pembrolizumab 200 mg every 3 weeks. The primary objective was evaluation of safety and tolerability using a modified toxicity probability interval method. Secondary objectives were pharmacokinetic (PK) and pharmacodynamic profiles of epacadostat alone and in combination with pembrolizumab. RESULTS: Six patients were enrolled in cohort 1 (epacadostat 25 mg, n = 3; epacadostat 100 mg, n = 3); none experienced dose-limiting toxicities (DLTs). Nine patients were enrolled in cohort 2 (epacadostat 25 mg and pembrolizumab, n = 3; epacadostat 100 mg and pembrolizumab, n = 6); one patient receiving epacadostat 100 mg and pembrolizumab experienced grade 4 rhabdomyolysis-a DLT. Grade 3 or 4 treatment-related adverse events occurred in two patients (13.3%). There were no treatment-related deaths. Pembrolizumab had no impact on epacadostat PK and vice versa. The PK profile of pembrolizumab in the current study was comparable with historical pembrolizumab PK data. CONCLUSION: Epacadostat in combination with pembrolizumab was generally safe and well tolerated among Japanese patients with advanced solid tumors. Clinical trial registration NCT02862457.

Safety, tolerability, and preliminary activity of IMGN529, a CD37-targeted antibody-drug conjugate, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: a dose-escalation, phase I study.

Background CD37 is expressed on B-cell lymphoid malignancies, thus making it an attractive candidate for targeted therapy in non-Hodgkin lymphoma (NHL). IMGN529 is an antibody-drug conjugate comprising a CD37-binding antibody linked to the maytansinoid DM1, a potent anti-mitotic agent. Methods This first-in-human, phase 1 trial recruited adult patients with relapsed or refractory B-cell NHL. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose. Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity. IMGN529 was administered intravenously once every 3 weeks, and dosed using a conventional 3 + 3 dose-escalation design. Results Forty-nine patients were treated at doses escalating from 0.1 to 1.8 mg/kg. Dose limiting toxicities occurred in eight patients and included peripheral neuropathy, febrile neutropenia, neutropenia, and thrombocytopenia. The most frequent treatment-emergent adverse events were fatigue (39%), neutropenia, pyrexia, and thrombocytopenia (each 37%). Adverse events led to treatment discontinuation in 10 patients (20%). Eight patients (16%) had treatment-related serious adverse events, the most common being grade 3 febrile neutropenia. The MTD (with growth factor support) was 1.4 mg/kg every 3 weeks. IMGN529 plasma exposure increased monotonically with dose and was consistent with target-mediated drug disposition. Five (13%) of 39 response-evaluable patients achieved an objective response (one complete response and four partial responses), four of which occurred in the subgroup of patients with diffuse large B-cell lymphoma. Conclusions The manageable safety profile of IMGN529 and preliminary evidence of activity, particularly in DLBCL patients, support the continued development of this novel CD37-targeting agent.

Focal segmental glomerulosclerosis in children complicated by posterior reversible encephalopathy syndrome.

An uncommon side effect of cyclosporine A (CsA) use is posterior reversible encephalopathy syndrome (PRES). PRES usually develops because of disturbed capacity of posterior cerebral blood flow to autoregulate an acute rise in blood pressure. We present the case of a 10-year-old girl who was previously diagnosed in our department with focal segmental glomerulosclerosis. She was treated with CsA and developed seizures, progressive loss of consciousness, and visual disturbance on the 7th day of treatment. Brain magnetic resonance imaging showed degeneration of white matter with diffuse demyelination in the parietal and posterior occipital lobes, consistent with the diagnosis of PRES. Cases of PRES reported in children are usually secondary to immunosuppressive therapy in oncological and haematological diseases. Our case is the fifth reported case of focal segmental glomerulosclerosis in children treated with CsA and complicated by PRES. Rapid recognition of PRES and stopping neurotoxic therapy early are essential for a good prognosis.

Investigator and independent review committee exploratory assessment and verification of tumor response in a non-Hodgkin lymphoma study.

Interpretation of endpoints (e.g. overall response rate) in clinical trials depends on the accurate and reliable measurement and identification of tumors. Regulatory agencies recommend blinded reviews of imaging data by independent review committees (IRCs). Differences in response outcomes that arise between IRCs and site investigators raise regulatory/sponsor concerns. Here, we evaluate discrepant tumor response assessments by the IRC and unblinded investigators (complete versus partial response, respectively) occurring in 52 (13% of 393 IRC-assessed responders) of 447 enrolled patients with treatment-naïve non-Hodgkin lymphoma from a randomized study. The IRC and investigators were 'likely correct' in 73% and 25% of cases, respectively (p < .001). Investigators were more likely to make errors by misinterpreting lymph node data and not utilizing PET results. This post hoc finding suggests a possible role for post-training site evaluation/audit, with retraining as needed, and a specialized consensus committee for concurrent blinded review of site/central data.

18F-FDG PET for Measurement of Response and Prediction of Outcome to Relapsed or Refractory Mantle Cell Lymphoma Therapy with Bendamustine-Rituximab.

In a single-arm, phase 2 clinical trial, bendamustine-rituximab (BR) demonstrated an overall response rate of 82% among 45 patients with relapsed or refractory mantle cell lymphoma (MCL), with manageable tolerability. A prespecified 18F-FDG PET analysis was conducted to assess the predictive value of the metabolic response to BR compared with the response by International Working Group (IWG) criteria. METHODS: Adult patients with relapsed or refractory MCL underwent 18F-FDG PET at screening and after 6 cycles of BR therapy. Scans were reviewed by a central facility and scored using the 5-point Deauville scale, comparing uptake to the liver and mediastinum in up to 6 lesions, to determine metabolic response rates, indicated by negative posttreatment scans. Metabolic responses were compared with study outcomes assessed by IWG criteria. RESULTS: Complete 18F-FDG PET data were available for 32 of 45 patients. All patients had positive baseline scans, with baseline scores ranging from 4 to 5. Complete metabolic responses (CMR) were observed in 24 (75%) patients after 6 cycles of BR. Patients attaining a CMR had a 96% overall response rate by IWG criteria, with 62.5% achieving a complete response. Of the 8 patients not attaining a CMR, 6 responded to BR but none achieved a complete response. CMR was associated with a greater 1-y progression-free survival of 91.5%, compared with 12.5% without CMR; a longer median duration of response of 20.6 mo, compared with 7.8 mo; and improved overall survival at 1 y. 18F-FDG PET data from patients with refractory or advanced disease demonstrated CMR in more than half. CONCLUSION: Compared with positive end-of-treatment 18F-FDG PET, negative scans, indicating a CMR, were predictive of improved 1-y survival, duration of response, and overall survival for patients with relapsed or refractory MCL receiving BR.

Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors.

Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of (14)C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m(2) (14)C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168 h or until radioactivity excreted within 24 h was <1 % of the dose. Total radioactivity (TRA) was measured in all matrices and concentrations of omacetaxine, 4'-desmethylhomoharringtonine (4'-DMHHT), and cephalotaxine were measured in plasma and urine. For each treatment cycle, patients received 1.25 mg/m(2) omacetaxine twice daily for 7 days. Results Mean TRA recovered was approximately 81 % of the dose, with approximately half of the radioactivity recovered in feces and half in urine. Approximately 20 % of the dose was excreted unchanged in urine; cephalotaxine (0.4 % of dose) and 4' DMHHT (9 %) were also present. Plasma concentrations of TRA were higher than the sum of omacetaxine and known metabolites, suggesting the presence of other (14)C-omacetaxine-derived compounds. Fatigue and anemia were common, consistent with the known toxicity profile of omacetaxine. Conclusion Renal and hepatic processes contribute to the elimination of (14)C-omacetaxine-derived radioactivity in cancer patients. In addition to omacetaxine and its known metabolites, other (14)C-omacetaxine-derived materials appear to be present in plasma and urine. Omacetaxine was adequately tolerated, with no new safety signals.

Differences in Quality of Life Between Bendamustine-Rituximab and R-CHOP/R-CVP in Patients With Previously Untreated Advanced Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma.

BACKGROUND: We previously reported results of the phase III, randomized, noninferiority trial comparing bendamustine-rituximab (BR) with standard R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone)/R-CVP (rituximab/cyclophosphamide/vincristine/prednisone) in previously untreated advanced indolent non-Hodgkin and mantle cell lymphomas. Here we report health-related quality of life (HRQOL) results from the trial. METHODS: HRQOL, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), was a secondary end point. Differences between group means in global health status (GHS), 5-item functioning, and 9 symptoms/single-item measures at week 1 of cycle 1 and end-of- cycles 3 and 6 were examined using the screening (baseline) score as a covariate in analysis of covariance. RESULTS: Overall EORTC QLQ-C30 compliance was 75.2%, 89.5%, and 89.9% at week 1 of cycle 1 and end-of-cycles 3 and 6, respectively. Patients treated with BR reported improvements in Cognitive Functioning, Physical Functioning, Social Functioning, Emotional Functioning, and GHS as well as reduction in dyspnea, constipation, and fatigue at some, but not all, time points. Patients treated with standard therapy reported less nausea/vomiting at one time point. CONCLUSION: Compared with patients treated with standard therapy, patients treated with BR reported better quality of life in several areas.

Incidence and management of myelosuppression in patients with chronic- and accelerated-phase chronic myeloid leukemia treated with omacetaxine mepesuccinate.

Omacetaxine mepesuccinate (Synribo) is an inhibitor of protein synthesis indicated for the treatment of patients with chronic- or accelerated-phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors. Myelosuppression is the most common and clinically significant toxicity experienced by patients treated with omacetaxine. Here, we further examine the patterns of hematologic toxicity observed in clinical trials and describe the approach to management as well as resolution of events. Omacetaxine-related myelosuppression typically occurs more frequently during induction cycles. In general, the myelosuppression observed with omacetaxine treatment is manageable and reversible, and long-term administration is feasible. Careful monitoring, dose delays and reduction in administration days, and appropriate supportive care are critical for successful management of hematologic toxicity. Concerns regarding myelosuppression, observed with many cancer treatments, should not prevent eligible patients from receiving omacetaxine, particularly CML patients with unsatisfactory responses to multiple lines of prior treatment.

Effect of bendamustine in combination with rituximab on QT interval duration in patients with advanced de novo indolent non-Hodgkin or mantle cell lymphoma.

PURPOSE: Bendamustine is used in chronic lymphocytic leukemia (first-line) and indolent B-cell non-Hodgkin lymphoma (NHL) that progressed during/within 6 months of treatment with rituximab or a rituximab-containing regimen. This study was a postapproval commitment to investigate bendamustine's effect on cardiac repolarization in treatment-naïve adults with advanced indolent NHL/mantle cell lymphoma (MCL). METHODS: In this multicenter, open-label, phase 3 study, patients received 6-8 28-day cycles of bendamustine (90 mg/m(2), days 1 and 2) and rituximab (375 mg/m(2), day 1). Exclusions included a history of cardiac conditions with potential for QT prolongation. The primary endpoint was change in Fridericia-corrected QT (QTcF; 3 electrocardiograms per time point) on day 2 of cycle 1, from just before infusion to end of infusion (immediately postinfusion, coinciding with maximum plasma concentration of bendamustine). Change 1 h postinfusion was also measured. Exploratory assessments included specific QTcF outlier analyses (new QTcF >500 ms, change >60 ms) and morphological changes. RESULTS: Of the 54 enrolled patients (mean age, 62.9 years), 53 received ≥1 dose; 49 completed ≥6 cycles. Mean QTcF change from baseline was 6.7 ms at end of infusion; no mean changes >20 ms were detected ≤1 h postinfusion. No patients met specific outlier criteria at end of infusion or 1 h postinfusion. No morphological changes were detected. CONCLUSIONS: In this small treatment-naïve population with advanced NHL/MCL, bendamustine did not produce a clinically relevant increase in mean QTcF on the second infusion day. The potential for delayed effects on QT interval after 1 h was not evaluated.

Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up.

BACKGROUND: Omacetaxine, a protein synthesis inhibitor, is indicated in the United States for the treatment of patients with chronic-phase (CP) or accelerated-phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors. METHODS: The final analysis, with 24 months of follow-up, included additional efficacy and safety analyses to assess the benefit of long-term omacetaxine administration (1.25 mg/m(2) twice daily for 14 days every 28 days followed by 7 days every 28 days) in CP-CML and AP-CML patients receiving >3 cycles. RESULTS: Eighteen percent of CP-CML patients achieved a major cytogenetic response (MCyR) with a median duration of 12.5 months (95% confidence interval [CI], 3.5 months to not reached [NR]); responses were maintained for ≥12 months in 3 of 14 responders, and the median overall survival (OS) was 40.3 months (95% CI, 23.8 months to NR). Among patients with AP-CML, 14% achieved or maintained a major hematologic response for a median of 4.7 months (95% CI, 3.6 months to NR); MCyR was not achieved, and the median OS was 14.3 months (95% CI, 6.7-18.7 months). In patients with CP-CML and patients with AP-CML who received >3 cycles of treatment (n = 50 and n = 14, respectively), the median OS was 49.3 months (95% CI, 23.8 months to NR) and 24.6 months (95% CI, 12-37.2 months), respectively. Grade 3 or higher hematologic toxicities were the major side effects (79% and 73% for CP-CML and AP-CML, respectively), with discontinuation due to toxicity in 10% of CP patients and in 5% of AP patients. CONCLUSIONS: These results suggest that the long-term administration of omacetaxine is feasible with dose adjustments to manage toxicities and that omacetaxine provides a durable benefit for some patients.

Results of a phase II study of bendamustine and ofatumumab in untreated indolent B cell non-Hodgkin's lymphoma.

The efficacy/tolerability of bendamustine, a unique alkylator, plus ofatumumab, a human anti-CD20 monoclonal antibody, was evaluated for previously untreated indolent B cell non-Hodgkin's lymphoma (NHL). The study investigated whether the overall response rate (ORR) for bendamustine-ofatumumab was similar to historical bendamustine-rituximab ORRs (≥90 %). In this multicenter, open-label, single-arm, phase II study, patients received six planned 28-day cycles of bendamustine (90 mg/m(2) on days 1 and 2 of each cycle) and ofatumumab (300 mg on day 1, 1000 mg on day 8 of cycle 1, and on day 1 of subsequent cycles). The primary outcome was ORR. Secondary objectives included safety and tolerability. Exploratory evaluations included percentage of patients with positive baseline [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans who converted to negative postbaseline and quality of life (QOL) scores. The treated/safety analysis population received ≥1 dose of either therapy. The bendamustine-ofatumumab ORR was 90 % (95 % confidence interval, 77.8-96.6) in 49 treated patients (67 % complete response, 22 % partial response). No patients had progressive disease. Bendamustine-ofatumumab was acceptably tolerated. All 49 patients had ≥1 adverse event, the most common being nausea (61 %), fatigue (55 %), and infusion-related reactions (45 %, all but 1 occurring during cycle 1). The proportion of patients whose FDG-PET scans converted to negative postbaseline was 88 %. Changes in QOL scores were minor. In patients with treatment-naive, indolent B cell NHL, bendamustine-ofatumumab exhibited a high degree of activity (90 % ORR), comparable with historical bendamustine-rituximab ORRs (≥90 %), and was adequately tolerated ( ClinicalTrials.gov identifier: NCT01108341).

An evaluation of the potential for drug-drug interactions between bendamustine and rituximab in indolent non-Hodgkin lymphoma and mantle cell lymphoma.

PURPOSE: Bendamustine plus rituximab has been reported to be effective in treating lymphoid malignancies. This analysis investigated the potential for drug-drug interactions between the drugs in patients with indolent non-Hodgkin lymphoma or mantle cell lymphoma. METHODS: Data were derived from a bendamustine-rituximab combination therapy study, a bendamustine monotherapy study, and published literature on rituximab monotherapy and combination therapy. Analysis of the potential for rituximab to affect bendamustine systemic exposure included comparing bendamustine concentration-time profile following monotherapy to that following combination therapy and comparing model-predicted Bayesian bendamustine clearance in the presence and absence of rituximab. Analysis of the potential for bendamustine to affect rituximab systemic exposure included plotting observed minimum, median, and maximum serum rituximab concentrations at the end of rituximab infusion (EOI) and 24 h and 7 days post-infusion in patients receiving combination therapy versus concentrations reported in literature following rituximab monotherapy. RESULTS: The established population pharmacokinetic model following bendamustine monotherapy was evaluated to determine its applicability to combination therapy for the purpose of confirming lack of pharmacokinetic interaction. The model adequately described the bendamustine concentration-time profile following monotherapy and combination therapy in adults. There was no statistically significant difference in estimated bendamustine clearance either alone or in combination. Also, rituximab concentrations from EOI to 24 h and 7 days demonstrated a pattern of decline similar to that seen in rituximab studies without bendamustine, suggesting that bendamustine does not affect the rituximab clearance rate. CONCLUSIONS: Neither bendamustine nor rituximab appears to affect systemic exposure of the other drug when coadministered.

Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study.

This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.

Open-label bendamustine monotherapy for pediatric patients with relapsed or refractory acute leukemia: efficacy and tolerability.

This open-label, single-arm, phase I/II, dose-escalation study was designed to determine the recommended phase II dose (RP2D), pharmacokinetics, tolerability, and efficacy of bendamustine in pediatric patients (age ranging from 1 to 20 y) with histologically proven relapsed/refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Patients (27 with ALL, 16 with AML) received intravenous bendamustine on days 1 and 2 of each treatment cycle. Phase I involved planned dose escalation of bendamustine to establish the RP2D for phase II. Objectives included overall response rate, duration of response, and tolerability. Eleven patients were treated in phase I, and the RP2D was 120 mg/m. In phase II, 32 patients received bendamustine 120 mg/m. Two patients with ALL (bendamustine 90 mg/m) experienced complete response (CR). Among patients who received bendamustine 120 mg/m, 2 experienced partial response (PR); 7 had stable disease. The overall response rate (CR+CR without platelet recovery [CRp]) was 4.7% and biological activity rate (CR+CRp+PR) was 9.3%. No AML patients responded. The most common adverse events were anemia, neutropenia, thrombocytopenia, pyrexia, nausea, vomiting, and diarrhea. Bendamustine monotherapy has acceptable tolerability in heavily pretreated children with relapsed/refractory ALL or AML and appears to have some activity in ALL, warranting further studies in combination trials.

Retrorectal dermoid cyst: a rare clinical entity.

The retrorectal space represents the anatomical site at which level we identify the embryologic reminiscents in which it can develop liquid tumors - cysts or solid tumors - neoplasia. These tumors are rare but pose a diagnostic and therapeutic interest. This paper presents the case of a young 18 years-old diagnosed incidentally at a gynecological examination, with a palpable tumor developed, at the retrorectal space. Imaging examinations - transvaginal ultrasound and abdominal - pelvic computer tomographic exam - have supported the presence of a cystic tumor with a maximum diameter of 7.8 cm., in the space retrorectal. The lesion presented surgical indication, so it needed a posterior approach with resection of the coccyx enough for the control and safety of the operation. Histopathological examination revealed a dermoid cyst. Five years after surgery the patient is presented in good general condition, asymptomatic without clinical and imaging signs of local-regional recurrence.

[Factors influencing responsiveness to treatment in children with renal anemia in end stage renal disease]. / Factorii care limiteaza raspunsul la tratament la copiii cu anemie secundara insuficientei renale cronice terminale.

UNLABELLED: Human recombined erythropoietin had proven its efficiency in the treatment of anemia in chronic dialyzed patients and allows the elimination of complete necessity of transfusion. PURPOSE: We proposed ourselves to identify the factors that limit the answer to the combined treatment with iron and erythropoietin in a group study of 71 children diagnosed with ESRD in the IVth Pediatrics Clinic and included in the chronic dialysis program. MATERIAL AND METHOD: We divided the patients in three groups, in relation to the time in which the patients had reached and maintained the hemoglobin value of 10.5 g/dl under sustained iron treatment, combined with EPO. We analyzed the correlations established between responsively/non-responsively to treatment and the medium value of Hb, Ht, reticulocytes number, plasma value of iron and ferritin, the parameters of phospho-calcium metabolism, malnutrition as presence and degree, the age of entrance in dialysis and the duration of renal function support. RESULTS: We observed that Hb and Ht have low medium values (Hb-8.44 g/dl, Ht-25.65%) in the non-responsive group, by comparison to the responsive patients group (Hb-10.98 g/dl, Ht -32.31%). The most elevated values of iPTH around 420 pg/ml and the most frequent cases of protein-caloric malnutrition (26.8%) are seen in the non-responsive group to EPO treatment. The age of 13 years old at the entrance in the chronic dialysis program and the time of support of renal function over 21 months are seen in the non-responder group. CONCLUSION: We consider the secondary hyperparathyroidism, the protein-caloric malnutrition, the older age in the moment of entrance in dialysis and the long time of support of renal function factors that are able to influence, in a negative manner, the response to this treatment.

Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors.

PURPOSE: A fully human monoclonal antibody to anti-alpha(v) integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors. EXPERIMENTAL DESIGN: In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [(18)F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months. RESULTS: Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- and post-treatment lesion biopsies confirmed tumor cell alpha(v) integrin expression, as well as CNTO 95 penetration of the tumor and localization to tumor cells in association with reduced bcl-2 expression. A lesion in one patient (10.0 mg/kg) with stable ovarian carcinosarcoma was no longer detectable by FDG-PET by day 49. Exposure to CNTO 95 seemed to increase in a greater-than-dose-proportional manner; dose-dependent mean half-life ranged from 0.26 to 6.7 days. CONCLUSIONS: CNTO 95 was generally well tolerated. Six patients received extended therapy, including one patient with a prolonged response. Biopsy data confirmed tumor localization and pharmacodynamic activity.