Median Progression-free Survival In Group Research Articles

Ibrutinib-Based Therapy in the Treatment of Relapsed and Refractory Chronic Lymphocytic Leukemia

Introduction. The development of Bruton's tyrosine kinase inhibitors and their introduction into clinical practice represent a major advance in the treatment of chronic lymphocytic leukemia (CLL). Several studies in CLL have determined the achievement of minimal residual disease (MRD) negativity as an independent favorable prognostic factor, associated with superior progression-free survival (PFS) and overall survival. MRD status is the single best posttreatment predictor of long-term outcomes after treatment, regardless of the treatment protocol or the presence of other pre-existing prognostic indicators.Aim.To estimate of response rate, PFS and MRD after ibrutinib-based therapy in the treatment patients with relapsed/refractory CLL.Methods.21 pts with relapsed/refractory CLL were included in the analysis. Stratification of patients into groups based on therapy. Group 1 (n = 14): 2nd and subsequent lines of rituximab-based chemotherapy (RB - 10, FCR - 4) and Group 2 (n = 12): ibrutinib-based therapy (420 mg daily oral Ibrutinib ± Chemoimmunotherapy). We have used NCI-IWCLL revised guidelines for treatment initiation and assessment of response. MRD was detected by multicolor flow cytometry of bone marrow in patients achieved a complete or partial remission: Group 1 - 7 pts, Group 2 - 5 pts.Results. The median age was 60.5 years (45-83) in Group 1 and 62.5 years (49-82) in Group 2 and median previous lines of therapy was 1 (1-4) and 2 (1-4), respectively. Patients with unfavorable chromosomal abnormalities were detected in each group: Group 1 - 2 pts (combination del(11q) with del(13q)); Group 2 - 1 pts (del(17p)).Overall response rate (ORR) in Group 1 was 71.4% (complete remission (CR) - 1 pt, partial remission (PR) - 9 pts, stable disease (SD) - 3 pts, progression disease - 1 pt). Group 2: ORR 91.7% (CR - 3 pts, PR - 8 pts; SD - 1 pt). Statistically significant differences in the frequency of ORR between groups were not detected (p>0.05).MRD-negative remission rate was 40% (2/5, CR - 1 pt) in Group 2 compared to 14.3% (1/7 pts, CR) in Group 1 (p>0.05). Statistically significant differences in PFS were detected between Group 1 vs. Group 2 (p=0.0006). Median PFS in Group 2 has not been reached. Median PFS in Group 1 was 16.9 month.Conclusion. Ibrutinib is highly effective at controlling disease, but best responses are typically partial remission, and patients must remain on treatment to maintain disease control. Evaluation of response and MRD after ibrutinib-containing therapy in the treatment of patients with relapsed/refractory chronic lymphocytic leukemia require further research. DisclosuresShuvaev:Pfizer: Honoraria; BMS: Honoraria; Novartis pharma: Honoraria.

Pre-Operative Perfusion Skewness and Kurtosis Are Potential Predictors of Progression-Free Survival after Partial Resection of Newly Diagnosed Glioblastoma.

ObjectiveTo determine whether pre-operative perfusion skewness and kurtosis derived from normalized cerebral blood volume (nCBV) histograms are associated with progression-free survival (PFS) of patients after partial resection of newly diagnosed glioblastoma.Materials and MethodsA total of 135 glioblastoma patients who had undergone partial resection of tumor (resection of < 50% of pre-operative tumor volume or surgical biopsy) confirmed with immediate postsurgical MRI and examined with both conventional MRI and dynamic susceptibility contrast (DSC) perfusion MRI before the surgery were retrospectively reviewed in this study. They had been followed up post-surgical chemoradiotherapy for tumor progression. Using histogram analyses of nCBV derived from pre-operative DSC perfusion MRI, patients were sub-classified into the following four groups: positive skewness and leptokurtosis (group 1); positive skewness and platykurtosis (group 2); negative skewness and leptokurtosis (group 3); negative skewness and platykurtosis (group 4). Kaplan-Meier analysis and multivariable Cox proportional hazards regression analysis were performed to determine whether clinical and imaging covariates were associated with PFS or overall survival (OS) of these patients.ResultsAccording to the Kaplan-Meier method, median PFS of group 1, 2, 3, and 4 was 62, 51, 39, and 41 weeks, respectively, with median OS of 82, 77, 77, and 72 weeks, respectively. In multivariable analyses with Cox proportional hazards regression, pre-operative skewness/kurtosis pattern (hazard ratio: 2.98 to 4.64; p < 0.001), Karnofsky performance scale score (hazard ratio: 1.04; p = 0.003), and post-operative tumor volume (hazard ratio: 1.04; p = 0.02) were independently associated with PFS but not with OS.ConclusionHigher skewness and kurtosis of nCBV histogram before surgery were associated with longer PFS in patients with newly diagnosed glioblastoma after partial tumor resection.

Survival of patients with KRAS wild-type metastatic colorectal cancer is identical after sequential treatment with cetuximab and bevacizumab regardless of the sequence - A retrospective single-center study.

Objective: To investigate the overall survival of patients with KRAS wild-type metastatic colorectal cancer (mCRC) after sequentially receiving both bevacizumab and cetuximab during the course of treatment.Methods: Twenty-six mCRC patients who received both bevacizumab and cetuximab at the Sun Yat-sen University Gastrointestinal Hospital were retrospectively analyzed. Group A (n = 8) comprised patients who received bevacizumab first, and group B (n = 18) comprised those who received cetuximab first. The objective response rate, progression-free survival, and overall survival were compared.Results: Baseline characteristics between the two groups were statistically similar. The objective response in groups A and B patients was 62.5% and 66.6%, respectively (P = 0.132). The median progression-free survival for groups A and B patients was 13 and 10 months, respectively (P = 0.798). The median overall survival for the entire cohort was 42 months, 44 months for group A and 39 months for group p B (P = 0.862) patients, respectively. Patients aged <40 years had worse survival than those aged ≥40 years (22 vs 44 months; P = 0.029). Patients with synchronous metastasis had worse survival than those with metachronous metastasis (unreached and 36 months, respectively). In multivariate analyses, synchronous metastasis and age remained statistically significant. The hazard ratio for synchronous metastasis was 4.548, and the HR for patients aged ≥40 years was 0.237.Conclusion: A longer median survival time was observed in patients regardless of the targeted therapy sequence, which warrants further investigation.

Impact of surgery on the prognosis of metastatic renal cell carcinoma with IVC thrombus received TKI therapy

To evaluate the impact of surgery on the prognosis of metastatic renal cell carcinoma (mRCC) with inferior vena cava (IVC) thrombus. In this retrospective study, the medical records of 45 patients who presented with synchronous mRCC with IVC thrombus, between 2005 and 2012, were reviewed. Twenty-eight patients underwent radical nephrectomy with IVC thrombectomy followed by targeted therapy (group 1) and 17 received targeted therapy alone (group 2). Cox proportional hazards regression models served to estimate the prognostic significance of variables. The median progression-free survival of group 1 and group 2 was 4.1 and 3.5 months, respectively (P = 0.672). Their median overall survival was 17.3 and 19.7 months, respectively (P = 0.353). Multivariate analysis revealed that non-clear cell type RCC (HR = 3.46, P = 0.007) and lymph node metastasis (HR = 2.31, P = 0.003) independently predicted progression-free survival, and Karnofsky performance status (HR = 3.82, P = 0.013) and non-clear cell type RCC (HR = 4.01, P = 0.003) independently predicted overall survival. Surgical resection of the primary renal mass with IVC thrombus did not affect the probability of progression or overall mortality. Our limited data set would suggest a limited role for surgery in this patient population and that a prospective study in this group may define the role of surgery.

Weekly AUC2 carboplatin in acquired platinum-resistant ovarian cancer with or without oral phenoxodiol, a sensitizer of platinum cytotoxicity: the phase III OVATURE multicenter randomized study

Platinum-resistant ovarian cancer (PROC) constitutes a therapeutic dilemma with limited efficacy from traditional cytotoxic agents. Based on prior data suggesting that scheduling alterations of platinum would increase activity, the aim of the present study was to assess the potential therapeutic benefit of phenoxodiol (PXD), a novel biomodulator shown to have chemoresistance reversing potential, when combined with weekly AUC2-carboplatin in PROC patients. A multicenter randomized double-blind placebo controlled phase-III-study was conducted to compare oral PXD plus AUC2-carboplatin (group 1) versus placebo plus AUC2-carboplatin (group 2) weekly in PROC patients. The primary end point was progression-free-survival (PFS). Secondary objectives included overall survival (OS), response rates, duration of response and quality of life. The study was terminated early 14 April 2009, after recruitment of 142 patients due to feasibility and recruitment challenges. A total of 142 patients were randomized. The groups were well balanced in terms of important baseline characteristics. The median PFS for group 1 was 15.4 weeks [95% confidence interval (CI) 11.1-21.0] versus 20.1 weeks for group 2 (95% CI = 13.1-33.4); P = 0.3. The objective response rate and median survival in group 1 versus group 2 was 0% versus 1% and 38.3 weeks (95% CI 32.0-45.3) versus 45.7 weeks (95% CI 35.6-58.0), respectively. PXD appeared to be well tolerated. The main reason for dose modification in both groups was hematologic toxicity. Orally delivered PXD showed no evidence of clinical activity, when combined with weekly AUC2-carboplatin in PROC. In addition, single-agent weekly AUC2-carboplatin appeared to be inactive by response criteria in a homogenously defined population of PROC. This has implications for the design of future studies.

A randomized phase 2 trial of a preparative regimen of bortezomib, high‐dose melphalan, arsenic trioxide, and ascorbic acid

Bortezomib is active for newly diagnosed and relapsed multiple myeloma, and it has synergistic activity with melphalan. The authors of this report conducted a randomized trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA), and melphalan. Among 60 patients who enrolled between October 2006 and September 2007, 58 patients underwent autologous transplantation with a preparative regimen of melphalan 200 mg/m(2) intravenously, AA 1000 mg daily intravenously for 7 days, and ATO 0.25 mg/kg intravenously for 7 days. Patients were randomized to receive no bortezomib (Group 1), bortezomib 1 mg/m(2) × 3 doses (Group 2), and bortezomib 1.5 mg/m(2) × 3 doses (Group 3). Primary endpoints were complete response (CR), grade IV toxicity, and 90-day treatment-related mortality (TRM). Secondary endpoints were progression-free survival (PFS) and overall survival (OS). The median follow-up of all surviving patients was 36 months (range, 20-43 months). The CR rates in Groups 1, 2, and 3 were 20%, 10%, and 10%, respectively. Grade 3 and 4 nonhematologic toxicities and TRM were comparable. The median OS was not reached in the groups, whereas the median PFS in Groups 1, 2, and 3 was 17.8 months, 17.4 months, and 20.7 months, respectively. PFS and OS were significantly shorter in patients who had high-risk cytogenetics (P = .016 and P = .0001, respectively) and relapsed disease (P = .0001 and P = .0001, respectively) regardless of the treatment group. Adding bortezomib to a preparative regimen of ATO, AA, and high-dose melphalan was safe and well tolerated in patients with multiple myeloma. There was no significant improvement in the CR rate, PFS, or OS in the bortezomib groups.

Serum Factors Predict Therapeutic Outcome In Patients with Chronic Lymphocytic Leukemia Treated In the CLL8 Trial of the German CLL Study Group (GCLLSG)

AbstractAbstract 918 Introduction:Various factors are used to predict the clinical course of chronic lymphocytic leukemia (CLL). Here we evaluated the importance of the serum markers soluble CD23 (sCD23), β2-microglobulin (s-β2m) and thymidine kinase (s-TK) compared to other prognostic markers in patients (pts) receiving a first-line therapy with fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR) in the CLL8 trial of the GCLLSG. Methods:The analysis of the serum factors was centrally performed prior to treatment. Kaplan-Meier method and the log-rank test were used to compare progression-free survival (PFS) and overall survival (OS). A Cox regression model was applied for the multivariate analysis and included the following parameters: age, sex, disease stage, time from first diagnosis, ECOG performance status, presence of B-symptoms, white blood cell count, sCD23, s-TK and s-β2m genomic aberrations, IGHV mutational status, and type of therapy (FC versus FCR). Cut-off values for s-β2m and for s-TK were 3.5 mg/l and 10 U/l, respectively. Results:Since exploratory analyses suggested a particular role for sCD23, the contribution of sCD23 was examined in more detail. Data for sCD23 was available for 616 pts. This cohort was representative of the full trial population (n=817) with respect to baseline characteristics. Results for response rates, PFS, OS and sCD23 were available for 574 pts. Based on their sCD23 levels, pts were categorized by quartiles: 139 pts were assigned to group A (≤2807.5 U/mL), 145 to group B (>2807.5 U/mL -≤5507 U/mL), 146 to group C (>5507 U/mL-≤10920.5 U/mL) and 144 to group D (>10920.5 U/mL). Significant differences were observed with respect to complete remissions (CR): Pts of group A achieved a double fold CR rate (48.2%) compared to pts of group D (23.6%; p<0.001). Correspondingly, group D had the highest rate of non-responses (11.8%). PFS and OS were longest for pts with low serum levels for sCD23: The median PFS in group A was 51.9 months (mo) compared to 29.8 mo in group D (p<0.001). The median OS for group D was 62.5 mo, but was not reached in the other groups.Next multivariate analyses (Table1) were performed and showed that s-TK, 17p-deletion (del(17p)) and the type of therapy were independent predictors of PFS and OS. del(17p) was the strongest adverse factor for both PFS and OS. sCD23 and IGHV were independent prognostic factors for PFS but not for OS. s-ß2m, age and ECOG status independently predicted OS.Finally, we investigated whether combinations of different serum markers would define distinct risk groups. Using the three serum markers, four risk categories were defined: Low risk (LR) = no serum factor elevation, intermediate risk (IR) = either s-ß2m or s-TK high, but sCD23 low, high risk (HR) = high s-ß2m and s-TK, but low sCD23, and very high risk (VHR) = high sCD23, regardless of s-ß2m and s-TK. Median PFS was significantly different for the four groups, with 59.7, 49.3, 35 and 29.8 months for LR, IR, HR, and VHR patients respectively (p<0.001). However, the difference between HR and VHR was not statistically significant (p=0.2). Conclusion:Elevated serum levels of s-ß2m, s-TK, and sCD23 predict poor outcome after first-line therapy with FC or FCR in pts with CLL, independently of other features such as IGHV status or del(17p). Measurement of sCD23 in addition to s-TK and s-ß2m seems to allow a more precise prediction of PFS.Table 1Multivariate analysis of the effects of various prognostic parameters on PFS and OSPFS n=504OS n=515ParameterHazard ratio95% CIp-valueHazard ratio95% CIp valuesCD23 (>10920.5 U/mL)1.3401.020–1.7610.036–––s-TK ≥10.0 U/L1.4541.052–2.0090.0232.0071.085–3,7110.026s-β2m ≥ 3.5mg/L–––1.7261.123–2.6520.013del(17p)6.4304.154–9.952<0.0018.6604.841–15.490<0.001IGHV unmutated1.4111.035–1.9220.029–––Age–––0.6460.419–0.9950.047ECOG pre ≥ 1–––1.8681.239–2.8160.003FCR treatment0.5060.393–0.651<0.0010.6710.447–1.0080.05 Disclosures:Fink:Roche: . Pflug:Roche: Travel grants. Eichhorst:Roche: Research Funding, Travel grants. Wendtner:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants. Mendila:Roche: Employment. Wenger:Roche: Employment. Stilgenbauer:Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Hallek:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fischer:Roche: Research Funding, Travel grants.

Surgical Resection of Isolated Retroperitoneal Lymph Node Recurrence of Renal Cell Carcinoma Following Nephrectomy

Durable survival has been reported following the resection of solitary metachronous metastasis of renal cell carcinoma at sites including the lung, bone and adrenal. We report our experience with resection of isolated retroperitoneal lymph node recurrence. Patients who underwent surgical resection of isolated metachronous recurrence of renal cell carcinoma in the retroperitoneal lymph nodes following radical nephrectomy for pT(any)N(any)M0 tumors were identified (group 1). Progression-free and cancer specific survival were estimated using the Kaplan-Meier method and compared to survival in patients who had pT(any)N+M0 disease at nephrectomy (group 2) and in patients who underwent complete resection of a solitary metachronous metastasis at other sites (group 3). A total of 15 patients underwent resection of isolated retroperitoneal lymph node recurrence of renal cell carcinoma. Median time from nephrectomy to resection was 10.3 months (range 3 to 159). No patient received systemic therapy before resection. Recurrence was asymptomatic in all except 1 patient. No intraoperative or postoperative mortality occurred. Six patients subsequently died of renal cell carcinoma at a median of 18 months (range 6 to 33.6) following resection. Median progression-free survival in groups 1 to 3 was 9.1, 8.7 and 15.6 months, while median cancer specific survival was 33.3, 20.8 and 46.9 months, respectively. Resection of isolated retroperitoneal lymph node recurrence may be associated with survival rates approaching those of resection of solitary metastasis at other sites. The decreased time to progression relative to patients with resected metastasis at other sites likely reflects the aggressive biology of nodal disease.

The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC–IV epithelial ovarian cancer

To determine the survival impact of adding extensive upper abdominal surgical cytoreduction to standard surgical techniques for advanced ovarian cancer. The records of all patients with stages IIIC-IV epithelial ovarian cancer who underwent primary surgery at our institution from 1998 to 2003 were reviewed. The cohort was divided into 3 groups. Group 1 patients required extensive upper abdominal surgery, such as diaphragm peritonectomy/resection, resection of parenchymal liver or porta hepatis disease and/or splenectomy with or without distal pancreatectomy, to achieve optimal cytoreduction (residual disease<or=1 cm). Group 2 patients were optimally cytoreduced by standard surgical techniques, including hysterectomy, oophorectomy, omentectomy, and bowel resection. Group 3 patients were suboptimally cytoreduced. Primary outcome measures were response to primary chemotherapy, progression-free survival, and overall survival. The cohort of 262 patients was divided as follows: Group 1, 57 patients; Group 2, 122 patients; and Group 3, 83 patients. The median follow-up was 36 months (range, 1-94 months). Frequency of clinical complete response in Groups 1, 2, and 3 was 82%, 78%, and 57%, respectively. The median progression-free survival for Groups 1, 2, and 3 was 24, 23, and 11 months, respectively. Progression-free survival for Groups 1 and 2 were equivalent (P=0.53) and were significantly longer than for Group 3 (P<0.001). The median overall survival was 84 and 38 months for Groups 2 and 3, respectively, and had not been reached for Group 1 by 68 months. Patients in Group 1 had equivalent overall survival to patients in Group 2 (P=0.74) and improved survival over patients in Group 3 (P<0.001). Prognostic factors significant on multivariate analysis included stage, optimal status, and ascites. Patients requiring extensive upper abdominal procedures to achieve optimal cytoreduction demonstrated a similar initial response, progression-free survival, and overall survival to patients optimally cytoreduced by standard surgical techniques. The presence of bulky upper abdominal disease alone did not appear to indicate poor tumor biology. This initial maximal surgical effort was associated with improved survival in patients who would have otherwise been suboptimally cytoreduced.

Yttrium-90 Ibritumomab Tiuxetan (Zevalin) for Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Not Appropriate for Autologous Stem Cell Transplantation: Results of an Open-Label Phase II Trial.

Presently, there is no standard second-line regimen for patients (pts) with diffuse large B-cell lymphoma (DLBCL) who cannot undergo stem cell transplantation. Since yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) is highly active in pts with follicular lymphoma, we wished to establish whether it is also effective in pts with relapsed DLBCL. We therefore conducted a prospective, single-arm, open-label, non-randomized, multicenter phase II trial to evaluate the efficacy and safety of 90Y ibritumomab tiuxetan in elderly pts with histologically confirmed first relapsed or primary refractory DLBCL not appropriate for autologous stem cell transplantation. Pts were divided into 2 groups: those previously treated with chemotherapy alone [Group A, n=76], and those previously treated with chemotherapy and rituximab [Group B, n=28]. Pts in Group A were further divided into 3 strata: pts with primary refractory disease (stratum 1, n= 33), pts relapsing within a year from presentation (stratum 2, n=10), and those relapsing more than 1 year from presentation (stratum 3, n=33). All pts were to receive a single dose of 90Y ibritumomab tiuxetan 14.8 MBq/kg (0.4 mCi/kg) up to a maximum dose of 1184 MBq (32 mCi). The primary endpoint was overall response (ORR) assessed by using IWNHL criteria at Weeks 6, 12, and 24. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). 104 pts were included. Three pts progressed after the first rituximab dose and in 1 patient the 111In labeling procedure failed; 103 pts were evaluable for efficacy and 104 for safety. An ORR of 44% was observed in the entire study population. In Group A, the ORR was 52% in stratum 1, 40% in stratum 2, 58% in stratum 3. In Group B, where 37% of pts were refractory to CHOP-rituximab, the ORR was 19%. The median PFS was 5.9, 2.3, and 6.2 months in strata 1, 2, 3 of Group A, respectively; the median PFS for Group B was 1.6 months. Median OS in Group A was 22.4 months in stratum 3 and has not yet been reached at a maximum follow-up time of 32 months in strata 1&2. Median OS was 4.5 months for Group B. Adverse events (AEs) with the exception of hematologic AEs were generally mild or moderate (CTC grade 1 and 2). There were 4 deaths due to SAEs. Three pts died of suspected cerebral hemorrhage, preceded by CTC grade 4 thrombocytopenias; another died of bleeding from a duodenal ulcer 280 days after the start of study medication, but this AE was determined not to be related to the study drug. The incidence of severe infection is low with 7% of pts hospitalized for infection during the study. In conclusion, 90Y ibritumomab tiuxetan has useful activity in the treatment of relapsed/refractory DLBCL, with no unexpected toxicities observed. The results of this study support a further evaluation of 90Y ibritumomab tiuxetan in combination with chemotherapy or immuno-chemotherapy earlier in the time course of DLBCL.

Three-Hour Paclitaxel Infusion and Carboplatin Is an Effective Outpatient Treatment for Stage III Epithelial Ovarian Cancer

Objective.The aim of this study was to determine the response rate and toxicity of a 3-h paclitaxel infusion and carboplatin delivered as outpatient therapy for the treatment of stage III/IV epithelial ovarian cancer.Methods.Thirty patients with stage III/IV epithelial ovarian cancer underwent cytoreductive surgery. The first 10 patients received adjuvant paclitaxel 150 mg/m2via 3-h infusion on day 1 and carboplatin 5 times area under the curve on day 2 (group 1) every 28 days. The paclitaxel dose was escalated to 175 mg/m2for the next 20 patients (group 2). χ2and Kaplan–Meier procedures were used for statistical analysis.Results.Nine of 51 cycles in group 1 (17.6%) and 19 of 116 cycles (16.4%) in group 2 were associated with grade 4 neutropenia (P= 0.96), but only 2 of the 161 total cycles (0.01%) had fever and neutropenia. One patient in group 1 experienced grade 3 thrombocytopenia. Two patients in the entire group (7.4%) required colony-stimulating factors. One patient in group 2 (3.7%) had grade 3 neurotoxicity. With a median follow-up of 29 months for the entire group, 5 of 8 patients (62.5%) in group 1 and 14 of 19 patients (73.7%) in group 2 are alive. Median progression-free survival for group 1 and 2 is 13 and 14 months, respectively. Median overall survival has not been reached.Conclusions.Paclitaxel via 3-h infusion and carboplatin is an effective outpatient treatment for epithelial ovarian cancer that can be safely administered on schedule in the majority of patients.