Duration Of PFS Research Articles

Treosulfan Based Conditioning Followed by Allogeneic Hematopoietic Cell Transplantation for Treatment of Patients with Non-Malignant Diseases: Preliminary Results of a Phase II Study

s / Biol Blood Marrow Transplant 19 (2013) S150eS166 S158 Conclusions: Both autoHCT and alloHCT are feasible and provide durable PFS and OS in this high risk cohort. Transformation to DLBCL > 1 year after dx of FL is associated with improved 1 yr PFS in both autoHCT and alloHCT groups, and superior 2 yr OS in the alloHCT group compared to those cases with transformation< 1year from dx of FL. Patients with primary induction failure also benefit from consolidation with HCT. PEDIATRIC DISORDERS ORAL

Prognostic Impact of the MRD Status After Induction Treatment with Rituximab Plus Fludarabine, Cyclophosphamide and Mitoxantrone (R-FCM) in Patients with Chronic Lymphocytic Leukemia Receiving Rituximab Maintenance Therapy

AbstractAbstract 3930Chemoimmunotherapy combination regimens achieve high rates of negative minimal residual disease responses in CLL, which has been correlated with prolonged PFS and OS. In the present study, we addressed the prognostic value of MRD levels obtained after rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) induction treatment in the response duration of patients with CLL included in the GELLC-1 trial and receiving maintenance rituximab treatment (Bosch et al. J Clin Oncol 27:4578–4584, 2009). Patients achieving CR or PR after R-FCM induction received rituximab maintenance consisting of rituximab 375 mg/m2 every three months for two years (up to 8 cycles). MRD was evaluated by four-color flow cytometry assays giving a sensitivity < 10−4 in paired peripheral blood (PB) and bone marrow (BM) samples three months after R-FCM induction therapy, every 6 months during rituximab maintenance, and at the final restaging 3 months after conclusion of treatment. Sixty-seven patients (median age 60 years, 70% male) received a median of 8 cycles of rituximab maintenance (range, 1 to 8), 76% of them completing the entire planned treatment. After R-FCM induction, MRD was considered negative in 45/59 patients (76%) in PB and in 35/63 patients (55%) in BM. Of note, these patients with negative MRD in PB had longer PFS in comparison to those with detectable MRD (at 4 years, 88%, [95%IC 98%-78%] vs 27%, [95%IC 51%-3%] respectively; p<0.01) (Figure 1). MRD negativity in BM showed a trend for a prolonged PFS (p=0.056). When MRD levels in BM after R-FCM induction where categorized, we observed that PFS was similar between the MRD negative (<10−4; n=35) and intermediate (>10−4 to <10−2; n=20) subgroups, whereas it was significantly shorter in patients showing high (>10−2, n=8) MRD levels (PFS at 4 years, 84%, 74%, and 25%, respectively, p<0.01). MRD levels after RFCM induction were compared between PB and BM paired samples. Whereas 12/57 patients (21%) that were MRD negative in PB resulted positive in BM, all patients with negative MRD in BM also had negative MRD in PB. Patients with discrepancies (negative in PB but positive in BM) in their MRD status presented a similar PFS than those with negative MRD in BM (4 year PFS, 85% vs. 90%, P=NS). The impact of MRD levels in PB achieved after R-FCM induction on PFS was also analyzed. MRD status proved to be a superior predictor for PFS than clinical response (Figure 2). In addition, when different prognostic variables (lymphocyte doubling time [LDT, cutoff 12 months], ZAP-70, serum ß2microglobulin and LDH, cytogenetic abnormalities, and MRD levels) were analyzed as predictors for PFS, only MRD status in PB along with LDT remained significantly predictive. After rituximab maintenance, 40.6% of patients achieved a MRD-negative CR, 40.6% a MRD+ CR, 5% a PR, and 14% failed to treatment. Median time to conversion from negative to positive MRD was 45.4 months, significantly longer than that observed in patients treated with FCM only (45.4 vs. 16.4 months; p=0.011) (Bosch et al. Clin Can Res 14:155–161,2008). Moreover, 3 patients that achieved MRD negative in PB but remained MRD positive in BM after the initial R-FCM treatment, became MRD-negative in BM upon rituximab maintenance. Patients that remained MRD negative in PB at the end of rituximab maintenance treatment had an excellent outcome with a PFS of 93% at 4 years in comparison to 68% in patients with MRD positive status (p=0.016). In conclusion, in patients receiving rituximab maintenance MRD levels obtained after R-FCM induction correlated with PFS duration, this correlation being independent of the clinical response attained. The sensitivity of the detection of MRD in these patients was higher in BM than in PB. Finally, maintenance treatment with rituximab seems to prolong the PFS of patients with MRD positive status, minimizing the negative impact of low levels of MRD after induction therapy. [Display omitted] [Display omitted] Disclosures:Off Label Use: Rituximab is currently not approved as maintenance therapy for patients with chronic lymphocytic leukemia. Bosch:Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

A Phase II Study of Sepantronium Bromide (YM155) Plus Rituximab in Previously Treated Subjects with Aggressive CD20-Positive B Cell Non-Hodgkin's Lymphoma Who Are Ineligible for or Have Previously Received an Autologous Stem Cell Transplant - Stage I Results.

AbstractAbstract 2731 Background:Survivin is responsible for preservation of cell viability and regulation of mitosis in tumor cells. Survivin is overexpressed in the majority of aggressive B-cell lymphomas and thus is an attractive target in subjects with relapsed lymphoma. YM155 is a survivin suppressant that in vitro, when combined with rituximab, synergistically enhances the induction of apoptosis in lymphoma cells. In human DLBCL xenograft models, this combination significantly inhibits tumor growth and prolongs survival. Based on these preclinical combination data and single agent clinical data, a Phase 2 study utilizing YM155 rituximab was initiated. Methods:The study employs a two-stage group sequential method, designed to enroll a total of 40 subjects with an interim futility assessment (Stage I). Eligible patients have histologically confirmed relapsed CD20-positive primary or transformed diffuse large B cell lymphoma (DLBCL) or grade 3 follicular lymphoma (FL) and are either not candidates or previously had an autologous stem cell transplant (ASCT). Subjects had received ≥ 1 prior anthracycline containing regimen with a documented response to the last regimen prior to study entry. Induction, ASCT and maintenance therapy were considered as one regimen. The dosing regimen was YM155 5 mg/m2/day as a 168 hour (7-day) continuous infusion in a 14 day cycle and rituximab 375 mg/m22 Days 1 and 8 cycles 1 – 4 and then repeated every 10 cycles. The primary endpoint of the study is objective response rate (ORR) per modified IWG 2007. Imaging studies are performed every 8 weeks (4 cycles) after initiation of therapy. In order to continue enrolling in the study, an overall response rate of 4/16 (25%) must be achieved. Results from the completed Stage I are reported here. Results:Sixteen subjects, the majority of whom were male 13/16 (81%), were enrolled in Stage I. The median age was 62.9 (range: 32 – 78) with a majority of subjects 15/16 (93.8%) with DLBCL. IPI/FLIPI scores were intermediate in 10 subjects (62.5%) and high in 3 subjects (18.8%). The median number of prior therapies was 2 (range: 1 – 5), 16/16 (100%) of patients received rituximab in 1st or subsequent lines of therapy. Seven patients (43.7%) had prior ASCT. The median number of cycles of YM155 administered was 11 (1–37). The overall response rate was 9/16 (56.3%) with 2/16 (12.5%) CR, 7/16 (43.8%) PR and 4/16 (25%) SD. The median time to response was 53 days (range: 52 – 109). Median duration of response and median PFS has not been achieved. Clinical benefit rate was 13/16 (81.3%). The most common adverse events reported, regardless of relationship, were pyrexia 8/16 (50%), cough 7/16 (43.8%), asthenia 5/16 (31%) and fatigue, back pain, vomiting, neutropenia and thrombocytopenia each 4/16 (25%). Five subjects (31.3%) experience Grade 4 adverse events and 2 (12.5%) had Grade 5 adverse events (disease progression and respiratory failure), neither of which was considered related to therapy. The most common Grade 4 event was neutropenia 4/16 (25%), with all other Grade 4 events occurring in only 1 subject (febrile neutropenia, thrombocytopenia, general physical health deterioration, infusion site extravasation, central line infection, infective thrombosis, mediastinitis, dyspnoea, pleural effusion). Conclusion:In subjects with relapsed aggressive NHL receiving combination YM155 and rituximab, the ORR for Stage I was 56.3%, which exceeds the requirement to continue to Stage II. Overall the combination regimen was well tolerated with limited hematologic toxicities. Stage II enrollment is ongoing. Disclosures:Papadopoulos:Astellas: Consultancy, Research Funding. Steinberg:Astellas Pharma: Employment. Papa:Astellas Pharma: Employment. Keating:Astellas Pharma: Employment.

Overall Survival Benefit for Patients with Relapsed Hodgkin Lymphoma Treated with Brentuximab Vedotin After Autologous Stem Cell Transplant

AbstractAbstract 3701 Background:Salvage chemotherapy and autologous stem cell transplantation (ASCT) in the management of relapsed or refractory Hodgkin's lymphoma (HL) results in prolonged disease-free survival in only around 50% of patients (pts). Median survival following relapse from ASCT is estimated at 2.4 years, with poor outcomes in those experiencing relapse or progressive disease within one year from ASCT (Horning 2008 et al). Recently, a pivotal multicenter Phase 2 trial investigated the efficacy of brentuximab vedotin (BV) in pts with recurrent HL following ASCT. The study demonstrated an overall response rate of 75% and median duration of response of 6.7 months. Furthermore, 34% of patients achieved a complete response (CR), with a median progression free survival of 29 months (mos). Whether treatment with BV renders an OS benefit in pts with relapsed or refractory disease after ASCT remains to be determined. Objective:1) To compare OS in pts with relapsed HL after receiving ASCT in a cohort of 102 HL pts treated with BV, with 756 pts from 6 international centers before the introduction of BV. 2) To evaluate predictors of durable CR in pts treated with BV. Methods:Kaplan-Meier method was used to depict time-to-event outcomes, including OS. The Chi-square test was used to evaluate the association between two categorical variables and log-rank test to compare time-to-event endpoints among pt groups. Based on the univariate proportional hazard model, we examined whether certain variables (sex, stage at diagnosis, number of prior treatments, and time to CR) were predictors of CR duration in pts receiving BV. Results:In the non-randomized comparison between those with relapsed-refractory HL following ASCT who received BV and those who did not, pts were well matched by age, with a relatively higher percentage of females treated on the pivotal study. Dates of progression from ASCT ranged from 1996–2009 in the BV group and 1981–2003 in the international cohort. Median follow-up after ASCT for the censored observations of pts who received BV and those in the international cohort was 49.4 and 58.8 mos. The difference in median OS was statistically significant (p<0.0001) between those receiving BV and those not exposed to the drug (91.49 vs. 27.99 mos). Improvement in OS was irrespective of time to relapse from ASCT, despite previous studies noting a higher risk of recurrence in pts relapsing within 12 mos of ASCT (Sureda 2005 et al). Neither age nor sex was found to impact OS. In the subgroup analysis of pts achieving a CR with BV, univariate analysis of duration of CR and PFS uncovered no significant factors, while only stage of disease at initial diagnosis had a significant effect on OS (P=0.0004). Disease status characterized as relapsed vs. refractory had borderline significance with a positive impact on OS (P=0.0581). No significant associations were noted between the variables and duration of response post BV stratified into periods of less or greater than 12 mos. However, among those pts who experienced a duration of CR greater than 12 mos, 81.8% (n=18) had an initial CR after receiving ≤ 4 doses of BV, compared with 58.3% entering CR after receiving > 4 doses. Conclusions:While the impact of BV on OS can only be determined through a randomized clinical trial, our analysis indicated that treatment with BV in pts with relapsed/refractory HL following ASCT is associated with prolonged OS when compared with historical control patients. Those who achieve a rapid CR with BV may also have a longer duration of response. A randomized clinical trial is ongoing to evaluate prospectively the efficacy of BV following ASCT.Table 1:Median OS post ASCT w/Univariate AnalysisNEventMedian OS Time in Mos (95%CI)OS Rate at 60 Mos (95%CI)OS Rate at 120 Mos (95%CI)P-valueAll patients85863433.44 (28.68, 38.44)0.3 (0.27, 0.34)0.16 (0.13, 0.2)BVNon-BV75659127.99 (24.05, 31.54)0.26 (0.23, 0.3)0.14 (0.11, 0.17)<0.0001BV1024391.49 (56.27, 177.2)0.58 (0.47, 0.71)0.33 (0.2, 0.56)Age<3038227234.2 (27.99, 40.05)0.32 (0.27, 0.37)0.17 (0.13, 0.23)0.6772>=3047636233.31 (28.09, 39.19)0.29 (0.25, 0.34)0.15 (0.12, 0.2)SexF35825928.88 (25.3, 38.11)0.31 (0.27, 0.37)0.18 (0.14, 0.24)0.8834M50037536.43 (29.73, 40.97)0.3 (0.26, 0.34)0.15 (0.11, 0.19) [Display omitted] [Display omitted] [Display omitted] Disclosures:Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau. Gopal:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding; Celgene: Consultancy. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Ramchandren:Seattle Genetics, Inc.: Speakers Bureau. Forero-Torres:Seattle Genetics: Research Funding. Moskowitz:Seattle Genetics: Speakers Bureau. Connors:Seattle Genetics, Inc.: Research Funding. de Vos:Seattle Genetics: Speakers Bureau. Engert:Takeda: Honoraria, Research Funding; Millennium: Honoraria, Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Morschhauser:Takeda: Honoraria. Younes:Seattle Genetics: Honoraria.

Bendamustine Salvage Therapy for T-Cell Non Hodgkin Lymphoma

AbstractAbstract 4860 BackgroundAt present, the standard salvage treatment for relapsed/refractory (R/R) T-cell non Hodgkin lymphoma (NHL) has not been defined yet. Several studies indicated the high therapeutic activity and good safety profile of Bendamustine in B-cell NHL while, on the contrary, only few data are available in T-cell NHL. Recently, a multicenter phase II study showed that Bendamustine is active in angioimmunoblastic lymphoma and other T-cell NHL with 50% overall response rates (OR) and 28% complete responses (CR) (Gressin et al. J Clin Oncol, 2012 ASCO Annual Meeting Proceedings, 30, 15 suppl: 8026). PurposeOn this basis we evaluated in the contest of everyday clinical practice the efficacy and safety of Bendamustine salvage monotherapy in unselected adult patients with T-cell NHL. Patients and MethodsHematological and Oncological Italian centers involved in the treatment of patients with lymphomas were asked to report retrospectively the results of their experience regarding the use of Bendamustine in T-cell NHL. Response status and toxicity were evaluated according to Cheson 2007 and to the Common Terminology Criteria For Adverse Events V 4.0. ResultsClinical data of 20 patients with R/R T-cell NHL (median age 73 years, range 31–83; 14 males) treated with Bendamustine in seven Italian centers between March 2009 and June 2012 were analyzed. Investigated series included 6 peripheral T-NHL-NOS, 4 angioimmunoblastic (AILT), 3 prolymphocytic T-cell leukemia (PLL), 3 advanced- stage Mycosis Fungoides (MF)/Sezary Syndrome (SS), 2 large granular lymphocyte (LGL) NHL and 2 ATLL- like HLTV-1 negative NHL. The median interval from diagnosis to Bendamustine treatment was 18 months (range 1–74). Eleven patients received up to 2 previous lines of therapy, while 9 received more than 2, including CHOP or CHOP-like therapy (14 patients), Fludarabine or Pentostatine (5), Gemcitabine based therapy (7), Alemtuzumab (4), Romidepsin (1), allogeneic stem cell transplant (1). Nearly 70% of patients were refractory to the last previous chemotherapy. Bendamustine was given as monotherapy at a dosage of 60 and 70 mg/m2 (7 patients) or 90–100 mg/m2(13) for a median number of 2.5 cycles (range 1–8) and a total number of 67 cycles. Response to Bendamustine was CR in 2 (10%) and PR in 8 (40%), with an ORR of 50%, including 3 PR in T-cell NHL/NOS, 1 CR in AILT, 3 PR in PLL, 1 PR in MF/SS, 1 CR and 1 PR in LGL NHL. The median period of observation was 6 months (range 1–18 months); 6- months estimated PFS, OS and response duration are 63%, 70% and 60%, respectively. Three patients in PR (2 PLL and 1 MF) progressed after 3, 4 and 7 months. Grade 3–4 neutropenia, thrombocytopenia and anemia were registered in 44%, 25% and 19% of cases. Three patients developed pneumonia (1 invasive aspergillosis) and 1 had septic shock; no grade 3–4 extra hematological toxicity was reported. ConclusionsBendamustine is a safe and active agent that desertes further investigation in patients with T-cell NHL. Combinations with other cytostatics or target therapy with potential synergistic effect should be assessed in future prospective trials. Disclosures:Zaja:Mundipharma: Honoraria. Off Label Use: Bendamustine In T-NHL. Fanin:Mundipharma: Honoraria.

Immunological Effects and Predictive Gene Signatures in Patients with Relapsed Follicular Lymphoma Treated with CT-011, a Humanized Anti-PD-1 Monoclonal Antibody

AbstractAbstract 162 Background:The coinhibitory receptor programmed death (PD)-1 is markedly increased on peripheral blood (PB) and intratumoral T cells in follicular lymphoma (FL) and is associated with impaired T-cell function. CT-011 (pidilizumab), a humanized anti PD-1 monoclonal antibody, blocks the PD-1/PD-ligand pathway and enhances the function of antitumor T and NK cells. We conducted a phase II trial to determine the safety and efficacy of CT-011 and rituximab in patients (pts) with relapsed FL and the clinical results are reported separately. Here, we evaluated the effects of CT-011 on immune cells both in the PB and tumor microenvironment. We also determined predictors of clinical outcome based on PB immune cell subsets and molecular features of tumor-infiltrating immune cells at baseline. Methods:CT-011 was given every 4 wks × 4 and rituximab weekly × 4 starting on day 17 after the first infusion of CT-011. Pts with response or stable disease received 8 additional optional infusions of CT-011 every 4 wks. PB and core needle biopsies from involved lymph nodes were collected prior to and on day 14 after the first infusion of CT-011. PB mononuclear cells (PBMC) were analyzed by multiparametric flow cytometry to determine various immune cell subsets. Whole genome gene expression profiling (GEP) was performed on core needle biopsies. Results:Of 29 pts eligible for efficacy analysis, 19 had an objective response for an ORR of 66%. CR was observed in 15 (52%) and PR in 4 (14%). After a median follow up of 14 mo, median PFS was 21.1 mo, and was not reached for the responders. We observed a significant increase in the absolute number of PB immune cells in day 14 samples compared with baseline including total lymphocyte count (p<0.01), CD3+ T cells (p=0.01), CD4+ T cells (p<0.01), and CD4+ naive (p=0.01), effector memory (p=0.02), and central memory T cells (p<0.05). We also observed increase in the expression of the activating receptor NKG2D on NK cells (p=0.01). In contrast, CD8+ terminally differentiated T cells were decreased (p=0.02). Comparison of GEP from core needle biopsies obtained pretreatment and day 14 (n=8 pairs) showed up regulation of several genes associated with T cell activation in day 14 samples including CD58, CTLA4, NFATC1, CCR5, PBK, TSLP, and ZBTB32.We analyzed GEP of baseline tumor biopsies from 18 pts to find gene signatures that correlated with clinical outcome, as measured by PFS and/or quantitative change in tumor size (%change). We tested a “PD-1hi_Down” signature of 41 genes previously reported by us (Chu et al, Blood, Nov 2011; 118:2648) to be less expressed in CD4+ T cells strongly positive for PD-1, likely to be follicular helper T cells (Tfh, PD-1hi), than in CD4+ T cells with intermediate or low levels of PD-1 surface staining, likely to be exhausted effector T cells (Teffs, PD-1int) or activated effector or naïve T cells (PD-1lo). The PD-1hi_Down gene signature correlated significantly with PFS by univariate Cox regression and was also significant when examined by gene set enrichment analysis based on ranking all genes by correlation with %change. Low expression of this signature, suggesting more Tfh and fewer PD-1+ Teffs within the tumor, predicted shorter PFS duration and less tumor shrinkage. Combined with our in vitro findings that anti-PD-1 Ab enhances the function of Tfh and PD-1+ Teffs but has no effect on PD-1lo T cells in FL, these results suggest that CT-011 therapy enhances the respective pro- and anti-tumor effects of one or both of these cell types. In support of our conclusion that the effect of the PD-1hi_Down signature on outcome depends on CT-011 therapy, we found that this signature did not correlate with overall survival in an external dataset of FL pts treated largely with chemotherapy alone (Dave et al., NEJM 2004; 351: 2109). Conclusions:Administration of CT-011 (pidilizumab) was associated with increase in the numbers of naïve, effector memory, and central memory CD4+ T cells and resulted in activation of T and NK cells in the PB and the tumor microenvironment in FL. A high expression of PD-1hi_Down gene signature, consistent with relatively increased numbers of antitumor Teffs compared with protumor Tfh was predictive of good response and improved PFS suggesting that CT-011 restores function of exhausted Teffs. These results provide insight into the mechanism of action of CT-011 and offer a predictive biomarker for selection of pts for future clinical trials with this class of agents in FL. Disclosures:Rotem-Yehudar:CureTech Ltd: Employment, Research Funding. Neelapu:Cure Tech, Ltd.: Research Funding.

Bendamustine As Salvage Therapy in Multiple Myeloma: A Retrospective, Multicenter Study From the Italian Compassionate Use Program in 78 Heavily Pre-Treated Patients.

AbstractAbstract 2971 Introduction:Bendamustine is a bifunctional alkylating agent approved for the treatment of several lymphoproliferative disorders. Studies have evidenced its efficacy in multiple myeloma (MM), but data so far available in this setting are scarce. We performed a retrospective analysis of Italian patients with relapsed/refractory MM, who had received bendamustine as salvage therapy within a national compassionate use program. Patients and methods:Seventy-eight patients (42 males, 36 females) were collected in 19 hematological centers. Mean age was 64.2 years (range 38–84). ISS was equally distributed, with about one third of patents being represented in single stages. Twenty-three of 43 analyzed patients had cytogenetic abnormalities, the most frequent being del13q (14 patients); t(4;14) and t(11;14) were observed in 4 and 2 patients, respectively, while t(6;14), del17p or complex karyotype occurred in single patients. The median number of prior lines of therapy was 4 (range 1–10). Ninety-seven percent of patients had previously received bortezomib, 94% IMIDs, 85% melphalan, 74% cyclophosphamide, 45% anthracyclines, 26% other drugs, 33% radiotherapy. Sixty percent of patients had undergone autologous and 4% allogeneic stem cell transplantation. The last treatment before bendamustine was a bortezomib-based regimen in 31%, an IMIDs-based regimen in 42%, a combined bortezomib/IMIDs-based regimen in 9%, while 18% of patients had received other therapies. Seventy-three percent of patients were resistant to last therapy received, while 27% had relapsed. Median duration of response to last treatment received before bendamustine was 9 months (range 2–46). Median Hb value was 10.1 g/dl (range 7.6–14.9), WBC count 2.700/μl (range 550–15.200), PLT count 130.000/μl (range 6.000–410.000). Serum creatinine, calcium, beta2-microglobulin and LDH levels were increased in 12 (15%), 4 (5%), and 44 (56%) patients, respectively, while albumin levels were decreased in 27 patients (35%). The median percentage of marrow plasma cells (as evaluated in 57 cases) was 60% (range 1–100). Seventy-six percent of patients had osteolytic bone involvement and 78% extramedullary localizations, with 13% showing secondary plasma cell leukemia and 7% documented amyloidosis or proteinuria. Finally, 45% of patients presented with at least one severe comorbidity, mainly cardio-vascular, liver or pulmonary dysfunction, and diabetes. Results:A total of 236 cycles was administered (median 3, range 1–9). In 47% of patients bendamustine was variously associated to bortezomib (23%), or IMIDs (21%), or to a combination of both (3%). In 80% of patients receiving bendamustine +/− steroids, a median dose of 90 mg/sqm for two consecutive days every 28 days was employed; the median dose was 80 mg/sqm when bendamustine was combined with bortezomib, 60 mg/sqm with IMIDs (total range: 40–140 mg/sqm). The remaining patients received single, monthly doses ranging from 60 to 150 mg/sqm. According to IMWG uniform response criteria, 21 out of 73 evaluable patients achieved a response after a median time of 3 months. In particular, there were 16 PR, 1 VGPR, 1 sCR, and 3 CR; overall response rate (ORR) was, therefore, 29%. Response rate was 10% (4/39) in bendamustine single agent +/− steroids, 38% (5/13) in bendamustine + bortezomib and 62% (10/16) in bendamustine + IMIDs subgroups, respectively. Responders had received a lower number of previous treatments than non responders (median 3 vs 4). Response rate was higher in relapsed (12/21, 57%) than in resistant patients (10/57, 17%). The time to best response ranged from 1 to 8 months. After a median follow-up of 8 months, median PFS duration was 6 months, with 13 out of 21 responding patients not yet progressed. Median OS of the entire cohort was 6.2 months (7 months in responders and 4 months in non responders, range 0–27). Grade 3–4 hematological and non-hematological toxicities occurred in 56% and 15% of patients, respectively, causing three interruptions of the treatment. Conclusions:Though with the clear limits due to the high heterogeneity of treatments applied and of population analyzed, our data indicate that bendamustine may be a therapeutic option in heavily pretreated MM, suggesting a possible non cross-resistance with other agents. Its earlier use with appropriate doses and combinations might further improve the results obtained in this study. Disclosures:Musto:Mundipharma: Honoraria. Off Label Use: Bendamustine in relapsed/refractory myeloma. Fragasso:Mundipharma: Honoraria. Baldini:Mundipharma: Honoraria. Storti:Mundipharma: Honoraria.

Is the Pretreatment Neutrophil to Lymphocyte Ratio an Important Prognostic Parameter in Patients with Metastatic Renal Cell Carcinoma?

BackgroundTyrosine kinase inhibitor is a standard treatment for mRCC. The NLR, an index of systemic inflammation, is associated with outcome in several cancer types. To study the association of pretreatment NLR with PFS and overall survival (OS) of patients treated with VEGF-targeted therapy. Patients and MethodsWe retrospectively studied an unselected cohort of patients with mRCC, who were treated with TKIs. Kaplan-Meier and log-rank analyses were employed on PFS and OS and multivariate Cox proportional hazard model analyzed clinical parameters for their prognostic relevance. ResultsA total of 100 patients with mRCC who had early progressed after first-line therapy with interferon-α were included in this retrospective multicenter study conducted at 4 centers between February 2008 and December 2011. The median of the NLR was 3.04 and patients were divided into 2 higher and lower NLR groups according to median of NLR. Median PFS was 9 versus 11 months in patients with baseline NLR > 3.04 versus ≤ 3.04 (P = .009). The median OS was 16 months versus 29 months, in patients with NLR > 3.04 versus ≤ 3.04, respectively (P = .004). In the whole group OS was independently associated with higher NLR (hazard ratio [HR], 2.406; P = .004), PFS more than 6 months (HR, 4.081; P = .0001), and sex (HR, 2.342; P = .040). On the other hand in the higher NLR group (HR, 1.107; P = .009) Memorial Sloan-Kettering Cancer Center score (HR, 3.398; P = .0001) was associated with PFS. ConclusionIn patients with mRCC treated with VEGF-targeted therapy, pretreatment NLR, the duration of PFS might be associated with OS. This should be investigated prospectively.

Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial.

LBA3500^ Background: Therapy targeting VEGF or EGFR demonstrated clinical activity in combination with chemotherapy (CT) in mCRC but monoclonal antibodies cannot be associated. The DREAM trial compares a maintenance therapy (MT) with bev +/- EGFR tyrosine kinase inhibitor erlotinib (E) after a first-line Bev-based induction therapy (IT) in pts with mCRC. Methods: Pts with previously untreated and unresectable mCRC were eligible. After a Bev-based IT with FOLFOX or XELOX or FOLFIRI, pts without disease progression were randomized to MT between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (B 7.5 mg/kg q3w, E 150 mg/day continuously; arm B). Pts were treated until progression or unacceptable toxicity. The primary endpoint was PFS on MT. Results: The study enrolled 700 pts from 01/2007 to 11/2011 in 3 countries (France, Canada, Austria). 446 (63.7%) pts were randomized for MT (arm A, N=224; arm B, N=222). Among the 446 randomized pts, IT regimen was FOLFOX-Bev in 265 pts (59.4%), XELOX-Bev in 135 pts (30.3%), and FOLFIRI-Bev in 46 pts (10.3%). Baseline characteristics of randomized pts were (arm A/B): ECOG PS 0, 60% in both arms; normal LDH level 47%/49%; normal alkaline phosphatase level 48%/50%; synchronous metastasis 83%/82%. The median no of MT cycles was 6 in both arms. With a median follow-up of 31.0 months, 327 PFS events were observed. Median MT-PFS were 4.6 m in arm A vs 5.8 m in arm B (HR 0.73 [95%CI: 0.59-0.91], P=.005). Median PFS from inclusion were 9.2 m vs 10.2 m. During MT, in arm A vs arm B, grade 3-4 diarrhea (&lt;1% vs 9%) and grade 3 skin toxicity (0% vs 19%) were the main differences in toxicity. Severe adverse events from randomization related to B or E were 6 in arm A and 7 in arm B. Overall survival is not mature. Conclusions: The addition of erlotinib to bevacizumab after induction therapy significantly improves the duration of maintenance PFS, following induction with first-line chemotherapy plus bevacizumab, in patients with unresectable metastatic colorectal cancer.

LUX-breast 2: Phase II, open-label study of oral afatinib in HER2-overexpressing metastatic breast cancer (MBC) patients (pts) who progressed on prior trastuzumab (T) and/or lapatanib (L).

TPS651 Background: Management of HER2-overexpressing MBC has improved over the past decade. However, pts still develop resistance to currently available HER2-targeted therapies and novel effective treatments are increasingly required as dual targeted combinations are given in early treatment lines already. Current therapies focus on targeting HER2 and do not inhibit all relevant ErbB Family dimers. Afatinib is an oral, irreversible ErbB Family Blocker that inhibits signaling through activated EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptors and transphosphorylation of ErbB3. Preclinical studies have demonstrated efficacy in T-sensitive and T-resistant human BC xenograft models dependent on ErbB signaling. Efficacy of afatinib in a T-resistant SUM 190 xenograft model has been shown to be increased by addition of IV vinorelbine (V). Afatinib monotherapy has shown promising clinical benefit in 46% of HER2-overexpressing MBC pts who progressed on prior T, with 10% of pts achieving PR. Methods: This open-label Phase II trial (NCT01271725) investigates efficacy and safety of afatinib alone (40 mg/d) followed by afatinib ‘beyond progression’ plus chemotherapy in 120 pts with HER2-overexpressing MBC, who progressed on prior neoadjuvant and/or adjuvant T and/or L. Pts who progress on afatinib monotherapy receive afatinib plus either weekly paclitaxel (P) 80 mg/m2 or V 25 mg/m2. Eligible pts have confirmed HER2-overexpressing BC, stage IV disease measurable by RECIST 1.1, progressed on T and/or L therapy in either neoadjuvant and/or adjuvant setting, are eligible for retreatment with P or V and should not have been pretreated with P (≤12 months) or V, respectively. Exclusion criteria: inadequate cardiac, renal, hepatic and hematological function, pre-existing gastrointestinal dysfunction, rapidly progressing visceral disease, ILD and active brain metastases. The primary endpoint is objective response (OR) and secondary endpoints include best overall response, duration of OR and PFS; safety will be assessed separately for afatinib mono- and combination therapy. Patient enrollment began in May 2011 in ~35 sites and 5 countries.

Bortezomib, Lenalidomide, and Dexamethasone (VRD) Consolidation and Lenalidomide Maintenance in Frontline Multiple Myeloma Patients: Updated Results of the IFM 2008 Phase II VRD Intensive Program

Abstract 1872 Background:Introduction of new drugs in the intensive pathway have markedly increased survival rates for MM patients within the last 10 years. Efforts to further improve response and survival are still needed, mainly by increasing the depth of tumor reduction and the duration of response. Bortezomib (Bor), Lenalidomide (Len) and Dexamethasone (Dex) combination demonstrated substantial activity in frontline MM (Richardson P et al., Blood 2010); the IFM reported primary results of the VRD regimen as induction and consolidation therapy in the transplant setting (Roussel M et al. ASH 2010). We currently present updated data of the IFM 2008 trial. Methods:This phase II study was conducted at 10 transplant centers in France, with enrollment between Sept. 7 and Dec. 15, 2009. Pts with symptomatic upfront MM were enrolled to receive three 21-day induction cycles of VRD= Bor 1.3 mg/m2 (D1, 4, 8, 11), Len 25 mg/day (D1–14), and Dex 40 mg/day once a week (D1, 8 and 15). Stem cell collection (STC) was planned after high dose cyclophosphamide (3g/m2). All pts then proceeded to melphalan 200 mg/m2 followed by ASCT. Two months after hematological recovery, pts received two 21-day consolidation cycles of VRD (same schedule) followed by 1 year of maintenance with Len at 15 mg/day. All pts received, unless contraindicated, anticoagulation for prevention of deep-vein thrombosis (DVT), and anti-viral therapy. Pts with grade ≥2 peripheral neuropathy (PNY) were excluded. The primary endpoint was the best response achieved after consolidation. The secondary endpoints were: response rate after 3 cycles of VRD as induction, after ASCT and after maintenance; safety profile of the program; feasibility and quality of STC; duration of response, PFS, and OS. Response was assessed according to International Uniform Response Criteria including stringent Complete Response (sCR). Flow cytometric analysis of bone marrow plasma cells for minimal residual disease (MRD) was performed before and after ASCT, after consolidation and after maintenance. Adverse events (AEs) were graded using the CTC for Adverse Events (AE) v4. Patients:Thirty-one pts were enrolled. Baseline characteristics were: median age= 58 (range 33–65); women= 55%; 55%/32%/13% had IgG/IgA/light chain MM; ISS= 1 in 52%, 2 in 32% and 3 in 16% of pts; chromosome 17p del in 18% and t(4;14) translocation in 11% among 27 assessable pts. Results:All pts but 7 remain on study program at data cut-off (01/08/11). One pt discontinued treatment due to mobilization failure, 5 pts stopped maintenance because of serious AE (1 extensive DVT unless efficient anticoagulation) or AEs ( 3 grade 3/4 neutropenia and/or thrombocytopenia, 1 grade 3 hypothyroidism) and 1 pt went off study because of progressive disease. Currently, Len maintenance is on going for 6 pts and 4 pts just completed their last cycle.Therefore, 30 pts are evaluable for response after consolidation, and 20 after maintenance. All results are summarized in table 1. In ITT analysis, the overall response rate (ORR) after consolidation is 94%, including 36% VGPR, 48% RC or better (9% CR, 39% sCR). Consolidation therapy with 2 VRD cycles upgraded response in 26% of pts but only 1 pt achieved MRD negative (among 24 assessed). At time of reporting, Len maintenance did not improve response rate but 1 pt get MRD negative. One pt progressed during maintenance phase and 2 pts turned into MRD positive again without evidence of relapse.Table 1:InductionASCTConsolidationMaintenancen%n%n%n%sRC51711361239838RC262639210RC+sRC723134215481048VGPR12398261136628RP1032723310210ORR2994289129941886SD26261315PD15Out of trial111Total31313121Considering the safety profile, 18 serious AEs were reported. There was no treatment-related mortality. The most common toxicities during consolidation therapy were: emergent PNY (23%), including 10% grade 1 and 13% grade 2; grade 3/4 neutropenia (17%), and thrombocytopenia (10%). The most common toxicities during Len maintenance were: grade 3/4 neutropenia (43%), and thrombocytopenia (10%); fatigue (13%); erythrodermia (10%); zona (10%). One extensive DVT and one pulmonary embolism were reported. There was no evidence of secondary malignancy. Conclusions:VRD consolidation plus Len maintenance after VRD induction and HDT produce high quality responses with 38% of sCR and is well tolerated in de novo MM pts. Updated efficacy and safety data will be presented at the meeting. Disclosures:Roussel:Janssen: Honoraria; Celgène: Honoraria. Off Label Use: bortezomib, lenalidomide and dexamethasone as induction and consolidation therapy lenalidomide maintenance. Moreau:Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria; Janssen: Advisory board, Honoraria. Hulin:Celgene: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria. Leleu:celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Facon:celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Avet-Loiseau:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Attal:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Abstract A6: Association of clinical outcomes and the change in circulating soluble VEGF receptor 2 (VEGFR2) levels in advanced gastric cancer patients treated with telatinib (Tel), capecitabine (X), and cislatin (P).

Abstract Background: Serum VEGFA concentrations and association with metastasic disease/and or poor outcome has been well documented in gastric cancer (GC) patients (pts). However, VEGFA has not been a useful predictor for outcome of treatment with VEGF pathway inhibitors. The soluble form of the VEGF receptor 2 (sVEGFR2) neutralizes circulating VEGF and functions as a negative feedback mechanism to enable partial inhibition of angiogenesis. Reduction in circulating sVEGFR2 levels has been shown upon treatment with multiple small molecule VEGFR inhibitors. Tel is a potent, oral and selective inhibitor of VEGFR 1, 2 and 3 and PDGF receptors. We investigated if marked decrease in the concentration of sVEGFR2 from baseline in response to Tel treatment were associated with lower risk of progression and death compared to pts with smaller decreases or no decrease from baseline. Methods: TEL0805, a phase 2 study, administered Tel with X and P (TEL-XP) as first-line treatment for advanced GC pts. Tel was administered at 900 mg bid beginning day (d)-7 (lead-in for PK/PD analysis) continuously until progression, X was administered d1–14, and P d1 of each 21 day cycle. Serum samples for sVEGR2 analysis were collected on d-7 (baseline) and d1 prior to treatment of the first and every other cycle. Pts whose maximum percentage decrease from baseline was &amp;gt;33% were considered to have “larger” decreases in sVEGFR2. Pts whose maximum percentage decrease from baseline was &amp;lt;33% were considered to have “smaller” decreases, this group included pts with sVEGFR2 levels unchanged or increased from baseline. Results: Twenty-eight pts (25 metastatic, 3 stage III) had sVEGFR2 levels available for analysis. The median baseline sVEGR2 levels were 6,780 pg/mL (range 3,750 to 9,100). Treatment with Tel alone demonstrated onset of reduction of sVEGFR2 by d 7 of the first cycle. Reductions were achieved regardless of tumor histology or disease location. The median of the distribution corresponds to a maximum decrease from baseline of 25%. The duration of OS and PFS were both significantly longer for pts with ≥33% in sVEGFR2 relative to pts with &amp;lt;33%. Median PFS was 4.7 vs. 11.6 months (mths) for pts with smaller versus larger decreases in sVEGFR2 (hazard ratio 0.19; 95% CI: 0.05 to 0.68; p=0.01 by log-rank test). Similarly, median OS was 7.6 mths for pts with smaller decreases in sVEGFR2 and was not reached for pts with larger decreases (hazard ratio 0.23; 95% CI: 0.05 to 1.03; P=0.04 by log-rank test). Follow-up for surviving pts with larger decreases in sVEGFR2 ranges from 9 to 14 mths. Conclusions: In GC pts treated with the TEL-XP regimen, larger percentage decreases in the concentration of sVEGFR2 from baseline were associated with lower risk of progression and death compared to pts with smaller decreases or no decrease from baseline. Further study of sVEGR2 levels as a predictor of response to TEL-XP will be explored in a randomized setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A6.

FCR (Fludarabine, Cyclophosphamide, Rituximab) regimen followed by 90yttrium ibritumomab tiuxetan consolidation for the treatment of relapsed grades 1 and 2 follicular lymphoma: a report of 9 cases

BackgroundThis retrospective analysis is focused on the efficacy and safety of radioimmunotherapy (RIT) with Zevalin® in nine patients with recurrent follicular lymphoma (FL) who were treated in a consolidation setting after having achieved complete remission or partial remission with FCR.MethodsThe median age was 63 yrs (range 46-77), all patients were relapsed with histologically confirmed CD20-positive (grade 1 or 2) FL, at relapse they received FCR every 28 days: F (25 mg/m2x 3 days), C (1 gr/m2 day 1) and R (375 mg/m2 day 4) for 4 cycles. Who achieved at least a partial remission, with < 25% bone marrow involvement, was treated with 90Yttrium Ibritumomab Tiuxetan 11.1 or 14.8 MBq/Kg up to a maximum dose 1184 MBq, at 3 months after the completion of FCR. The patients underwent a further restaging at 12 weeks after 90Y-RIT with total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy.ResultsNine patients have completed the treatment: FCR followed by 90Y-RIT (6 patients at 14.8 MBq/Kg, 3 patients at 11.1 MBq/Kg). After FCR 7 patients obtained CR and 2 PR; after 90Y-RIT two patients in PR converted to CR 12 weeks later. With median follow up of 34 months (range 13-50) the current analysis has shown that overall survival (OS) is 89% at 2 years, 76% at 3 years and 61% at 4 years. The most common grade 3 or 4 adverse events were hematologic, one patient developed herpes zoster infection after 8 months following valacyclovir discontinuation; another patient developed fungal infection.ConclusionsOur experience indicate feasibility, tolerability and efficacy of FCR regimen followed by 90Y-RIT in patients relapsed with grades 1 and 2 FL with no unexpected toxicities. A longer follow up and a larger number of patients with relapsed grades 1 and 2 FL are required to determine the impact of this regimen on long-term duration of response and PFS.

Refractory NK/T Cell Lymphoma Treated with Bortezomib+Chemotherapy and APBSCT.

AbstractAbstract 4602 Backgrouds:NK/T cell lymphoma is a rare disease, but usually shows a highly aggressive clinical course and its prognosis is poor due to the stumbling block in early diagnosis and effective management. Until present, there are no consensus treatments especially for recurrent patients. Bortezomib, and other new drugs are subject to active investigation, although only limited preliminary information is available. Here, 3 cases of refractory disseminated NK/T cell lymphoma were treated with Bortezomib plus high dose chemotherapy as salvage therapy. Patients and methods:From 2008–2010, 3 cases of refractory NK/T cell lymphoma, 2 males, 1 female, aged from 26–35, PS 0–1 were enrolled. Former treatments included at least 2–9 months of chemotherapy (CHOP or CHOP like) and local radiotherapy. The stage of patients was III in 2, IV in 1. IPI scores were all in high risk. Result:3 patients received high dose chemotherapy combined with bortezomib as re-induction treatment. 2 patients received hyperCVAD as induction therapy with bortezomib given 1.3mg/m2 on d2, 5, 9 and 12. 1 patient received bortezomib and SMILE protocol, included bortezomib 1.3 mg/m2 on days1, 4, 8, 11, dexamethasone 20 mg twice a day on days 1 through 4, etoposide 100 mg/m2 on days 1 through 3, ifosphamide 1.0 g/m2 on days 1 through 5, methotrexate 30 mg/m2 on days 4, 11, L-asparaginase 6000U/m2 on days 7, 9, 11, 13, 15. All 3 patients had response to the treatment. HyperCVAD, HDAC+MTX and SMILE protocol combined with bortezomib were also given to the patients as consolidation therapy for 1–4 courses. After 2 course of treatment, 1 patient got CR, 2 got PR. Then ASCT was performed. Condition protocol was SEAM+Bz1.3 mg/m2 on days-4, -1. At a median follow-up for 15 months, the median duration of PFS was 12 months. No PN was found in all patients. SAE were neutropenia and thrombocytopenia grade 4, mucositis grade 3, increase AST grade 2 in 3 patients and HZV infection in 1. Conclusion:Bortezomib combined with high dose therapy may be effective salvage therapy in some refractory disseminated NK/T cell lymphoma, especially in young adults. More cases need to be carefully investigated to explore the effect and side effect in bortezomib plus high dose therapy in this special disease. Disclosures:No relevant conflicts of interest to declare.

The Addition of Rituximab and/or Alpha-Interferon to High Dose Chemotherapy and Autologous Stem Cell Transplantation for Patients with Relapsed Follicular Lymphoma Produces Durable Progression Free Survival and Molecular Remissions

AbstractAbstract 1357 Introduction:High dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is historically effective treatment for patients with relapsed follicular lymphoma (FL) but relapse is common possibly due to contaminated stem cell grafts or inadequate eradication of primary disease. The addition of immunotherapy to HDT/ASCT may augment “in vivo” graft purging and achieve more effective eradication of minimal residual disease (MRD) post ASCT. This may lead to improved PFS and OS. Methods:We conducted 3 sequential prospective phase 2 trials of HDT/ASCT combined with immunotherapy in patients with relapsed FL from 1997–2010. Protocol 1 (n=13) used a-interferon 3 MU/m2 SC TIW for 2 years post ASCT. Protocol 2 (n=23) used a single infusion of rituximab (R) 375 mg/m2 for ‘in vivo’ purging 3–5 days pre-stem cell collection and 2 sets of 4 weekly R at 2 and 6 months post ASCT respectively. Protocol 3 (n=32) used 3 infusions of R 375 mg/m2 pre stem cell collection, followed by a-interferon 3 MU/m2 SC TIW × 2 years + R 375mg/m2 × 6 weekly infusions post ASCT. Eligibility included adult patients age 18–65 with stage III or IV follicular lymphoma grades 1–3a in first or second relapse. Salvage chemotherapy was either CHOP or DHAP depending on prior anthracycline exposure. High dose therapy was cyclophosphamide, carmustine, and etoposide (CBV). Minimal residual disease (MRD) assessment of t(14; 18) by quantitative PCR was serially performed in blood, PBSC and marrow. Studies were REB approved and all patients gave informed consent. Results:Sixty-eight patients from the 3 trials are included. Median age at study enrolment was 47 (30-71) and patients were a median of 31 mo (9-197) from diagnosis. 54% were male. Median FLIPI score was 2. Median # of prior chemotherapies was 1. Median number of cycles of salvage chemotherapy was 4 (2 - 10). 63 patients proceeded to ASCT. 5 patients were not transplanted either do to disease progression (2), or failed stem cell mobilization (3). Baseline characteristics of the patients enrolled in the three trials were similar, with the exception of rituximab(R) exposure in 22% of the patients in Protocol 3. 4 (6%) patients were lost to follow up.Median time to death or last follow was 84.5 mo (7-166). 32 patients (47%) relapsed and 20 (29%) have died. Median follow up times for each trial were 116, 99 and 57 mo. Actuarial median OS for Protocol 1 was 136 mo from enrolment and has not yet been reached for Protocols 2 and 3. Actuarial median PFS for Protocols 1 and 3 are 49 and 78 mo respectively and has not yet been reached for Protocol 2.MRD assessment by PCR was collected on 48 patients. Compared with study 1, the increased use of R pre SC collection improved in vivo purging by 2 logs. In Protocols 1 and 2, most still had detectable disease in the graft to a sensitivity of 1 cell/100,000. In Protocol 3, 56% had MRD negative apheresis products. 91% of 46 evaluable patients achieved molecular remission post stem cell transplant.Thirteen patients (19%) developed secondary malignancies post ASCT with a median time to malignancy of 88.5 mo (39-144). 1 patient developed 2 distinct malignancies. Secondary malignancies present were: MDS (4), AML (1), ALL (1), basal cell carcinoma (2), squamous cell carcinoma (3), thyroid cancer (1), non small cell lung cancer (1) and adenocarcinoma of unknown origin (1). Five (7%) patients transformed to DLBCL, with a median time to transformation post ASCT of 43.5 mo (17-142).The majority of patients who received rituximab immunotherapy pre and post ASCT developed persistent hypogammaglobulinemia. 17 patients (26%) developed interstitial pneumonitis or >2 respiratory complications post rituximab. 4 patients (6%) require monthly IVIG to treat recurrent respiratory infections. 10 patients (15%) developed herpes zoster <90 days post ASCT.15% and 30% of patients in Protocols 1 and 3 did not complete the 2 years of alpha-IFN post ASCT secondary to one or more of depression, fatigue or cytopenias. Conclusion:HDT + ASCT combined with R +/− a-IFN produces durable PFS and molecular remissions but is associated with prolonged hypogammaglobulinemia and higher rates of interstitial pneumonitis. Three infusions of R pre SC collection achieve higher rates of molecular remission. Compliance with 2 years of a-IFN added to R post ASCT is poor and may not add clinical benefits to R alone. The additional role of HDT/ASCT in the era of R-chemotherapy for FL needs to be explored. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Open-label phase II trial of everolimus monotherapy in treatment-naive patients with advanced papillary renal cell carcinoma.

TPS234 Background: Papillary renal cell carcinoma (RCC) is genetically and morphologically distinct from other RCCs, and accounts for up to 10% of RCC diagnoses. All RCC histologies are generally resistant to chemotherapy. Newer targeted treatment approaches have demonstrated clinical benefit in patients with clear cell RCC, but options for the treatment of papillary RCC remain limited. Everolimus, an oral mTOR inhibitor, has demonstrated efficacy in the pivotal RECORD-1 study in patients with mRCC with a “clear cell component” histology that progressed on vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy, and everolimus is now indicated for use in this patient population. Because mTOR is also aberrantly activated in papillary RCC, mTOR inhibition presents a novel means for targeted therapy in papillary RCC. The ongoing RAPTOR (RAD001 in Advanced Papillary Tumor Program in Europe) trial is evaluating the efficacy and safety of everolimus monotherapy in treatment-naive patients with advanced papillary RCC. Methods: RAPTOR is an open-label, single-arm, non-randomized, single-stage, multicenter phase II trial currently recruiting participants. Up to 60 patients ≥18 years of age with a centrally confirmed histologic diagnosis of advanced type I or II metastatic papillary RCC, ≥1 measurable baseline lesion as per RECIST criteria, ECOG performance status of 0 or 1, and adequate liver, renal, and bone marrow function will be enrolled. Patients who have received prior systemic RCC therapy (ie, sorafenib, sunitinib, bevacizumab) are excluded. Patients will receive everolimus 10 mg/d orally until disease progression, unacceptable toxicity, death, or study discontinuation for any other reason. The primary study endpoint is PFS rate at 6 months. Disease control rate, objective response rate, duration of response, median PFS, overall survival, and safety will also be assessed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bayer Pharma, Pfizer, Roche Bayer, Genentech, Novartis, Pfizer, Roche

Phase II study of ifosfamide, carboplatin, and etoposide in patients with a first recurrence of glioblastoma multiforme.

e12512 Background: The prognosis of recurrent glioblastoma multiforme (GBM) remains unsatisfactory. The authors conducted a phase II study of ifosfamide, carboplatin, and etoposide (ICE) for a first recurrence of GBM to determine whether it prolonged a patient's good quality life. Methods: This trial was an open-label, single-center phase II study. Forty-two patients with a first GBM relapse after surgery followed by standard radiotherapy (60 Gy) and first-line temozolomide- or nimustine-based chemotherapy were eligible to participate. The primary end point was progression-free survival at 6 months after the ICE treatment (PFS-6), and secondary end points were response rate, toxicity, and overall survival. Chemotherapy consisted of ifosfamide (1,000 mg/m2 on Days 1, 2, and 3), carboplatin (110 mg/m2 on Day 1), etoposide (100 mg/m2 on Days 1, 2, and 3), every 6 weeks. Results: Progression-free survival at 6 months after ICE treatment was 35% (95% CI 22%–50%). The median duration of PFS was 17 weeks (95% CI 10–24 weeks). The response rate was 25% (95% CI 9%–34%). Adverse events were generally mild and consisted mainly of alopecia. Conclusions: This regimen was well tolerated and has some activity and could be one of the options for patients with recurrent GBM. No significant financial relationships to disclose.

Continuous Sunitinib Treatment in Patients with Advanced Hepatocellular Carcinoma: A Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) Multicenter Phase II Trial (SAKK 77/06)

Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients with hepatocellular carcinoma (HCC). Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease, and Child-Pugh class A or mild Child-Pugh class B liver dysfunction. Patients received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 12 weeks (PFS12). Forty-five patients were enrolled. The median age was 63 years; 89% had Child-Pugh class A disease and 47% had distant metastases. PFS12 was rated successful in 15 patients (33%; 95% confidence interval, 20%-47%). Over the whole trial period, one complete response and a 40% rate of stable disease as the best response were achieved. The median PFS duration, disease stabilization duration, time to progression, and overall survival time were 1.5, 2.9, 1.5, and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent. None of the 33 deaths were considered drug related. Continuous SU treatment with 37.5 mg daily is feasible and has moderate activity in patients with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design (>13 PFS12 successes), the therapy is considered promising. This is the first trial describing the clinical effects of continuous dosing of SU in HCC patients on a schedule that is used in an ongoing, randomized, phase III trial in comparison with the current treatment standard, sorafenib (ClinicalTrials.gov identifier, NCT00699374).

Phase II study of ifosfamide, carboplatin, and etoposide in patients with a first recurrence of glioblastoma multiforme

The prognosis of recurrent glioblastoma multiforme (GBM) remains unsatisfactory. The authors conducted a Phase II study of ifosfamide, carboplatin, and etoposide (ICE) for a first recurrence of GBM to determine whether it prolonged a patient's good-quality life. This trial was an open-label, single-center Phase II study. Forty-two patients with a first GBM relapse after surgery followed by standard radiotherapy (60 Gy) and first-line temozolomide- or nimustine-based chemotherapy were eligible to participate. The primary end point was progression-free survival at 6 months after the ICE treatment (PFS-6), and secondary end points were response rate, toxicity, and overall survival. Chemotherapy consisted of ifosfamide (1000 mg/m(2) on Days 1, 2, and 3), carboplatin (110 mg/m(2) on Day 1), etoposide (100 mg/m(2) on Days 1, 2, and 3), every 6 weeks. Progression-free survival at 6 months after ICE treatment was 35% (95% CI 22-50%). The median duration of PFS was 17 weeks (95% CI 10-24 weeks). The response rate was 25% (95% CI 9-34%). Adverse events were generally mild and consisted mainly of alopecia. This regimen was well tolerated and has some activity and could be one of the options for patients with recurrent GBM.

Phase II study of cladribine with rituximab (R-2-CdA) therapy in patients with relapsed indolent B-cell non-Hodgkin's lymphoma

e19501 Background: Although cladribine has been reported to be one of active purine analogs against indolent B-cell non-Hodgkin's lymphoma (B-NHL), there are few reports of combination usage of cladribine and rituximab. We conducted a multicenter phase II study to investigate efficacy and toxicity of cladribine with rituximab (R-2-CdA) therapy for relapsed indolent B-NHL. Methods: Eligibility criteria were as follows: relapsed pts with indolent B-NHL from systemic chemotherapy, ages less than 75 years; PS 0–2 by ECOG's scale. Patients received 0.09mg/kg of cladribine intravenously (2 hrs infusion) on days 1 to 5 and 375mg/m2 of rituximab intravenously on days 1 and 15, every 4 weeks, for a total of 4 cycles. Primary endpoint was overall response rate (ORR). Secondary endpoints were % complete response (%CR), 2 years progression free survival (2-y PFS), and 2 years overall survival (2-y OS). Results: A total of 20 out of 45 planned patients were enrolled and received R-2-CdA therapy from Apr 2005 to Jul 2007. Their median age was 58.5 (42–72), and the median number of prior regimens was 2 (1–3). Histologies included 16 follicular lymphomas, 2 MALT lymphomas, 1 nodal marginal B cell lymphoma, and 1 lymphoplasmacytic lymphoma. Fifteen pts (75%) were previously treated with rituximab. The ORR was 90% with 70% of % CR. Median PFS was 20.1 months (5.6–32.9 months) at a median follow-up time of 27 months. 2-y PFS and 2-y OS were 63.2% (95%CI, 28.1–67.8%), and 89.5% (95%CI, 69.8–97.2%), respectively. Severe neutropenia and thrombocytopenia of grade 3 or 4 were observed in 15% and 10% respectively. Conclusions: R-2CdA therapy was demonstrated to have high activity with durable PFS and acceptable toxicity in relapsed indolent B-NHL, even if patients were previously treated with rituximab. Although a large-scaled further trial remains to be needed, R-2-CdA therapy could be a good option of salvage therapy in relapsed indolent B-NHL. No significant financial relationships to disclose.