FCR Chemoimmunotherapy Research Articles

CLL-035 Long-Term Survival After Fludarabine, Cyclophosphamide, and Rituximab Treatment in Previously Untreated Chronic Lymphocytic Leukemia Patients

Chronic lymphocytic leukemia (CLL) is characterized by a lower incidence rate in Iraq and Kurdistan as compared to Western countries. However, a good prognosis of CLL is dependable on diagnosis, risk stratification, and a better choice of an appropriate treatment regimen. To evaluate the effectiveness of fludarabine, cyclophosphamide, and rituximab (FCR) regimen in comparison to other chemotherapy regimens in the management of patients with CLL in Kurdistan, Iraq. A retrospective review study carried out in three cancer centers in the Kurdistan region of Iraq for a duration of 10 years through the period from January 1, 2010 to December 31, 2019, on 152 CLL patients. CLL was diagnosed according to the International Workshop on CLL. The treatment of CLL patients was either by FCR chemoimmunotherapy regimen or other chemotherapies. The FCR chemoimmunotherapy was the treatment of 38.8% of CLL patients, while 61.2% of CLL patients were treated by other chemotherapies. There was a significant association between younger age patients and the use FCR chemoimmunotherapy (P = 0.001). There was a significant association between a complete response and treatment by FCR chemoimmunotherapy (P = 0.02). The mean overall survival duration and progression free survival of CLL patients treated by FCR chemoimmunotherapy were significantly longer than the mean survival time of CLL patients treated by other chemotherapies (P = 0.01). Complete response and survival of CLL patients treated by FCR chemoimmunotherapy were better than the complete response and survival of CLL patients treated by other chemotherapies.

CLL-093 Long-Term Survival After Fludarabine, Cyclophosphamide, and Rituximab Treatment in Previously Untreated Chronic Lymphocytic Leukemia Patients

Chronic lymphocytic leukemia (CLL) is characterized by a lower incidence rate in Iraq and Kurdistan as compared to Western countries. However, a good prognosis of CLL is dependent on diagnosis, risk stratification, and a better choice of an appropriate treatment regimen. To evaluate the effectiveness of fludarabine, cyclophosphamide, and rituximab (FCR) regimen in comparison to other chemotherapy regimens in the management of patients with CLL in the Kurdistan region of Iraq. A retrospective review study was carried out in three cancer centers in the Kurdistan region of Iraq for a duration of 10 years from January 1, 2010, to December 31, 2019, on 152 CLL patients. CLL was diagnosed according to the International Workshop on CLL. The treatment of CLL patients was either by FCR chemoimmunotherapy regimen or other chemotherapies. The FCR chemoimmunotherapy was the treatment of 38.8% of CLL patients, while 61.2% of CLL patients were treated by other chemotherapies. There was a significant association between younger age patients and the use of FCR chemoimmunotherapy (P=0.001). There was a significant association between a complete response and treatment by FCR chemoimmunotherapy (P=0.02). The mean overall survival duration and progression-free survival of CLL patients treated by FCR chemoimmunotherapy were significantly longer than the mean survival time of CLL patients treated by other chemotherapies (P=0.01). The complete response and survival of CLL patients treated by FCR chemoimmunotherapy were better than the complete response and survival of CLL patients treated by other chemotherapies.

Time-to-progression after front-line fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy for chronic lymphocytic leukaemia: a retrospective, multicohort study.

Fludarabine, cyclophosphamide, and rituximab (FCR) has become a gold-standard chemoimmunotherapy regimen for patients with chronic lymphocytic leukaemia. However, the question remains of how to treat treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia. We therefore aimed to develop and validate a gene expression signature to identify which of these patients are likely to achieve durable remissions with FCR chemoimmunotherapy. We did a retrospective cohort study in two cohorts of treatment-naive patients (aged ≥18 years) with chronic lymphocytic leukaemia. The discovery and training cohort consisted of peripheral blood samples collected from patients treated at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), who fulfilled the diagnostic criteria of the International Workshop on Chronic Lymphocytic Leukemia, had received at least three cycles of FCR chemoimmunotherapy, and had been treated between Oct 10, 2000, and Oct 26, 2006 (ie, the MDACC cohort). We did transcriptional profiling on samples obtained from the MDACC cohort to identify genes associated with time to progression. We did univariate Cox proportional hazards analyses and used significant genes to cluster IGHV-unmutated samples into two groups (intermediate prognosis and unfavourable prognosis). After using cross-validation to assess robustness, we applied the Lasso method to standardise the gene expression values to find a minimum gene signature. We validated this signature in an external cohort of treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia enrolled on the CLL8 trial of the German Chronic Lymphocytic Leukaemia Study Group who were treated between July 21, 2003, and April 4, 2006 (ie, the CLL8 cohort). The MDACC cohort consisted of 101 patients and the CLL8 cohort consisted of 109 patients. Using the MDACC cohort, we identified and developed a 17-gene expression signature that distinguished IGHV-unmutated patients who were likely to achieve a long-term remission following front-line FCR chemoimmunotherapy from those who might benefit from alternative front-line regimens (hazard ratio 3·83, 95% CI 1·94-7·59; p<0·0001). We validated this gene signature in the CLL8 cohort; patients with an unfavourable prognosis versus those with an intermediate prognosis had a cause-specific hazard ratio of 1·90 (95% CI 1·18-3·06; p=0·008). Median time to progression was 39 months (IQR 22-69) for those with an unfavourable prognosis compared with 59 months (28-84) for those with an intermediate prognosis. We have developed a robust, reproducible 17-gene signature that identifies a subset of treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia who might substantially benefit from treatment with FCR chemoimmunotherapy. We recommend testing the value of this gene signature in a prospective study that compares FCR treatment with newer alternative therapies as part of a randomised clinical trial. Chronic Lymphocytic Leukaemia Global Research Foundation and the National Institutes of Health/National Cancer Institute.

Ibrutinib-Based Therapy Improves Anti-Tumor T Cell Killing Function Allowing Effective Pairing with Anti-PD-L1 Immunotherapy Compared to Traditional FCR Chemoimmunotherapy; Implications for Therapy and Correlative Immune Functional Data from the Phase III E1912 Trial

The targeted therapy ibrutinib inhibits B cell receptor signaling (BTK inhibitor) and has yielded high response rates and durable remissions in patients with chronic lymphocytic leukemia (CLL). However, it is widely believed that the addition of immune therapies to targeted drugs will be required to activate anti-tumor immunity and work towards curative therapy. Identifying effective combinations of targeted drugs and/or standard chemotherapy with immunotherapy is a priority research area and particularly relevant for CLL, as patients' T cells have been shown to exhibit profound tolerance/exhaustion and notably, no activity was reported in a recent trial of anti-PD-1 immunotherapy for relapsed disease.Ibrutinib has shown beneficial immunomodulatory activity in CLL by inhibiting IL-2-inducible T cell kinase (ITK) as well BTK that is associated with increased effector CD4+and CD8+ T cell numbers and decreased expression of inhibitory checkpoint receptors such as PD-1 on patient T cells. Here we have performed comparative immune bioassays from a randomized phase III trial comparing ibrutinib-based therapy to traditional FCR chemoimmunotherapy to assess the effects of treatments on anti-tumor T cell function.Viable peripheral blood mononuclear cell samples were collected serially (baseline, 6 months and 12 months) from CLL patients on the randomized phase III E1912 trial of ibrutinib and rituximab versus FCR for previously untreated disease to allow longitudinal batched immune analysis.Cytotoxicity assays revealed that highly purified CD3+ T cells from the FCR treated patients at 6 and 12-month time-points did not change their activated killing function against autologous baseline CD19+ CLL tumor B cells (acting as target antigen-presenting cells pulsed with superantigen, sAg) compared to pre-treatment/baseline exhausted T cells (n=22). In contrast, patients treated with ibrutinib-based therapy had a significant increase in activated anti-tumor T cell killing function (P<.01, n=22) at both 6-month (66% increase) and 12-month (89% increase) time-points.Flow cytometric analysis of circulating immune subsets revealed that the percentage of PD-1 and PD-L1 positive cells among CD8+ and CD4+ T cells (particularly effector compartments) were reduced with ibrutinib-based therapy, whereas only a partial reduction was detected following FCR treatment. However, patients' T cells from both treatment arms responded normally to T cell receptor engagement by upregulating these checkpoint molecules. This led us to explore ex vivo treatment of highly purified CD3+ T cells and CD19+ CLL B cells from both treatment arms with anti-PD-L1 or anti-PD-1 immunotherapy prior to cytotoxicity assays. Our functional data revealed that the T cells from both FCR time-points (6 and 12-months) were not sensitive to either anti-PD-L1 (n=14) or anti-PD-1 (n=14) treatment. In contrast, ibrutinib-based treatment sensitized anti-tumor T function (23% increase in killing) following anti-PD-L1 treatment (n=14) at the 6-month time-point only (P<.01) but not with anti-PD-1.To investigate the mechanism underlying these effector function differences, we compared the ability of highly purified CD3+ T cells from each treatment arm (n=45) time-point to form F-actin immunological synapses with baseline autologous CLL tumor B cells. Quantitative confocal image analysis revealed that ibrutinib-based therapy significantly (P<.01) enhanced polarization of F-actin, tyrosine-phosphorylated proteins and granzyme B at immune synapses with tumor cells at both 6 and 12-month time-points, whereas FCR treated patient T cells failed to mobilize these lytic synapse molecules. Importantly, our assays have revealed that T cells from both FCR treatment time-points formed “non-polarized” immune synapses with tumor cells, in keeping with cytotoxic dysfunction and insensitivity to additional checkpoint immunotherapy. In contrast, our functional correlative bioassays have revealed that ibrutinib-based therapy can reactivate exhausted cytolytic T cell function and suggest to us, a potential therapeutic window for anti-PD-L1 immunotherapy at the earlier 6-month time-point.We believe this data supports the concept of incorporating functional bioassays to immune-monitoring assays associated to clinical trials that should aid knowledge-led design of future combination immunotherapy. DisclosuresKay:Janssen: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shanafelt:Pharmacyclics: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Jansen: Research Funding. Ramsay:Celgene Corporation: Research Funding; Roche Glycart AG: Research Funding; MedImmune: Research Funding.

MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells.

The variable clinical course in chronic lymphocytic leukaemia (CLL) largely depends on p53 functionality and B-cell receptor (BCR) signalling propensity; however, it is unclear if there is any crosstalk between these pathways. We show that DNA damage response (DDR) activation leads to down-modulating the transcriptional factor FOXP1, which functions as a positive BCR signalling regulator and its high levels are associated with worse CLL prognosis. We identified microRNA (miRNA) miR-34a as the most prominently upregulated miRNA during DDR in CLL cells in vitro and in vivo during FCR therapy (fludarabine, cyclophosphamide, rituximab). MiR-34a induced by DDR activation and p53 stabilization potently represses FOXP1 expression by binding in its 3'-UTR. The low FOXP1 levels limit BCR signalling partially via derepressing BCR-inhibitory molecule CD22. We also show that low miR-34a levels can be used as a biomarker for worse response or shorter progression free survival in CLL patients treated with FCR chemoimmunotherapy, and shorter overall survival, irrespective of TP53 status. Additionally, we have developed a method for the absolute quantification of miR-34a copies and defined precise prognostic/predictive cutoffs. Overall, herein, we reveal for the first time that B cells limit their BCR signalling during DDR by down-modulating FOXP1 via DDR-p53/miR-34a axis.

Dynamic changes of the normal B lymphocyte repertoire in CLL in response to ibrutinib or FCR chemo-immunotherapy

ABSTRACTUsing next-generation immunoglobulin (IGH) sequencing and flow cytometry, we characterized the composition, diversity and dynamics of non-malignant B cells in patients undergoing treatment with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib or chemo-immunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR). During ibrutinib therapy, non-malignant B cell numbers declined, but patients maintained stable IGH diversity and constant fractions of IGH-mutated B cells. This indicates partial preservation of antigen-experienced B cells during ibrutinib therapy, but impaired replenishment of the normal B cell pool with naïve B cells. In contrast, after FCR we noted a recovery of normal B cells with a marked predominance of B cells with unmutated IGH. This pattern is compatible with a deletion of pre-existing antigen-experienced B cells followed by repertoire renewal with antigen-naïve B cells. These opposite patterns in B cell dynamics may result in different responses towards neoantigens versus recall antigens, which need to be further defined.

Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial

AbstractDespite promising results with targeted drugs, chemoimmunotherapy with fludarabine, cyclophosphamide (FC), and rituximab (R) remains the standard therapy for fit patients with untreated chronic lymphocytic leukemia (CLL). Herein, we present the long-term follow-up of the randomized CLL8 trial reporting safety and efficacy of FC and FCR treatment of 817 treatment-naïve patients with CLL. The primary end point was progression-free survival (PFS). With a median follow-up of 5.9 years, median PFS were 56.8 and 32.9 months for the FCR and FC group (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.50-0.69, P < .001). Median overall survival (OS) was not reached for the FCR group and was 86.0 months for the FC group (HR, 0.68; 95% CI, 0.54-0.89, P = .001). In patients with mutated IGHV (IGHV MUT), FCR improved PFS and OS compared with FC (PFS: HR, 0.47; 95% CI, 0.33-0.68, P < .001; OS: HR, 0.62; 95% CI, 0.34-1.11, P = .1). This improvement remained applicable for all cytogenetic subgroups other than del(17p). Long-term safety analyses showed that FCR had a higher rate of prolonged neutropenia during the first year after treatment (16.6% vs 8.8%; P = .007). Secondary malignancies including Richter's transformation occurred in 13.1% in the FCR group and in 17.4% in the FC group (P = .1). First-line chemoimmunotherapy with FCR induces long-term remissions and highly relevant improvement in OS in specific genetic subgroups of fit patients with CLL, in particular those with IGHV MUT. This trial was registered at www.clinicaltrials.gov as #NCT00281918.

Analysis of Early Mortality of Chronic Lymphocytic Leukemia (CLL) Patients Treated in US Practices in the Connect CLL® Registry

Analysis of Early Mortality of Chronic Lymphocytic Leukemia (CLL) Patients Treated in US Practices in the Connect CLL® Registry

A Molecular Model to Predict Durable Remission after First Line Fludarabine-Cyclophosphamide-Rituximab Treatment in Chronic Lymphocytic Leukemia

Background. Fludarabine, cyclophosphamide, and rituximab (FCR) has represented a significant advancement in the treatment of patients with chronic lymphocytic leukemia (CLL) and has the potential of inducing durable remissions of the disease. In the new scenario of targeted agents for CLL, there is an increasing interest in identifying patients who may gain the maximum benefit in terms of disease control by a single shot of FCR chemo-immunotherapy.Purpose. Here we aimed at identifying predictors of durable remission after first line FCR treatment.Methods. The study was based on 405 progressive and previously untreated CLL patients who consecutively received standard FCR (up to 6 cycles) as first line therapy in 19 hematologic centers between 2001 and 2010. According to an intention to treat approach, all patients who received at least one FCR cycle were registered in the study. This series was representative of a FCR treated CLL cohort with respect to baseline characteristics, including age (median: 61 years; >65 years in 33% of patients), gender (male in 68% of patients), stage (progressive Binet A in 11% of patients; Binet B in 59%; Binet C in 30%) and number of FCR courses (median: 6; <6 in 42% of patients). Most patients were evaluable for IGHV mutation status (unmutated in 192/296, 65%) and genomic aberrations at treatment requirement (17p deletion in 30/306, 9.8%; 11q deletion in 56/300, 19%; +12 in 70/298, 23%; 13q deletion in 108/301, 36%).Results. After a median follow-up of five years, 159 patients have progressed and 72 have died, accounting for a 5-year progression free survival (PFS) according to the IWCLL criteria of 47% (median: 58 months) and for a 5-year overall survival (OS) of 81% (median: not reached). When the demographic effects of age, gender and year of treatment were compensated, the 5-year and 10-year survival of the whole CLL cohort were 85% and 68%, respectively, of those expected in the matched normal general population (p<0.001). By multivariate analysis, unmutated IGHV genes, 11q deletion and 17p deletion maintained independent association with both PFS and OS, thus providing the rationale to utilize them in the development of a model to predict remission duration after FCR. By recursive partitioning analysis, 17p deletion was the most important variable in predicting PFS after FCR, followed by 11q deletion and IGHV mutation status (Fig. 1A). Based on the application of an amalgamation algorithm, cases harboring unmutated IGHV genes and 11q deletion were grouped into a single category because they showed an identical drop of the PFS curve (Fig. 1A). By this approach, three CLL subgroups were hierarchically classified. Clinical features and treatment indication were superimposable across the three risk groups. The low risk category comprised patients harboring mutated IGHV genes but neither 11q or 17p deletion, and accounted for 26% of all cases. Most of the low risk patients (67%) remained free of progression after FCR (Fig. 1B), and their hazard of relapse dropped to zero after 5 years of follow-up. Consistently, the PFS curve of low risk patients plateaued after 5-years from FCR (Fig 1B). The life expectancy of low risk patients (91% at 5 year) was superimposable to that observed in the matched normal general population (Fig. 1D), indicating that neither the disease, nor complications of its treatment affected survival in this favorable group of CLL. Conversely, patients belonging to the intermediate risk (IGHV unmutated and/or 11q deleted) and high risk (17p deleted) categories showed a constant increase of the hazard of progression over time and almost all were projected to relapse after FCR, although at a different rate: 10% per year of follow-up in the intermediate risk group and 17% per year of follow-up in the high risk group (Fig. 1B-C). The 5-year life expectancy of intermediate and high-risk patients was significantly impaired compared to that observed in the matched general population (85% and 60%, respectively) (Fig. 1D), indicating an excess of deaths related to the disease or treatment complications in these unfavorable groups of CLL.Conclusions. The combination of three biomarkers that are routinely tested at treatment allows to segregate a subgroup of CLL (IGHV mutated without 17p or 11q deletion) that may achieve a durable remission after first line FCR treatment and experience an expected survival similar to that of the general population. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cenersen, An Antisense Inhibitor of p53, in Combination with Fludarabine, Cyclophosphamide, and Rituximab Shows Clinical Activity in High Risk CLL.

Abstract 3430Poster Board III-318 Background and SignificanceChronic lymphocytic leukemia (CLL) is a malignant B cell lymphoproliferative disorder characterized by the clonal expansion and accumulation of CD5+ B cells. CLL is quite heterogeneous in clinical behavior, where some patients remain asymptomatic and require no therapy for many years, whereas other patients follow an aggressive clinical course with early need for therapy and short overall survival. Those patients with somatic deletions and / or mutations of p53, a central mediator of cell cycle control, apoptosis, and a potent tumor suppressor, follow the most aggressive clinical courses of all patients with CLL. Furthermore, these patients tend to be refractory to conventional CLL chemotherapy regimens, and therefore novel therapeutic approaches are needed. Cenersen (Eleos Inc.) is a 20-mer antisense molecule and binds to a coding region of exon 10 in p53 mRNA and has been shown in vitro to increase apoptosis in lymphoma cell lines. We hypothesize that the addition of cenersen to chemo-immunotherapy will enhance leukemic cell apoptosis and thus increase chemotherapy sensitivity in vivo for patients with aggressive CLL. Here we report early clinical responses to cenersen in combination with FCR chemo-immunotherapy at a planned interim analysis for efficacy and safety after enrollment of 17 patients. MethodsWe have undertaken a clinical trial at Duke University Medical Center of cenersen in combination with chemo-immunotherapy for patients with CLL or SLL (ClinicalTrials.gov identifier: NCT00636155). Patients with relapsed CLL or previously untreated patients with a deletion or mutation of p53 requiring therapy were enrolled. Cenersen was administered at 2.4 mg/kg/day as a continuous infusion over 24 hours starting on day 1 and ending on day 4. Fludarabine was administered daily at 25 mg/m2 on days 2 through 4, cyclophosphamide was administered daily at 250 mg/m2 on days 2 through 4, and rituximab was administered at 375 mg/m2 on day 2. Cycles were repeated every 28 days for a maximum of 6 cycles. The primary outcome measure was the overall response rate (complete and partial responses by iwCLL response criteria), and secondary outcome measures included progression free survival, event free survival and overall survival. All patients received growth factor support as well as prophylaxis with acyclovir and trimethoprim / sulfamethoxazole. Interphase cytogenetics and sequencing analysis for somatic mutations of p53 was performed in all patients. ResultsTo date, 17 patients have been enrolled to a protocol-defined interim analysis of efficacy and safety. Of the enrolled patients, 1 was previously untreated, and the remaining 16 were relapsed (median number of prior therapies 4, range 1 - 8). Among previously treated patients, the mean response duration of the most recent prior regimen was 2 months. 15 of 16 had previously received fludarabine and 14 of 16 patients had previously received rituximab. 10 of 16 patients tested showed 17p deletions by FISH. Among the 14 patients tested to date, 8 showed somatic mutations in p53 by sequence analysis, of these, 6 showed both deletion of 17p as well as somatic mutation of p53. Of the 17 patients enrolled, 14 are evaluable for response: 1 patient has not yet received 3 cycles of therapy and 2 patients voluntarily discontinued trial participation. To date, 5 patients show a partial response by iwCLL criteria, including 2 patients who have concluded all therapy and show a partial response with incomplete hematologic recovery (PRi) with no detectable CLL B cells by flow cytometry analysis of bone marrow aspirate. One of these patients has subsequently undergone allogeneic stem cell transplantation. The remainder of the patients had stable disease (SD), though 3 were removed from study prior to the completion of 3 cycles for inadequate response as determined by the treating physician. There have been 4 episodes of febrile neutropenia, and there have been no toxicities specifically attributed to cenersen. ConclusionsWe have observed encouraging clinical responses to the combination of cenersen with FCR chemo-immunotherapy among a group of extensively pretreated patients with high risk genetic features. There does not appear to be any excess toxicity associated with the investigational agent. The results to date suggest that there may be therapeutic benefit to p53-targeted therapies in high risk CLL. This study will be continued to full accrual. DisclosuresLanasa:Genentech: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab, in combination with fludarabine and cyclophosphamide, for the treatment of CLL. Cook:Eleos: Employment. Rizzieri:Eleos: Research Funding.

First-Line Treatment with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Improves Overall Survival (OS) in Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Randomized Phase III Trial On Behalf of An International Group of Investigators and the German CLL Study Group.

Abstract 535 Introduction: In 2008, first results of a multicenter, international randomized phase III trial (CLL8) were presented, showing superiority of FCR chemoimmunotherapy for response rates and progression-free survival (PFS) when compared to FC chemotherapy. We now report updated results with a longer median observation time of 37.7 months (mo). Methods and Patients: 817 treatment-naive patients (pts) with good physical fitness and CD20-positive CLL randomly (1:1) received treatment with 6 courses of either FCR or FC therapy. Both treatment arms were well balanced with regard to sex, age, stage, genomic aberrations and IGVH gene status. The median age was 61 years (range 30 to 81), 25.7% pts were female in both arms, 64.1% were Binet B, 31% Binet C and 4.9% Binet A. The median cumulative illness rating scale (CIRS) score was 1 (range 0-8). The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively. A mean number of 5.2 treatment courses were delivered in the FCR arm vs 4.8 courses in the FC arm (p=0.006). Dose reductions by more than 10% in at least one treatment course were performed in 47% (FCR) and 27% (FC) of pts (p Results: As of June 2009, the median observation time was 37.7 (mo). 761 pts (FCR 388; FC 371) were evaluable for response, 790 pts (FCR 401; FC 389) for PFS and all for OS. FCR induced a higher overall response rate than FC (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p As previously reported more hematologic adverse events, particularly neutropenia, were observed with FCR treatment, but this did not result in an increased infection rate. More deaths have occurred in the FC arm (86/396, 21.7%) than in the FCR arm (65/404, 16.1%). In the majority of cases, the underlying cause of death was progressive disease (FC 48/86, FCR 33/65), secondary malignancies (FC 13/86, FCR 5/65) or unrelated causes of death such as myocardial infarction (FC 15/86, FCR 17/65). Treatment related mortality occurred in 8 (2.0%) of pts in each arm. Of these, 7 FC-treated pts and 5 FCR-treated pts died from infections related to treatment. In 7 pts (3 FC vs. 4 FCR), treatment was discontinued before the third treatment course due to fatal toxicity. Multivariate analysis was performed to evaluate factors predicting outcome. Age, sex, FCR-treatment, response, number of cycles (0-3), 17p-deletion, increased serum levels of thymidine kinase and β2-microglobulin and unmutated IGVH genes were independent prognostic factors predicting OS or PFS. Conclusion: Treatment with FCR chemoimmunotherapy is more effective than FC chemotherapy. The partial failure to demonstrate a benefit for FCR in Binet stage C patients may be related to an insufficient treatment intensity in these patients with higher tumor load. To our knowledge, this is the first time that a randomized trial is able to demonstrate that a specific first-line treatment for CLL results in an improved overall survival. The results corroborate the recommendation to use FCR as standard therapy in physically fit pts with CLL requiring therapy. Disclosures: Hallek: Roche: Consultancy, Honoraria, Research Funding. Fingerle-Rowson: Roche: Honoraria, travel grants. Fink: Roche: Travel grants. Mayer: BMS: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; GSK: Consultancy; Fresenius: Consultancy; Roche: Research Funding; Pfizer: Research Funding. Hensel: Roche: Honoraria, Travel Grants; Bayer: Honoraria. Hopfinger: Roche: Membership on an entity9s Board of Directors or advisory committees. Hess: Roche: Honoraria. Bergmann: Roche: Honoraria for monitoring and CRFs. Catalano: Roche: Honoraria, Research Funding, Travel grants. Seymour: Bayer Schering: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Travel Grants. Berrebi: Roche: travel grants. Jaeger: Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Travel grants. Trneny: Roche: Honoraria, Research Funding. Westermann: Roche: Travel Grants. Wendtner: Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Eichhorst: Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Hospira: Honoraria. Staib: Roche: Research Funding. Boettcher: Roche: Honoraria, Research Funding, Travel grants. Ritgen: Roche: Research Funding. Mendila: Roche: Employment. Kneba: Roche: Honoraria, Research Funding. Doehner: Roche: Research Funding. Stilgenbauer: Roche: Consultancy, Honoraria, Research Funding, travel grants. Fischer: Mundipharma: Research Funding; Roche: travel grants.

Long Term Outcome Following Treatment Failure of FCR Chemoimmunotherapy as Initial Therapy for Chronic Lymphocytic Leukemia.

Abstract 2381Poster Board II-358The natural history of patients (pts) who fail or relapse after chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has not been established. Three hundred pts received FCR as initial therapy for progressive or advanced chronic lymphocytic leukemia (CLL) (Tam CS; Blood 112(4):975-980, 2008). Fifteen (5%) pts failed to respond, 72% achieved a CR and 22% a PR. Treatment failure occurred in 18 pts because of the development of AML, MDS or Richter's transformation and there were 15 deaths in remission (infection (7), cancer (6), or cardiac events (2)). Fourteen relapsed pts have not received therapy and are considered to be “watch and wait.”One hundred and twelve pts have received therapy. A large variety of treatment programs were administered at time of relapse during the ten years of the study. The most commonly used were FCR-like regimens (33) with or without lumiliximab or bevacizumab, FCR + alemtuzumab (CFAR) 9 pts, rituximab-based regimens (28) +/- GMCSF or steroids, Campath-based regimens (16) +/- rituximab, and a variety of other phase I and miscellaneous salvage treatments. 79 pts received salvage therapy at M. D. Anderson Cancer Center (MDACC) and the 33 others in their local community. 17 patients (16%) achieved a CR and 46 a PR (4%). CR rates were 15% for FCR, 56% for CFAR, 4% for rituximab regimens, 31% for alemtuzumab regimens and 4% for other regimens. While higher CR rates were noted in alemtuzumab regimens, no difference in time-to-treatment failure or survival was noted. The median overall survival was 33 months with a 40% five-year survival rate. A number of characteristics shown in Table 1 associated with complete remission and overall response rate.Outcome of 1st Salvage – FCR Relapsed/Refractory (112 pts)CharacteristicValuePatients%CR%ORMed Surv (Mths)Age / years<6579185742.04≥653395522Beta-2 microglobulin (mg/L)<45024*6046.005≤43985117Rai Stage0 - III50246841.01IV35114015Time to Rx Failure (Mths)<3643124212<.0001≥3669176544FISH17p1191811.00211q-2623*6541Other24446NR*p<0.05All of the listed characteristics were significantly associated with survival. Abnormalities in 17p detected by FISH, short time to treatment failure, and Rai stage IV were associated with the worst prognosis. 31 pts received an allogeneic stem cell transplant (SCT) either at MDACC or elsewhere. The SCT was usually done as second or subsequent salvage therapy with a five-year survival fraction of approximately 35%.More than half the patients who relapsed after FCR can achieve at least a partial response with salvage therapy. The optimum treatment for this group of pts is ill-defined. Preparation for and consideration of allogeneic stem cell transplantation should be considered for all pts who achieved only a partial response after salvage therapy. Disclosures:Keating:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Genentech: Consultancy, Honoraria; Genzyme: Research Funding. O'Brien:Genentech: Research Funding; Biogen Idec: Research Funding.

Immunochemotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Fludarabine and Cyclophosphamide (FC) Improves Response Rates and Progression-Free Survival (PFS) of Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL)

Introduction: Previous phase II studies have suggested that a combination of FCR may increase the outcome of both untreated and relapsed CLL pts. In order to validate this concept the German CLL study group (GCLLSG) initiated a multicentre, multinational phase III trial, CLL8, to evaluate the efficacy and tolerability of FCR versus FC for the first-line treatment of pts with advanced CLL.Methods and Patients: 817 pts with good physical fitness as defined by a cumulative illness rating scale (CIRS) score (Extermann et al., JCO 1998) of up to 6 and a creatinine clearance (cr cl) □d 70 ml/min were enrolled between July 2003 and March 2006. Pts were randomly assigned to receive 6 courses of either FC (N=409; F 25mg/m2 i.v. d1–3 and C 250 mg/m2 i.v. d1–3; q 28 days) or FC plus R (N=408; 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days). Both treatment arms were well balanced with regard to age, stage, genomic aberrations and VH status. 64% were Binet B, 32% Binet C and 5% Binet A. The median age was 61 years (range 30 to 81), the median CIRS score was 1 (range 0–8). The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively, with no statistically significant differences between treatment arms. A mean number of 5.2 courses was given in the FCR arm versus 4.8 courses in the FC arm (p=0.006). 74% (FCR) and 67% (FC) of pts received 6 cycles. Dose was reduced by more than 10% in at least one treatment course in 43% (FCR) and 30% (FC) of pts, and in 21% (FCR) and 17% (FC) of all treatment courses given. 17 pts did not receive any study medication, 10 due to violation of enrolment criteria (4 decreased renal function, 2 active secondary malignancies, 2 active infections, 1 autoimmune thrombocytopenia, 1 pt not requiring treatment), 3 due to withdrawal of consent, 2 due to worsened concomitant diseases. 2 pts were lost before start of treatment. 56 pts were not evaluable for response: 17 did not receive any study medication, 16 withdrew consent before interim staging, 7 due to violation of enrolment criteria, 4 discontinued treatment due to toxicity and 12 due to early death (caused by toxicity, progression or secondary malignancy). Prophylactic use of antibiotics or growth factors was not generally recommended in the protocol.Results: At the time of analysis, June 2008, the median observation time was 25.5 months (mo). 761 pts (FCR 390; FC 371) were evaluable for response, 787 pts (FCR 400; FC 387) for PFS and all for OS. The overall response rate (ORR) was significantly higher in the FCR arm (95%; 370/390) compared to FC (88%; 328/371 (p=0.001). The complete response rate of the FCR arm was 52% as compared to 27.0% in the FC arm (p<0.0001). PFS was 76.6% at 2 years in the FCR arm and 62.3% in the FC arm (p<0.0001). There was a trend for an increased OS rate in the FCR arm (91% vs 88% at 2 years p=0.18). Hazard Ratio for PFS was 0.59, for OS 0.76. The largest benefit for FCR was observed in Binet stage A and B with regard to CR, ORR and PFS (A: p=0.01, B: p<0.0001). FCR treatment was more frequently associated with CTC grade 3 and 4 adverse events (47% of FC vs 62% of FCR treated pts). Severe hematologic toxicity occurred in 55% (FCR) versus 39% (FC) of all patients. Significant differences were observed for neutropenia (FCR 33,6%; FC 20,9% p=0.0001) and leukocytopenia (FCR 24%; FC 12,1% p<0.0001) but not for thrombocytopenia (FCR 7,4%; FC 10,8% p=0.09) and anemia (FCR: 5,4% FC 6,8% p=0.42). The incidence of CTC grade 3 or 4 infections was not significantly increased in the FCR arm (18,8% versus 14,8% in the FC arm, p=0.68). Tumor lysis syndrome (FCR 0,2% FC 0,5%) and cytokine release syndrome (FCR 0,2% FC 0,0%) were rarely observed in both arms. Treatment related mortality occurred in 2.0% in the FCR and 1.5% in the FC arm. Multivariate analyses were performed to evaluate factors predicting outcome. Amongst these variables age, sex, Binet stage, CIRS score, renal function (cr cl < 70 ml/min) were independent prognostic factors predicting OS or PFS.Conclusion: Treatment with FCR chemoimmunotherapy improves response rates and PFS when compared to the FC chemotherapy. FCR caused more neutropenia/leukopenia without increasing the incidence of severe infections. These results suggest that FCR chemoimmunotherapy might become the new standard first-line treatment for physically fit CLL patients.

Salvage therapy following failure or relapse after FCR chemo-immunotherapy as initial treatment for chronic lymphocytic leukemia (CLL)

7009 Background: CLL treatment evolved from single agents to combination chemotherapy to chemo-immunotherapy e.g. fludarabine and rituximab (FR) or with cyclophosphamide (FCR). Reports usually describe initial response, time-to-treatment failure (TTF), and survival. Follow-up of relapsed/failed patients (pts) is rarely reported. This report summarizes our experience with such pts after FCR. Methods: 300 pts initially treated with FCR were analyzed. 15 pts failed, 6 died in remission, six developed Richter's transformation (RT) or another malignancy (14) or relapsed (77). Ten have not required therapy. Results: 67 pts received first salvage therapy (S1) with a variety of regimens. The median age was 59 years and 70% were male. Most pts were Rai stage III - IV (56%). Median TTF after initial FCR was 31 months. Initial FCR responses were CR (36 pts), NPR (10 pts), PR (14 pts), and failure (7 pts). Following S1 therapy, CR was obtained in 17%, NPR (8%) and PR (14%). Initial FCR response of CR or NPR, Rai stage, and β2-microglobulin significantly predicted S1 response. The initial TTF did not predict salvage response. OR rate for FCR-based regimen alone or with alemtuzumab (A) or lumilixamab was 62%, rituximab (R) regimens (31%) and A + R (6/9, 67%). Median survival after S1 therapy was 30 months (28 deaths) and was significantly longer for CR/NPR pts (46 months) than PR/Fail (10 months) P&lt;.001. Duration of initial FCR response, β2-microglobulin level and Rai stage predicted survival (P&lt;.01) but the S1 regimens did not. 9/13 pts who eventually received an allogeneic transplant (allo SCT) are still alive (8 in CR). Conclusions: The results of salvage therapy following FCR initial treatment are unsatisfactory. Patients who failed to obtain a CR or NPR to FCR or S1 therapy should be considered for allo SCT. No significant financial relationships to disclose.