Fludarabine And Cyclophosphamide Research Articles

Consolidation Therapy with Subcutaneous Alemtuzumab After Induction Treatment with Oral FC (Fludarabine and Cyclophosphamide) in Previously Untreated Patients Aged 65–70 Years with Advanced Stage Chronic Lymphocytic Leukemia (CLL): Final Results of a Phase II Study From the FCGCLL/WM,

Abstract 3900Current treatment approaches in CLL aim at achieving the best clinical response without detectable minimal residual disease (MRD) in order to prolong the duration of response and potentially overall survival. Such a goal could be achieved by combining chemotherapy and monoclonal antibodies. This phase II trial was designed to evaluate the safety and the efficacy of alemtuzumab given as consolidation therapy after 3 courses of oral FC (F 40 mg/m2 and C 250 mg/m2 D1 to D3 every 4 weeks) in patients (pts) aged 65 to 70 years with previously untreated Binet stage B or C CLL. Pts who had achieved either complete response (CR) or partial response (PR) after FC were eligible for consolidation with alemtuzumab. Alemtuzumab was administered subcutaneously (SC) at the dose of 10 mg thrice a week for 8 consecutive weeks. CMV antigenemia was monitored every week and alemtuzumab should be discontinued in pts with more than 3 positive nuclei. Such stringent stopping rules for CMV reactivation, as well as the limitation of FC regimen to 3 courses and of the duration of alemtuzumab treatment to 8 weeks, were adopted in this trial targeting elderly patients in their first line treatment because of the severe infectious toxicities reported by others with similar strategies. MRD was evaluated by 6 color flow cytometry before, during and after alemtuzumab treatment and all samples were centralized in one center (RL & FC).From June 2004 to January 2008, 55 patients with advanced (stage B or C) fully annotated CLL have been recruited in 14 french centers. Response to induction is evaluable in 51 of them (suicide before FC 1 pt and missing data 3 pts). A CR was achieved in 18 pts (34.6%) and a PR in 22 pts (42.3%) for an overall response rate (ORR) of 77% after 3 courses of FC. FC regimen was discontinued in 6 pts (progression 1 pt, renal carcinoma 1 pt, neutropenia 2 pts, PRCA 1 pt, myocardial infarction 1 pt) and a stable disease was observed in 5 pts. All the responding pts except two of them (onset of breast cancer in one CR pt and of lung carcinoma in one PR pt) proceeded to alemtuzumab consolidation after a planned 2 month period of rest (median 63 days, range 33 to 152). Alemtuzumab treatment was fully completed in 29/38 pts (76%) while it has been stopped prematurely (mainly between the 6th and 8th weeks) in 9 pts (24%). CMV reactivation occurred in 8 pts (21%) but it was associated with systemic symptoms in only one case (febrile pneumonia). A grade 3–4 neutropenia was observed in 9 pts at some point during alemtuzumab treatment. Eleven of the 21 PR pts (52%) converted from PR to CR after alemtuzumab consolidation while 2 patients went down from CR to PR. Overall, 26 pts were in CR after the whole treatment strategy (FC followed by alemtuzumab) accounting for 51% of the entire cohort. Blood MRD could be assessed sequentially in roughly two thirds of pts. While all patients but one (33/34 pts) were MRD positive after chemotherapy and before alemtuzumab treatment, only 8/22 pts (36%) had detectable MRD at the sensitivity level of 10-4 after the end of alemtuzumab consolidation, and 12 out of the 25 assessed pts (48%) still had undetectable MRD at 6 months after the end of treatment. With a median follow up of 34 months (range 2 to 58), only 6 out of the 38 pts (16%) who received FC followed by alemtuzumab consolidation, had CLL disease progression. Five patients have died but only one from CLL (solid tumors 3 pts, stroke 1 pt). No serious delayed infectious complication was observed and two patients developed auto-immune cytopenia (AIHA 1 pt and ITP 1 pt). Because of the few number of events (disease progression) observed so far, no correlation between the duration of response and the MRD data could be done by now.In conclusion, three courses of FC only yielded a rather high response rate in previously untreated elderly CLL patients and a short (8 weeks) alemtuzumab consolidation course could thereafter be administered safely, leading to a high rate of PR to CR switches, a high proportion of patients with undetectable blood MRD after the end of treatment and durable responses. Disclosures:Cazin:LFB Biotechnologies: Honoraria. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding.

The Addition of Rituximab to Fludarabine and Cyclophosphamide (FC) Improves Overall Survival in Newly Diagnosed Mantle Cell Lymphoma (MCL): Results of the Randomised UK National Cancer Research Institute (NCRI) Trial

Abstract 440▪▪This icon denotes a clinically relevant abstract Background:Rituximab is widely used in combination with chemotherapy for treating B cell lympho-proliferative disorders. In MCL, two randomised trials explored the addition of Rituximab to standard initial therapy. Neither demonstrated a significant improvement in either PFS or OS. In 2002 the NCRN initiated a phase II randomised trial of FC chemotherapy with or without Rituximab to evaluate response rates. In 2006 this was extended to a phase III study with overall survival as the primary end point. Trial:Newly diagnosed patients with MCL requiring therapy received up to 8 cycles of oral FC (Fludarabine 40mg/m2 and Cyclophosphamide 250mg/m2 both daily × 3) given every 4 weeks with a randomisation to the addition of Rituximab 375mg/m2 on day 1. There was no age limit to the study, no risk stratification and no consolidation of responses with transplantation or maintenance therapy. Results:370 patients were randomised. Median age was 66 years (range 36 – 88) with 76% male patients. The arms were well balanced by Mantle Cell International Prognostic Index (MIPI); 77% in the FCR arm and 71% in the FC arm were in the intermediate or high risk groups. 78% and 72% respectively received 4 or more cycles of FCR/FC. At the end of treatment the ORR was 90.6% in the FCR arm and 79.8% in the FC arm (p = 0.01) with CR + CRu rates of 64.7% and 46.9% (p = 0.002) respectively. 5.8% of patients in the FCR arm and 11.9% in the FC arm had PD at the end of treatment. Patients in the FCR arm had longer progression free and overall survival with HRs of 0.56 (95% CI: 0.43–0.73, p < 0.001) and 0.72 (95% CI: 0.54–0.97, p = 0.03) respectively. At a median follow up of 38.8 months the median PFS is 30.6 months in the FCR arm and 16.1 months in the FC arm. The median OS is 45.7 months for FCR and 37 months for FC. The major toxicities were haematological. Significantly more patients in the FCR arm experienced grade 3 or 4 Leucopoenia and Thrombocytopenia however the numbers of grade 4 were not significantly different. Combined grade III/IV toxicity showed 23.3% thrombocytopenia, 45.8% leucopoenia, 12.9% anaemia and 51.4% neutropenia. 11.8% of patients had significant infections. Renal toxicity was modest. 1 patient experienced grade III but there was no grade IV toxicity.Lymphoma was the commonest cause of death, but 29% of patients in the FCR arm and 24% in the FC arm died of other causes, of which almost half were infection related. An additional 11 patients died of a second malignancy, 4 of whom had AML. 14% of patients in the FCR arm and 10% in the FC arm died without evidence of disease progression. Conclusion:The addition of Rituximab to FC chemotherapy leads to a significant improvement in both PFS and OS with an acceptable level of additional toxicity. A significant number of patients treated with FC based chemotherapy die whilst in remission of non lymphoma related causes. [Display omitted] [Display omitted] Disclosures:Rule:Roche: Consultancy, Research Funding. Off Label Use: Rituximab in mantle cell lymphoma. Follows:Roche: Consultancy, Honoraria. Hillmen:Roche Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKine: Honoraria, Speakers Bureau; Genzyme: Research Funding; MundiPharma: Honoraria, Speakers Bureau. Walewski:Janssen-Cilag: ; Hoffman La Roche: Honoraria, Institutional/personal grants, travel/accommodation expenses; Mundipharma: Honoraria; Celgene: Honoraria.

Long-Term Outcome of B-CLL Patients Treated in a Prospective Trial Evaluating Combination of Oral Fludarabine and Cyclophosphamide As Frontline Therapy

Abstract 1795 Introduction.The combination of fludarabine and cyclophosphamide (FC) has become the core combination of modern frontline chemotherapy for fit and young B-CLL patients (pts). Recently the association with rituximab to FC (IV administration) has been shown to increase the response and extend both progression free survival (PFS) and overall survival (OS) in untreated pts (Hallek et al., Lancet 2010). So far few data are available concerning the very long term outcome of pts treated by FC containing regimen. Methods. We previously reported a prospective phase II trial (Cazin et al., BJH 2008) of the oral combination of FC over 5 days in 75 patients with untreated B-CLL and less than 66 years old. The study was conducted between October 1999 and February 2001. Briefly, oral FC then demonstrated high efficacy with overall response rate (ORR) and complete response (CR) rate of 80% and 53% respectively despite the absence of rituximab in this regimen. We here propose to examine 10-year end points of progression-free survival (PFS), overall survival (OS), impact of genomic features, and risk of therapy-related myeloid neoplasm (t-MN) by updating survival data of all the pts incuded in this trial. Results. With a median follow-up of 10.7 years, the median 10-year OS was 51.7%. Responders presented better 10-year OS than non-responders (57% vs. 38%, p=0.031) but quality of response (CR vs. PR) did not significantly impact 10-year OS. A major prognostic impact of IGVH mutational status could be observed since 10-year OS was 81% for mutated patients vs. 44% for unmutated pts (p=0.012). The median 10-year PFS was 30% and clearly influenced by the mutational status (50% if mutated profile vs. 12% if unmutated profile, p=0.02). However there is no trend of a plateau and even long term responding patients still relapse with time. Finally, only one patient developed t-MN but 9 others presented solid neoplasms. Conclusion. Long-term follow-up of B-CLL patients prospectively treated in a phase II clinical trial demonstrates extended OS and PFS with oral FC without high risk of t-MN. Disclosures:No relevant conflicts of interest to declare.

Correlations Between Ofatumumab Exposure and Treatment Outcomes for Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Frontline Ofatumumab, Fludarabine, and Cyclophosphamide Chemoimmunotherapy

Abstract Abstract 1793 Introduction: Results: Seven pts (4 male) with a medianLittle is known about the pharmacokinetics (PK) and pharmacodynamics of CD20 monoclonal antibody (mAb) with chemotherapy in patients (pts) with CLL. Ofatumumab (O) is a human mAb targeting a membrane-proximal small-loop epitope on CD20 and mediates efficient complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Safety and efficacy of O at 2 dose levels in combination with fludarabine and cyclophosphamide (FC) were evaluated in previously untreated pts with CLL. Relationship between O PK, baseline characteristics, and clinical outcomes were studied. Pts and Methods: Pts with active CLL were randomized to O 500 mg (n=31) or 1000 mg (n=30) on Day 1 with F 25 mg/m2 and C 250 mg/m2 on Days 2–4 (Course 1) or Days 1–3 (Courses 2–6) every 4 weeks for 6 courses. O dose at Course 1 was 300 mg for both groups. Response (1996 NCI-WG criteria) was assessed by an Independent Review Committee up to 3 months after last course. Serial blood samples were collected at Courses 1 and 6 for noncompartmental PK analyses; pre- and post-infusion samples were collected at other courses. Relationship between PK parameters and baseline pt characteristics and disease factors was evaluated by univariable and multivariable analyses. Associations between PK and complete response (CR), overall response (OR), or progression-free survival (PFS) were explored using univariable regression analyses. Results: 22/31 (71%; 500 mg) and 19/30 (63%; 1000 mg) of pts received all 6 O doses; 2 pts at 1000 mg did not receive FC for Course 6. CR (primary endpoint) rates of 32% and 50% and OR rates of 77% and 73% were observed in the 500 mg and 1000 mg groups, respectively. O PK parameters are summarized (Table). O PK at Dose 6 appeared proportional to dose. Factors associated with PK in multivariable analyses are shown (Table). The factor most associated with PK at Dose 1 was sex, with higher Cmax/AUC and lower CL and Vss/longer t½ in women vs. men. PK at Dose 6 was not consistently associated with any factor tested. Median Cmax and Cmin values were similar at first dose between pts who had CR, partial response (PR)/nPR, and stable disease (SD)/progressive disease (PD; Figure); at later doses, median Cmax and Cmin values appeared different between CR and the other groups, although number of subjects decreased over time, especially in the SD/PD group. Based on univariable analyses, higher Cmax and Cmin at Dose 3 and higher Cmax and AUC at Dose 6 were associated with increased likelihood of CR (P&lt;.05); higher Cmin before Dose 6 was associated with increased likelihood of OR and longer PFS. Conclusions: PK of O in combination with FC appeared proportional to dose after repeated dosing. Higher concentrations at Doses 3 and 6 were associated with CR. O PK was similar at first dose and different at later doses between patients who had CR, PR/nPR, and SD/PD, suggesting that response to O-FC treatment leads to clearance differences due to decreased B-cell mass and thus concentration differences with continued dosing. Further analyses of associations between disease-related factors, PK, and treatment response will be performed at study completion. Disclosures: Wierda: GlaxoSmithKline: Research Funding; Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Merck: Consultancy; Abbott: Research Funding. Off Label Use: Ofatumumab is an anti-CD20 monoclonal antibody approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia, and is currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma), as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Jewell:GlaxoSmithKline: Employment. Kipps:Gilead Sciences: Consultancy, Research Funding; GSK: Research Funding; Genentech: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Abbot Industries: Research Funding; Celgene: Consultancy, Research Funding; Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Dürig:Santaris Pharma: Consultancy, Research Funding; GSK: Speakers Bureau; Roche: Speakers Bureau; Celgene: Research Funding. Stilgenbauer:Genmab: Research Funding; GSK: Consultancy, Honoraria, Research Funding. Smolej:Roche: Honoraria, Travel Grants; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants; Genzyme: Honoraria, Travel Grants. Hernandez-Ilizaliturri:Genmab: Research Funding; Celgene: Honoraria; Amgen: Research Funding. Fang:PharStat: Employment; GSK: Consultancy; Gilead Sciences: Consultancy; Pharmasset Inc: Consultancy. Gorczyca:GlaxoSmithKline: Employment. Chan:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Lisby:Genmab A/S: Employment.

5.32 Long-term Outcome of B-CLL Patients Treated in a Prospective Trial Evaluating Combination of Oral Fludarabine and Cyclophosphamide as Frontline Therapy

Abstract 1795 Introduction. The combination of fludarabine and cyclophosphamide (FC) has become the core combination of modern frontline chemotherapy for fit and young B-CLL patients (pts). Recently the association with rituximab to FC (IV administration) has been shown to increase the response and extend both progression free survival (PFS) and overall survival (OS) in untreated pts (Hallek et al., Lancet 2010). So far few data are available concerning the very long term outcome of pts treated by FC containing regimen. Methods. We previously reported a prospective phase II trial (Cazin et al., BJH 2008) of the oral combination of FC over 5 days in 75 patients with untreated B-CLL and less than 66 years old. The study was conducted between October 1999 and February 2001. Briefly, oral FC then demonstrated high efficacy with overall response rate (ORR) and complete response (CR) rate of 80% and 53% respectively despite the absence of rituximab in this regimen. We here propose to examine 10-year end points of progression-free survival (PFS), overall survival (OS), impact of genomic features, and risk of therapy-related myeloid neoplasm (t-MN) by updating survival data of all the pts incuded in this trial. Results. With a median follow-up of 10.7 years, the median 10-year OS was 51.7%. Responders presented better 10-year OS than non-responders (57% vs. 38%, p=0.031) but quality of response (CR vs. PR) did not significantly impact 10-year OS. A major prognostic impact of IGVH mutational status could be observed since 10-year OS was 81% for mutated patients vs . 44% for unmutated pts (p=0.012). The median 10-year PFS was 30% and clearly influenced by the mutational status (50% if mutated profile vs. 12% if unmutated profile, p=0.02). However there is no trend of a plateau and even long term responding patients still relapse with time. Finally, only one patient developed t-MN but 9 others presented solid neoplasms. Conclusion. Long-term follow-up of B-CLL patients prospectively treated in a phase II clinical trial demonstrates extended OS and PFS with oral FC without high risk of t-MN. Disclosures: No relevant conflicts of interest to declare.

Comprehensive assessment of prognostic factors predicting outcome in Chinese patients with chronic lymphocytic leukemia treated with fludarabine and cyclophosphamide

To determine whether prognostic factors remain relevant to chronic lymphocytic leukemia (CLL) patients treated with fludarabine and cyclophosphamide (FC), we prospectively evaluated 86 Chinese CLL patients who received FC in first-line therapy. Twenty-four patients (27.9%) achieved complete remission (CR), and overall response rate was 75.6%. With a median follow-up of 41 months, the median progression-free survival (PFS) was 36.0 months and median overall survival (OS) has not been reached. The strong correlations of lower CR rate with advanced Binet stage, unmutated IGHV, cytogenetic abnormalities of del(17p13) or del(11q23), and p53 mutations were observed by univariable analyses. Stepwise logistic regression identified that unmutated IGHV and p53 abnormality (p53 deletion or mutation) were associated with a decreased odds of achieving CR. The less cycles of treatment, not achieving CR, advanced Binet stage, and p53 abnormality significantly correlated with a shortened PFS. Furthermore, in a multivariate analysis, p53 abnormality and advanced Binet stage were identified as being significant risk factors for early relapse. Not achieving CR, advanced Binet stage, ZAP-70-positive, and p53 abnormality were the adverse factors in determining OS. Only p53 aberration was independently associated with significantly shorter OS by a multivariate analysis. These results suggest that patients with p53 abnormality should be considered for alternative therapies.

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Therapy-related myelodysplastic syndrome and acute myeloid leukemia in patients with chronic lymphocytic leukemia treated with fludarabine and cyclophosphamide

We retrospectively studied four cases of t-MDS/AML among 210 (1.9%) consecutive patients with CLL treated at a single center with fludarabine and cyclophosphamide (FC) either as the first- or second-line therapy. The median follow-up of the whole cohort of patients was 46 months (range: 7–60). Two of these patients (2/130, 1.7%) had been treated with FC only, and two more (2/80, 2.3%) with CHOP and CHOP + FND, respectively, prior to FC. The median age was 61.5 years (range: 49–71); three were male. They developed t-MDS/AML after a median latency period of 41 months (range: 7–56) from the FC completion. Chromosomal aberrations with an adverse prognostic impact were present in the karyotype of all four patients, including abnormalities of chromosome 5 in three of them, and a rare chromosomal translocation in one patient. Median survival after t-MDS/AML diagnosis was 4 months (range: 2–8). Although the agents administered prior to FC make it difficult to assess the risk of t-MDS/AML attributable to FC, this report might be a valuable addition to the literature.

Second line chemotherapy in patients with enteropathy-associated T cell lymphoma: a retrospective single center analysis

Enteropathy-associated T cell lymphoma (EATL) is a rare disease with a dismal prognosis. Due to the low efficacy of chemotherapy and the poor performance status of patients failing first line, no data on second line therapy exist. A retrospective analysis of 19 patients with EATL at our institution identified six patients (31%) undergoing second line chemotherapy after CHOP-like regimens. Three patients had progressive disease (PD) during first line therapy, while the other three patients showed relapse after an initial complete remission (CR). The time from the last cycle of first line chemotherapy to second line therapy was 1-62 months. Two patients received ifosfamide, carboplatin and etoposide (ICE), two were given fludarabine and cyclophosphamide (FC) and one each had dexamethasone, cisplatin and cytarabine (DHAP) and cladribine chemotherapy. One patient progressed after one course of cladribine, while two patients developed intestinal perforation and died after one course of ICE and DHAP, respectively. Three patients achieved a CR lasting 4, +7 and +64 months, with two being alive without evidence of disease. Our data again confirm the poor prognosis of patients with EATL. A small subset of patients, however, apparently benefits from initiation of second line chemotherapy.

U.S. Food and Drug Administration Approval: Rituximab in Combination with Fludarabine and Cyclophosphamide for the Treatment of Patients with Chronic Lymphocytic Leukemia

To describe the clinical studies that led to the FDA approval of rituximab in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with chronic lymphocytic leukemia (CLL). The results of two multinational, randomized trials in CLL patients comparing rituximab combined with fludarabine and cyclophosphamide versus FC were reviewed. The primary endpoint of both studies was progression-free survival (PFS). The addition of rituximab to FC decreased the risk of a PFS event by 44% in 817 previously untreated patients and by 24% in 552 previously treated patients. Median survival times could not be estimated. Exploratory analysis in patients older than 70 suggested that there was no benefit to patients when rituximab was added to FC. The safety profile observed in both trials was consistent with the known toxicity profile of rituximab, FC, or CLL. On the basis of the demonstration of clinically meaningful prolongation of PFS, the FDA granted regular approval to rituximab in combination with FC for the treatment of patients with CLL. The magnitude of the treatment effect in patients 70 years and older is uncertain.

Low-grade lymphoma: Beyond fludarabine-single therapy

Low-grade lymphoma: Beyond fludarabine-single therapy

The Pentostatin Plus Cyclophosphamide Nonmyeloablative Regimen Induces Durable Host T Cell Functional Deficits and Prevents Murine Marrow Allograft Rejection

We describe a novel animal model of nonmyeloablative bone marrow transplantation (BMT) using the purine analog pentostatin. Other cohorts of mice received another purine analog, fludarabine, which we and others have previously evaluated in nonmyeloablative murine models. We evaluated pentostatin for its ability to (1) operate synergistically with cyclophosphamide to induce host T cell depletion; (2) induce host T cell suppression, as defined by modulation of cytokine secretion in vitro and abrogation of host-versus-graft reactivity in vivo; (3) constrain host T cell recovery post-therapy; and (4) prevent the rejection of T cell-depleted, fully major histocompatibility complex-mismatched bone marrow allografts. Relative to single-agent regimens, combination regimens with pentostatin and cyclophosphamide (PC) and with fludarabine and cyclophosphamide (FC) worked synergistically to deplete host CD4(+) and CD8(+) T cells. PC and FC regimens were developed that yielded similar levels of host T cell and myeloid cell depletion. In the setting of these generally comparable states of host T cell and myeloid cell depletion, the PC regimen was found to be highly immunosuppressive, as evidenced by a reduced host T cell capacity to secrete interleukin-2 and interferon-γ in vitro, to mediate host-versus-graft reactivity in vivo, and to recover numerically and functionally during a 2-week observation period after chemotherapy. Finally, using B6 hosts treated with the 14-day chemotherapy regimens, the PC regimen more consistently prevented the rejection of BALB/c T cell-depleted allografts compared with the FC regimen (rate of alloengraftment, 14/15 [93%] of PC-treated recipients vs 8/14 [57%] of FC-treated recipients; P < .05); similar results were observed using an 8-day conditioning regimen. These data suggest that host T cell suppression, distinct from T cell depletion, may be a critical determinant of engraftment after purine analog-based regimens and also may be preferentially attained by the use of pentostatin.

Fludarabine, Cyclophosphamide and Lenalidomide (FCL) for Previously Treated Patients with Chronic Lymphocytic Leukemia (CLL): Results of the Dose-Finding Phase of the GIMEMA LLC606 Study

AbstractAbstract 1377Targeting the CLL microenvironment with immunomodulatory agents like lenalidomide results in antileukemic activity. Addition of lenalidomide to an effective regimen such as fludarabine and cyclophosphamide (FC) could further increase therapeutic activity. On this basis, we designed a study aimed at evaluating the activity and safety profile of FC combined with lenalidomide (FCL) in previously treated CLL patients.Treatment consists of 6 monthly courses of FC (F, fudarabine: 30 mg/m2 iv and C, cyclophosphamide: 250 mg/m2, days 1–3) combined with 14 consecutive days of lenalidomide administration (days1-14). The first phase of this study was focused on defining the maximum tolerated dose (MTD) of lenalidomide given in combination with FC. In all patients, lenalidomide was given at the starting dose of 2.5 mg daily during the first course. For the subsequent courses the dose of lenalidomide was progressively escalated to reach a maximum daily dose of 5 mg, 10 mg and 15 mg, respectively, in each 3 cohorts of 3 patients, unless a dose limiting toxicity (DLT) was experienced. DLT was defined as persistent and severe hematologic toxicity, grade ≥2 tumor lysis syndrome (TLS), grade ≥3 tumor flare reaction (TFR) or other grade ≥3 toxicities. Supportive treatment included primary prophylaxis of granulocytopenia (G-CSF, days 6–11), PC and HVZ prophylaxis, thromboembolic prophylaxis with low molecular weight heparin (enoxaparin, 4000 units/sc/day) and TLS prophylaxis (oral hydration, allopurinol 300 mg/day, days -3 - 90). Strict contraceptive measures were required for all males and females with childbearing potential. At present, 9 relapsed CLL patients with advanced disease have been included in the first phase of the study focused on identifying the MTD for lenalidomide given in combination with FC. The median age was 63 years (range: 50–68); the median number of prior treatments was 2 (range: 1–2). All patients but 1 had been previously treated with the FC/FCR regimens; the majority showed a considerably high white blood count (range: 33–216 × 109/L) and 2 had a bulky nodal disease. Adverse cytogenetic abnormalities were detected by FISH in 5 cases (17p-, 2 cases; 6q-, 3 cases). While no DLT was observed in 3 patients who reached the 5 mg dose of lenalidomide given in combination with FC, a DLT was recorded in 2 of 3 patients who received 10 mg of lenalidomide (pneumonia; grade 3 hepatic toxicity). The 5 mg dose of lenalidomide was tested in 3 further patients with no DLT. Thus, 5 mg of lenalidomide was defined as the MTD of lenalidomide given in combination with FC. A marked reduction of white blood count was observed within the first 2 weeks of treatment in all cases but 1. A response was observed in 6 patients (67%; CR, 3; PR, 3), while a treatment-failure was recorded in 3 cases (SD, 2; Richter's syndrome,1). Despite G-CSF prophylaxis, the majority of patients experienced transient grade 3–4 neutropenia. Grade 1 fatigue and constipation were frequently observed during the first course of treatment. A transient grade 1 TFR was documented, while no episodes of TLS and thrombosis were recorded. Our findings indicate that 5 mg daily is the MTD of lenalidomide given in combination with FC. Initial responses suggest that FCL is a promising investigational regimen for patients with CLL who have failed prior treatment with fludarabine-based combinations. In the ongoing phase 2 of this study 32 patients are planned to receive 5 mg of lenalidomide in combination with FC. Disclosures:Foà:Celgene: Membership on an entity's Board of Directors or advisory committees.

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

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

Presenting Features and Outcome of Elderly Chronic Lymphocytic Leukemia Patients Diagnosed at the Age of 80 Years or Above. An ICLLSG Study.

AbstractAbstract 4620Chronic lymphocytic leukemia (CLL) is the most common leukemia of the elderly people in the western world. Its age-adjusted incidence rate is about 4.1 per 100,000 men and women per year. CLL increases exponentially with age and for patients above the age of 80 the CLL incidence rate increases to >20 per 100,000 per year. The clinical characteristics and outcome of CLL patients diagnosed at age 80 or above are unknown. The Israel Chronic Lymphocytic Leukemia Study Group reviewed retrospectively the records of 214 such patients diagnosed between the years 1979–2009 in 7 medical centers (118 males, 96 females; mean age: 84 years, range; 80–94). 153 (71%) were Ashkenazi Jews, 43 (20%) were Sephardic Jews, and 3 (1.4%) were Arabs. 104 (48%) were referred due to routine blood analysis and 80 (37%) due to disease manifestations. At diagnosis 120 (56%) had Rai stage 0, 67(31%) Rai stages I and II, and 27(13%) Rai stages III and IV. The mean hemoglobin level was 12.2g/dL (range 5.8–17.3), mean WBC 33,241/μ L (range 6,100-400,000) and mean platelets of 194,622/μ L (range 56,000-617,000). Lymphadenopathy was noted in 33% and splenomegaly in 22%. LDH at diagnosis was elevated in 26% of the patients. 161 patients (75%) were on follow-up only without any treatment. Fifty three patients received treatment for the CLL (25%). Treatment consisted of chlorambucil and or prednisone in 36 patients, COP (cyclophosphamide, vincristine and prednisone) in 6 patients, CHOP (cyclophosphamide, adriamycine, vincristine and prednisone) in 5 patients, FC (fludarabine and cyclophosphamide) in 3 patients and RCOP (rituximab and COP) in 2 patients, 1 patient received irradiation. By June 2010,155 patients (72%) have died with a mean overall survival of 68±5 months, median 56±5.4 months and 5 years survival of 47.2%±3.6. In univariate analysis a better survival was associated with younger age (the mean survival of patient age 80–84 years at diagnosis was 76±6.3 months, median 71±5.8 months compared to mean survival of 48.8±4.8 months and median 43±9.3 months for patients ≥85 years old at diagnosis, p=0.002), Rai stage (the mean survival of patients diagnosed at Rai stage 0 was79.5±8.5 months, median 62±6.5 months compared to mean of 55.7±6.2 months, median 47±7.6 months for patients diagnosed at Rai stages I and II, p=0.023), WBC count at diagnosis (the mean survival of patient with WBC count at diagnosis ≤30,000/μ L was 77±7.6 months, median 62±6.1 months compared to mean survival of 51.8±6.7 months, median 32±8 months in patients diagnosed with a WBC >30,000/μ L, p=0.015), β2 microglobulin levels (the mean survival of the 39 patients with β2 microglobulin level at diagnosis < 3mg/L was 103±19.6 months, median 70±13 months compared to mean of 50.2±7.6 months, median 39±8 months in the 28 patients with β2 microglobulin levels ≥ 3 mg/L, p=0.006), reason for diagnosis (the mean survival of patients diagnosed due to routine blood counts was 88.4±11.2 months, median 72±4.8 months, compared to 43.2±4.6 and 27±6.8 in patients diagnosed due to disease manifestations, p< 0.001), and CD38 level (the mean survival of 87 patients with CD38 levels ≤30% was 81.1±7.9 months, median 72±4.6 months compared to 52±8.9 32±6.9 months respectively in the 24 patients with CD 38 levels >30 %, p=0.036). No correlation was found between overall survival and patients' gender, receiving or not chemotherapy, year of diagnosis before or after 2000, or ethnicity (Ashkenazi Jews vs. Sephardic Jews). Multivariate analysis using Cox regression analysis found younger age, low WBC count, and routine blood test as the reason for diagnosis as 3 independent good prognostic factors (HR 1.8, 1.6, 1.9 respectively). CLL patients diagnosed at the age of 80 or more can still expect to live long life. Disclosures:No relevant conflicts of interest to declare.

Effect of FCGR2A and FCGR3A variants on CLL outcome

AbstractPolymorphisms of activating Fc-γ receptors (FCGRs) on natural killer cells and macrophages result in variable affinity for immunoglobulin G1 monoclonal antibodies and subsequently modulate antibody-dependent cellular cytotoxicity (ADCC) activity. Whether single-nucleotide polymorphisms of FCGRs correlate with survival of chronic lymphocytic leukemia (CLL) patients treated with a monoclonal antibody containing regimen is unclear. We assessed the FCGR3A and FCGR2A genotype of patients enrolled in the REACH trial, where patients received fludarabine and cyclophosphamide (FC) or rituximab plus FC (R-FC). FCGR3A and FCGR2A polymorphisms did not demonstrate prognostic significance in the FC arm (P = .42 and P = .64, respectively) or R-FC arm (P = .41 and P = .88, respectively) with respect to progression free survival. Patients with intermediate affinity genotypes (FV and HR) benefited significantly from addition of rituximab (hazard ratio = 0.55 [0.37-0.8 CI]; P = .0017 and hazard ratio = 0.63 [0.44-0.9 CI]; P = .011, respectively). Similar benefit was suggested for patients with high- affinity VV and HH (hazard ratio = 0.86 [0.4-1.84 CI]; P = .7 and hazard ratio = 0.7 [0.41-1.18 CI]; P = .18, respectively) and low-affinity FF and RR (hazard ratio = 0.85 [0.56-1.29 CI]; P = .44 and hazard ratio = 0.82 [0.47-1.42 CI]; P = .48, respectively). Overall, our results suggest that FCGR2A and FCGR3A polymorphisms do not significantly influence the outcomes of relapsed or refractory CLL patients treated with FC or the monoclonal antibody regimen R-FC.

The clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia: an evidence review of the submission from Roche

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia (CLL) based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer's searches for clinical effectiveness and cost-effectiveness data were appropriate and included all relevant studies. The submission's evidence came from a single, unpublished, well-conducted randomised controlled trial (RCT) comparing rituximab in combination with fludarabine and cyclophosphamide (R-FC) with fludarabine and cyclophosphamide (FC) alone for the first-line treatment of CLL. There was a statistically significant increase in progression-free survival (PFS) with R-FC compared with FC alone {median 39.8 months vs 32.2 months; hazard ratio [HR] 0.56 [95% confidence interval (CI) 0.43 to 0.72]}. However, the initial significant treatment benefit for R-FC compared with FC for overall survival was not maintained at a slightly longer follow-up time [median 25.4 months; adjusted HR 0.72 (95% CI 0.48 to 1.09)]. Response rates, numbers of patients with event-free survival and duration of response all favoured treatment with R-FC. Additional evidence from a mixed-treatment comparison model indicated R-FC to be significantly superior to chlorambucil alone for both PFS and overall and complete response rates. The incidence of grade 3 or 4 adverse events was higher in the R-FC arm (77%) than in the FC arm (62%). Dose modifications were also more frequent in this arm, but this did not lead to differences in treatment discontinuation. Roche used a three-state Markov model (PFS, progressed and death) to model the cost-effectiveness of R-FC compared with FC and chlorambucil alone. The model used a cycle length of 1 month and a lifetime time horizon. The approach taken to modelling was reasonable and the sources and justification of estimates were generally sound. The base-case analysis produced an incremental cost-effectiveness ratio (ICER) of 13,189 pounds per quality-adjusted life-year (QALY) for R-FC versus FC, and 6422 pounds per QALY for the comparison of R-FC versus chlorambucil, suggesting that R-FC is cost-effective at normal willingness-to-pay thresholds. One-way sensitivity analyses produced a range of ICERs from 10,249 pounds to 22,661 pounds per QALY for R-FC versus FC, and 5612 pounds and 6921 pounds per QALY for R-FC versus chlorambucil. Probabilistic sensitivity analysis results matched the deterministic results very closely. However, the sensitivity analysis did not fully investigate the uncertainty associated with differential values across arms or with the structural assumptions of the model, and utility values were not drawn from an empirical study. The NICE guidance issued as a result of the STA states that: Rituximab in combination with fludarabine and cyclophosphamide (R-FC) is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia in people for whom fludarabine in combination with cyclophosphamide (FC) is considered appropriate. Rituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide is not recommended for the first-line treatment of chronic lymphocytic leukaemia.

The clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia: an evidence review of the submission from Roche

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia (CLL) based upon a review of the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer’s searches for clinical effectiveness and cost-effectiveness data were appropriate and included all relevant studies. The submission’s evidence came from a single, unpublished, well-conducted randomised controlled trial (RCT) comparing rituximab in combination with fludarabine and cyclophosphamide (R-FC) with fludarabine and cyclophosphamide (FC) alone for the first-line treatment of CLL. There was a statistically significant increase in progression-free survival (PFS) with R-FC compared with FC alone {median 39.8 months vs 32.2 months; hazard ratio [HR] 0.56 [95% confidence interval (CI) 0.43 to 0.72]}. However, the initial significant treatment benefit for R-FC compared with FC for overall survival was not maintained at a slightly longer follow-up time [median 25.4 months; adjusted HR 0.72 (95% CI 0.48 to 1.09)]. Response rates, numbers of patients with event-free survival and duration of response all favoured treatment with R-FC. Additional evidence from a mixed-treatment comparison model indicated R-FC to be significantly superior to chlorambucil alone for both PFS and overall and complete response rates. The incidence of grade 3 or 4 adverse events was higher in the R-FC arm (77%) than in the FC arm (62%). Dose modifications were also more frequent in this arm, but this did not lead to differences in treatment discontinuation. Roche used a three-state Markov model (PFS, progressed and death) to model the cost-effectiveness of R-FC compared with FC and chlorambucil alone. The model used a cycle length of 1 month and a lifetime time horizon. The approach taken to modelling was reasonable and the sources and justification of estimates were generally sound. The base-case analysis produced an incremental cost-effectiveness ratio (ICER) of £13,189 per quality-adjusted life-year (QALY) for R-FC versus FC, and £6422 per QALY for the comparison of R-FC versus chlorambucil, suggesting that R-FC is cost-effective at normal willingness-to-pay thresholds. One-way sensitivity analyses produced a range of ICERs from £10,249 to £22,661 per QALY for R-FC versus FC, and £5612 and £6921 per QALY for R-FC versus chlorambucil. Probabilistic sensitivity analysis results matched the deterministic results very closely. However, the sensitivity analysis did not fully investigate the uncertainty associated with differential values across arms or with the structural assumptions of the model, and utility values were not drawn from an empirical study. The NICE guidance issued as a result of the STA states that: Rituximab in combination with fludarabine and cyclophosphamide (R-FC) is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia in people for whom fludarabine in combination with cyclophosphamide (FC) is considered appropriate. Rituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide is not recommended for the first-line treatment of chronic lymphocytic leukaemia.

Rituximab for the treatment of relapsed/refractory chronic lymphocytic leukaemia

This paper presents a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of rituximab with chemotherapy compared to chemotherapy only for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) based on the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. Evidence was available in the form of one open-label, ongoing, unpublished randomised controlled trial (RCT), REACH (Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia), conducted by the manufacturer, which compared rituximab with a fludarabine and cyclophosphamide combination (R-FC) to fludarabine and cyclophosphamide (FC) only. REACH was scheduled to run for 8 years; however, the data provided were immature, with a median observation time at the time of data analysis of 2.1 years. REACH provided evidence of prolonged progression free survival with R-FC compared to FC (10 months, investigators' data), but no evidence of an overall survival benefit with R-FC. Patients refractory to fludarabine and with prior rituximab exposure were excluded from REACH and no controlled studies were identified by the ERG for these patient groups. The ERG had concerns about the structure of the economic model submitted by the manufacturer, which did not allow improvement in quality of life from treatment while in a progressed state. The manufacturer's model further assumed a divergence in cumulative deaths between the R-FC and FC treatment arms from the outset, which did not accord with observed data from REACH. When the survival advantage was removed, the manufacturer's base-case incremental cost-effectiveness ratio (ICER) changed from 15,593 pounds to between 40,000 pounds and 42,000 pounds per quality-adjusted life-year (QALY). With no survival advantage, the ICER became sensitive to changes in utility. There was no good empirical evidence on the utility of CLL patients in different states. Allowing for the possibility of a survival advantage with rituximab (although not supported by current evidence), the ERG performed further modelling, which found that rituximab would be cost-effective at 20,000 pounds/QALY (30,000 pounds/QALY) if a reduction in survival advantage relative to the manufacturer's base case of 40% (80%) was assumed. The guidance issued by NICE in July 2010 as a result of the STA recommends rituximab with FC for people with relapsed or refractory chronic lymphocytic leukaemia, except when the condition is refractory to fludarabine or where there has been previous treatment with rituximab.

Rituximab for the treatment of relapsed/refractory chronic lymphocytic leukaemia

This paper presents a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of rituximab with chemotherapy compared to chemotherapy only for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) based on the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. Evidence was available in the form of one open-label, ongoing, unpublished randomised controlled trial (RCT), REACH (Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia), conducted by the manufacturer, which compared rituximab with a fludarabine and cyclophosphamide combination (R-FC) to fludarabine and cyclophosphamide (FC) only. REACH was scheduled to run for 8 years; however, the data provided were immature, with a median observation time at the time of data analysis of 2.1 years. REACH provided evidence of prolonged progression free survival with R-FC compared to FC (10 months, investigators’ data), but no evidence of an overall survival benefit with R-FC. Patients refractory to fludarabine and with prior rituximab exposure were excluded from REACH and no controlled studies were identified by the ERG for these patient groups. The ERG had concerns about the structure of the economic model submitted by the manufacturer, which did not allow improvement in quality of life from treatment while in a progressed state. The manufacturer’s model further assumed a divergence in cumulative deaths between the R-FC and FC treatment arms from the outset, which did not accord with observed data from REACH. When the survival advantage was removed, the manufacturer’s base-case incremental cost-effectiveness ratio (ICER) changed from £15,593 to between £40,000 and £42,000 per quality-adjusted life-year (QALY). With no survival advantage, the ICER became sensitive to changes in utility. There was no good empirical evidence on the utility of CLL patients in different states. Allowing for the possibility of a survival advantage with rituximab (although not supported by current evidence), the ERG performed further modelling, which found that rituximab would be cost-effective at £20,000/QALY (£30,000/QALY) if a reduction in survival advantage relative to the manufacturer’s base case of 40% (80%) was assumed. The guidance issued by NICE in July 2010 as a result of the STA recommends rituximab with FC for people with relapsed or refractory chronic lymphocytic leukaemia, except when the condition is refractory to fludarabine or where there has been previous treatment with rituximab.