Fit Chronic Lymphocytic Leukemia Patients Research Articles

Del(8p) and TNFRSF10B loss are associated with a poor prognosis and resistance to fludarabine in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, the prognosis of which varies according to the cytogenetic group. We characterized a rare chromosomal abnormality (del(8p), deletion of the short arm of chromosome 8) in the context of CLL. By comparing the largest cohort of del(8p) CLL to date (n = 57) with a non-del(8p) cohort (n = 155), del(8p) was significantly associated with a poor prognosis, a shorter time to first treatment, worse overall survival (OS), and a higher risk of Richter transformation. For patients treated with fludarabine-based regimens, the next-treatment-free survival and the OS were shorter in del(8p) cases (including those with mutated IGHV). One copy of the TNFRSF10B gene (coding a pro-apoptotic receptor activated by TRAIL) was lost in 91% of del(8p) CLL. TNFRSF10B was haploinsufficient in del(8p) CLL, and was involved in the modulation of fludarabine-induced cell death - as confirmed by our experiments in primary cells and in CRISPR-edited TNFRSF10B knock-out CLL cell lines. Lastly, del(8p) abrogated the synergy between fludarabine and TRAIL-induced apoptosis. Our results highlight del(8p)'s value as a prognostic marker and suggest that fit CLL patients (i.e. with mutated IGHV and no TP53 disruption) should be screened for del(8p) before the initiation of fludarabine-based treatment.

Phase II, Multicenter Trial, Exploring “Chemo-Sparing” Strategy Associating Obinutuzumab+Ibrutinib Followed By a MRD Driven Strategy, in Previously Untreated Symptomatic Medically Fit Chronic Lymphocytic Leukemia Patients (CLL): Preliminary Results of the Induction Phase of the Icll-07 Filo Study

Phase II, Multicenter Trial, Exploring “Chemo-Sparing” Strategy Associating Obinutuzumab+Ibrutinib Followed By a MRD Driven Strategy, in Previously Untreated Symptomatic Medically Fit Chronic Lymphocytic Leukemia Patients (CLL): Preliminary Results of the Induction Phase of the Icll-07 Filo Study

Long Term Follow-up Data and Health-Related Quality of Life in Frontline Therapy of Fit Patients Treated With FCR Versus BR (CLL10 Trial of the GCLLSG).

Fludarabine, cyclophosphamide and rituximab (FCR) was compared to bendamustine and rituximab (BR) in an international, randomized, open label, phase 3 trial in 561 previously untreated, fit patients with chronic lymphocytic leukemia (CLL) without del (17p). Primary endpoint was progression free survival (PFS). The final primary endpoint analysis after 37.1 months median follow up failed to show the non-inferiority of BR as compared with FCR. With extended median follow up of 58.2 months, median PFS was 42.3 months in BR-treated patients versus 57.6 months for FCR-treated patients (Hazard Ratio [HR] 1.593; 95% CI 1.271-1.996; p < 0.0001). For patients > 65 years, median PFS was 48.5 months with BR versus 57.9 months with FCR without reaching statistical significance (HR 1.352; 95% CI 0.912-2.006; p = 0.134). Median OS was not reached for both arms with 5-year OS rates of 80.1% vs 80.9%, respectively (HR 1.108; 95% CI 0.755-1.627; p = 0.599). No statistically significant difference was found in the time to secondary malignancy between the 2 groups (at 5 years, 86.6% free from secondary malignancies in the BR group vs 83.8% in the FCR group [HR 0.801; 95% CI 0.507-1.267; p = 0.344]). In patients >65 years secondary neoplasia occurred more frequently after FCR treatment [28 of 86 (32.6%) patients] as compared with BR [18 of 107 (16.8%) patients; p = 0.011]. Health-related quality of life was similar in both treatments. Despite the improved PFS for FCR, OS did not differ. These results also suggest an increase in secondary neoplasia associated with FCR in elderly fit CLL patients.

Sequential Treatment with Bendamustine, Obinutuzumab (GA101) and Ibrutinib in Chronic Lymphocytic Leukemia (CLL): Final Results of the CLL2-BIG Trial of the German CLL Study Group (GCLLSG)

Sequential Treatment with Bendamustine, Obinutuzumab (GA101) and Ibrutinib in Chronic Lymphocytic Leukemia (CLL): Final Results of the CLL2-BIG Trial of the German CLL Study Group (GCLLSG)

Obinutuzumab plus fludarabine and cyclophosphamide in previously untreated, fit patients with chronic lymphocytic leukemia: a subgroup analysis of the GREEN study

GREEN (NCT01905943) is a nonrandomized, open-label, single-arm, phase 3b study investigating the safety and efficacy of obinutuzumab alone or in combination with chemotherapy in chronic lymphocytic leukemia (CLL). We report the preplanned subgroup analysis of 140 previously untreated, fit CLL patients who received obinutuzumab plus fludarabine and cyclophosphamide (G-FC). The primary endpoint was safety and tolerability. Efficacy was the secondary endpoint. Obinutuzumab 1000 mg was administered intravenously on Day (D)1 (dose split D1‒2), D8 and D15 of Cycle (C)1, and D1 of C2–6 (28-day cycles). Standard intravenous/oral doses of fludarabine and cyclophosphamide were administered on D1–3 of C1–6. Overall, 87.1% of patients experienced grade ≥ 3 adverse events (AEs), including neutropenia (67.1%) and thrombocytopenia (17.1%). Serious AEs were experienced by 42.1% of patients. Rates of grade ≥ 3 infusion-related reactions and infections were 19.3% and 15.7%, respectively. Overall response rate was observed in 90.0%, with 46.4% of patients achieving complete response (CR; including CR with incomplete marrow recovery). Minimal residual disease negativity rates were 64.3% in peripheral blood and 35.7% in bone marrow (intent-to-treat analysis). After a median observation time of 25.6 months, 2 year progression-free survival was 91%. Frontline G-FC represents a promising treatment option for fit patients with CLL.

PB1913 CIRS SCORE AS A RELIABLE COMORBIDITY EVALUATION TOOL MAY INFLUENCE THERAPEUTIC DECISIONS IN ELDERLY CLL PATIENTS

Background:Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the elderly population and many of these patients have multiple comorbidities, which might limit the eligibility for upfront chemoimmunotherapy options. The Cumulative Illness Rating Scale (CIRS) score seems to be a reliable tool for assessment of the burden of comorbidity in elderly cancer patients. It may identify fit and unfit CLL patients and influence the therapeutic decision‐making process.Aims:The primary objective of our study was to assess the CIRS score status in CLL patients in real clinical practice. The secondary objective was to analyze which treatment option was used in each patient's group, classified according to CIRS.Methods:In our prospective, single‐center study we focused on CLL patients that visited the University clinic for hematology in Skopje between March 20th 2017 and January 22nd 2019. Comorbidity was assessed by the CIRS‐G score in all patients included in our study (n = 56) prior to reaching a multidisciplinary treatment decision.Results:In our series, 56 CLL patients; 30 (53.6%) males and 26 (46.4%) females, were included. Median age was 69 (± 9.4) years (range 38‐85). Comorbidities were identified in 80.4% of the study population, with an average CIRS score of 3.9 (range 0‐13). Only 19.6% of the patients were comorbidity free. There was a positive correlation between the CIRS score and the age (rs = 0.2276, p = 0.04). Two thirds, or 67.9% of the patients had a CIRS score &lt;6, 21.4% had CIRS score between 6 and12 and CIRS score was &gt;12 in only 8.9% of patients. The three most common comorbidities were related to affections of the vascular system (41.1%), endocrine‐metabolic disorders (32.1%), and respiratory system disorders (17.9%). Only 16.1% of the patients had only 1 affected organ or system, other than hematological issues, while 64% of the patients had ≥2 affected systems. In 33.9% of the study patient cohort, the watch and wait approach was the standard of care; 66.1% of patients were eligible for treatment as follows: chemotherapy (chlorambucil, fludarabine + cyclophosphamide, bendamustine) only (30.4%), rituximab‐based therapy (33.9%) and 1.8% of patients, due to the high comorbidity burden, received only supportive care. There was a stable trend of correspondence between the CIRS score assessment and the treatment option prescribed (rs = 0.7188, p &lt; 0.000001). Despite their eligibility for novel therapies (e.g. obinutuzumab, ibrutinib, idelalisib etc.) none of the patients received them due to their local unavailability.Summary/Conclusion:Our study shows that comorbidity is a very common feature in CLL patients and that it is increasing with age. Despite the fact that 8 out of 10 patients had at least one affected organ/system, the general comorbidity burden was low. CIRS is helpful in identifying the best treatment combination for the patients, that will enhance achieving long‐term control of CLL, maintaining an optimal quality of life level.

Dynamic BH3 Profiling Predicts Patient Response and MRD Status in Chronic Lymphocytic Leukemia (CLL) Patients Undergoing Frontline Treatment with Kinase Inhibitor Plus FCR (KI+FCR)

Dynamic BH3 Profiling Predicts Patient Response and MRD Status in Chronic Lymphocytic Leukemia (CLL) Patients Undergoing Frontline Treatment with Kinase Inhibitor Plus FCR (KI+FCR)

Favorable Toxicity Profile and Long Term Outcome of Elderly, but Physically Fit CLL Patients (pts) Receiving First Line Bendamustine and Rituximab (BR) Frontline Chemoimmunotherapy in Comparison to Fludarabine, Cyclophosphamide, and Rituximab (FCR) in Advanced Chronic Lymphocytic Leukemia (CLL): Update Analysis of an International, Randomized Study of the German CLL Study Group (GCLLSG) (CLL10 Study)

Favorable Toxicity Profile and Long Term Outcome of Elderly, but Physically Fit CLL Patients (pts) Receiving First Line Bendamustine and Rituximab (BR) Frontline Chemoimmunotherapy in Comparison to Fludarabine, Cyclophosphamide, and Rituximab (FCR) in Advanced Chronic Lymphocytic Leukemia (CLL): Update Analysis of an International, Randomized Study of the German CLL Study Group (GCLLSG) (CLL10 Study)

CLL2-BIG - a Novel Treatment Regimen of Bendamustine Followed By GA101 and Ibrutinib Followed By Ibrutinib and GA101 Maintenance in Patients with Chronic Lymphocytic Leukemia (CLL): Results of a Phase II-Trial

CLL2-BIG - a Novel Treatment Regimen of Bendamustine Followed By GA101 and Ibrutinib Followed By Ibrutinib and GA101 Maintenance in Patients with Chronic Lymphocytic Leukemia (CLL): Results of a Phase II-Trial

Impact of Gender on Outcome after Chemoimmunotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) or Bendamustine Plus Rituximab (BR) in Patients with Chronic Lymphocytic Leukemia (CLL): A Meta-Analysis of Three Phase II/III Studies of the German CLL Study Group (GCLLSG)

Impact of Gender on Outcome after Chemoimmunotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) or Bendamustine Plus Rituximab (BR) in Patients with Chronic Lymphocytic Leukemia (CLL): A Meta-Analysis of Three Phase II/III Studies of the German CLL Study Group (GCLLSG)

CLL2-BIG - a Novel Treatment Regimen of Bendamustine Followed By GA101 and Ibrutinib Followed By Ibrutinib and GA101 Maintenance in Patients with Chronic Lymphocytic Leukemia (CLL): Interim Results of a Phase II-Trial

CLL2-BIG - a Novel Treatment Regimen of Bendamustine Followed By GA101 and Ibrutinib Followed By Ibrutinib and GA101 Maintenance in Patients with Chronic Lymphocytic Leukemia (CLL): Interim Results of a Phase II-Trial

Abbreviated Regimen with 4 Cycles of Fludarabine, Cyclophosphamide and Rituximab (FCR) in Physically Fit Patients with Chronic Lymphocytic Leukemia Who Achieve Early Complete Remission with Undetectable Minimal Residual Disease: Safety and Efficacy Follow-up Results of a Single Center Experience

Introduction: Chemoimmunotherapy with 6 cycles of fludarabine, cyclophosphamide and rituximab (FCR) is considered standard therapy for physically fit patients with chronic lymphocytic leukemia (CLL). Due to treatment toxicity, some patients are unable to undergo standard 6 cycles of FCR. We evaluated safety and efficacy of abbreviating FCR treatment to 4 cycles in a cohort of 35 untreated physically fit CLL patients who achieved CR with negative minimal residual disease (MRD).Patients and methods: Within 150 physically fit CLL patients treated with FCR on 1st line at our Center, from April 2003 to November 2014, a subgroup of 35 patients interrupted treatment after achieving negative MRD at the end of the 4th cycle. Median age at start of treatment was 62.8 years (34-81). Binet A/B: 24pts and C: 11. CD38 expression was positive (>7% off cells) in 57.1% and negative in 9% of the pts. A bone marrow biopsy was performed at start of treatment and 1 month post 4th cycle. Response was assessed in peripheral blood (PB) or bone marrow (BM). Negative MRD was defined as < 10-4. We used NCI criteria for response modified for the evaluation of MRD by flow cytometry. Progression was defined according to the NCI recommendations. Overall survival (OS) was defined as the time of initiation of therapy until death or last follow-up and progression free survival (PFS) as the time to progression. Data analysis included frequency and contingency tables, survival curves were plotted by the Kaplan Meier method. Treatment schedule: Fludarabine 25 mg/m2 IV day 1-3, cyclophosphamide 250 mg/m2 IV day 1-3, rituximab 375 mg/m2 IV day 3 cycle 1 and day 1 cycles 2-4, in all cycles every 28 days.Results: All 35 patients had negative MRD in PB after one month post 4th cycle. In addition, 28 had bone marrow evaluation showing CR with negative MRD in all of them. No splenomegaly nor hepatomegaly, enlarged lymphadenopathies nor lymphocytosis was observed in all the patients with negative MRD. After a median follow-up of 57 months (7 -141), median PFS was 65.8 months, not being yet reached the median of OS. PFS and OS at 72 months was 46% and 68% respectively. A total of 10 pts ( 3.5%) died: 7 on progressive disease, 3 on secondary neoplasms. Patients who progressed before 24 months had a median of survival of 22 months; median not reached on the group who progressed after 24 months (p=0.0001). Neutropenia grade 3-4 and infectious events were observed in 25.7% and 9.1% during all cycles respectively. Grade 3-4 neutropenia showed to increase over time (Cycle 1: 24%, Cycle 4: 39%). There was no treatment related death.Conclusion: With a long median follow-up, abbreviating treatment to 4 courses of FCR in patients who obtained negative MRD showed durable remissions with high PFS and OS at 72 months, minimizing treatment related toxicity. Sixty five percent of the patients who progressed after 24 months are still alive. Large randomized trials will be necessary to confirm our data. DisclosuresPavlovsky:Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Pavlovsky:Novartis: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

Fludarabine, Cyclophosphamide, Ofatumumab (FC-O2) As Front-Line Treatment for Young and Fit Patients with Chronic Lymphocytic Leukemia (CLL): Preliminary Results of the Prospective Phase 2 LLC0911 Gimema Study

Introduction. The fludarabine, cyclophosphamide, rituximab (FCR) regimen is associated with high complete response (CR) rates and a negative residual disease status in a significant proportion of cases and is considered the optimal front-line treatment for fit patients with chronic lymphocytic leukemia (CLL). In addition, long-term follow-up of patients treated with FCR at the MD Anderson Cancer Center, in the multicenter German CLL8 study and at Italian institutions indicate that a sizable fraction of patients characterized by a favorable biologic profile remains free from progression in excess of 10 years. FC combined with ofatumumab (FC-O), a human monoclonal antibody which targets an epitope of the CD20 molecule, has also been associated with a high CR rate. The aim of this study was to evaluate whether a double dose of ofatumumab (O2) combined with FC could improve the CR rate in young (≤65 yrs) and fit patients with CLL.Methods. Sixty-one fit CLL patients from 15 Italian institutions were enrolled in this front-line study and treated with the FC-O2 regimen based on the FC schedule (F 25 mg/sqm i.v. d1-3, C 250 mg/sqm i.v. d1-3) combined with 13 doses of O (300 mg i.v. d14; 1000 mg d21 at the first cycle; 1000 mg d1 and d15 at cycles 2-6 and d28 at cycle 6). As infection prophylaxis, patients received bactrim and peg-filgrastim in order to prevent granulocytopenia. CLL diagnosis, treatment requirement and response were assessed according to the 2008 iwCLL guidelines. Minimal residual disease (MRD) was evaluated by flow cytometry in the peripheral blood (PB) and bone marrow (BM), and also by RQ-PCR in flow negative cases. CT scan evaluation was included in the response assessment. Adverse events (AEs) were graded according to the NCI-CTCAE.Results. The median age of patients was 60 years (range 36-65), Binet stages B and C were recorded in 86% of cases, B-symptoms in 21%, increased β2M values in 74% and bulky nodes (≥5 cm) in 10%. An IGVH unmutated status was recorded in 60% of cases, deletion 13q in 37%, no aberrations in 33%, deletion 11q in 14%, trisomy 12 in 12%, 17p deletion and/or TP53 mutation were found in 10% of cases. At present, the median follow-up of patients is 7 months (range 1-20). Response to treatment has been assessed in 29 patients after a median number of 6 courses of treatment (range 2-6). The overall response rate is 90%, with a CR rate of 69% (20 patients). No evidence of MRD was observed by flow cytometry in both PB and BM in 15/20 CR patients (75%). To date, 11 patients with cytometric MRD negative CR have been evaluated by RQ-PCR and no residual disease was detected in 3. Grade 3-4 granulocytopenia was recorded in 4 patients (7%), a severe infection in 4 (7%) and 5 patients (8%) experienced a severe infusion-related reaction during ofatumumab administration. Treatment was discontinued in 8 patients as a result of toxicity (infection, 2 cases; FUO, 1; infusion-related toxicity, 1; autoimmune hemolytic anemia, 1; recurrent granulocytopenia, 1; tachyarrhythmia, 1; non-specified toxicity,1). A non-treatment-related death (traumatic aortic transaction due to a dislocated aortic endoprostheses) has been recorded in a patient after 2 months from treatment discontinuation and 1 showed a disease progression after 4 courses of FC-O2.Conclusions. Taken together, the first analysis of this ongoing front-line study suggests that the combination of FC with an increased dose of ofatumumab is well tolerated with acceptable and no unexpected toxicity. Our preliminary results show that the FC-O2 treatment is associated with a high rate of cytometric MRD-negative CR in young and fit patients with previously untreated CLL. DisclosuresCarella:Seattle Genetics Inc.: Research Funding. Foà:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Chronic Lymphocytic Leukemia in the Elderly, Which Investigations Are Necessary: A Map for the Practicing Oncologist.

Chronic lymphocytic leukemia (CLL), the most prevalent leukemia in the Western world, is predominantly a disease of older individuals who also have other comorbidities as well as declining organ and bone marrow reserve. Although chemoimmunotherapy is the frontline therapy for fit CLL patients who can tolerate the therapy, many elderly patients cannot tolerate such intense therapy. The authors first reviewed the most recent findings concerning CLL cytogenetics, molecular biology, and prognostic models. They then surveyed recent and ongoing trials of novel CLL agents and strategies, with a focus on those most relevant to elderly patients. Novel therapies, revised staging procedures, and careful assessment of individual patients' frailty and functional status will allow clinicians to provide optimal care management for older CLL patients. Therapy for the elderly CLL population must be tailored to each patient's fitness level and comorbid conditions, with special consideration for the potential quality-of-life impacts of various treatment recommendations.

Frontline Chemoimmunotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Shows Superior Efficacy in Comparison to Bendamustine (B) and Rituximab (BR) in Previously Untreated and Physically Fit Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Final Analysis of an International, Randomized Study of the German CLL Study Group (GCLLSG) (CLL10 Study)

Frontline Chemoimmunotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Shows Superior Efficacy in Comparison to Bendamustine (B) and Rituximab (BR) in Previously Untreated and Physically Fit Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Final Analysis of an International, Randomized Study of the German CLL Study Group (GCLLSG) (CLL10 Study)

The Fate of Chronic Lymphocytic Leukemia Patients After Failure of Fludarabine, Cyclophosphamide, and Rituximab Regimen

AbstractAbstract 4603 Background:The clinical course of patients with chronic lymphocytic leukemia (CLL) is remarkably heterogeneous. All CLL patients who require therapy are destined to relapse. The prognosis and management of these relapsed patients differs based on the nature of the first-line therapy and the quality and duration of remission to that therapy, as well as biological prognostic factors. Currently, the first treatment option for younger and fit CLL patients is FCR (fludarabine, cyclophosphamide, rituximab) chemoimmunotherapy. Although it regards a very potent treatment option, patients inevitably relapse after the treatment and even approximately 7% of the patients, during initial FCR regimen treatment would fit the standard definition of refractory CLL. So far, little is known about the efficacy of subsequent therapy of patients who relapsed after FCR or were refractory to FCR. Therefore, the goal of this study was to analyze the fate of these patients in the context of routine hematological practice. Methods:We retrospectively analyzed the data of 119 patients (85 males; 34 females) consecutively entered into the databases of three large tertiary Czech hematological centers. All patients were indicated to receive FCR regimen in standard doses (F: 25mg/m2i.v. day 1–3; C: 250mg/m2i.v. day 1–3; R: 375mg/m2i.v.day 0 cycle 1, and 500mg/m2day 1 of all subsequent cycles). Results:The median age was 57 years (range, 31–75) at the time of the CLL diagnosis, and 60 years (range, 32–78) at the start of FCR therapy. The median follow-up was 42 months (range, 3–114). Our cohort of patients consisted of two groups of patients which received the FCR regimen as first-line therapy (Group 1; n=63) and patients receiving FCR in second or subsequent line of treatment (Group 2; n=56). With respect to the basic parameters (age, clinical stage, FISH cytogenetics, molecular genetics), the statistics of these groups did not differ significantly. In Group 1, the overall response rate (ORR) was 84%, in Group 2, 78% (p=ns) after FCR. Complete remission (CR) rate was 53% in Group 1, and 38% in Group 2 (p=0.04). The median progression-free survival (PFS) was 18.6 months for Group 1 and 14.7 months for Group 2 (p=ns). With subsequent therapy (repeated FCR, alemtuzumab, R-CHOP, rituximab plus high-dose corticosteroids) for relapsed disease after FCR, ORR was 59% in Group 1 (33% CR) and 44% in Group 2 (21% CR) (p=ns). PFS after subsequent therapy after FCR was 13.3 months (Group 1) and 5.9 months (Group 2) (p=0.01). The median OS was insignificantly shorter in Group 2 (44.5 months in Group 2 vs. not reached in Group 1; p=ns). After FCR therapy, there was no statistically significant change in cytogenetic findings, however, new occurrence of 17p deletion was observed in 5 patients. Prior to FCR therapy and during relapse after FCR, the p53 function was analyzed in 37 patients. After FCR, the new mutation of p53 was newly found in 6 patients (16%). These patients received a higher cumulative dose of FCR than the patients who did not develop the mutation (F 591 mg vs. 334 mg; C 5072 mg vs. 3375mg; R 3700mg vs. 2000 mg) (p=ns). Conclusion:Subsequent treatment for patients who relapse after FCR or are FCR refractory is very heterogeneous. Regardless of the type of therapy selected, the prognosis of these patients is poor. In addition, new p53 mutations/deletions occur after FCR. Disclosures:No relevant conflicts of interest to declare.

Safety and Efficacy of Abbreviated Induction with Oral Fludarabine (F) and Cyclophosphamide (C) Combined with Dose-Dense IV Rituximab (R) in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL) Aged > 65 years : Results of a Multicenter Trial (LLC 2007 SA) On Behalf of the French Goelams/Fcgcll-WM Intergroup

AbstractAbstract 434 Introduction:The German CLL8 trial has demonstrated that addition of R to FC improves quality and durability of response in CLL (Hallek et al, 2010), which has led to the recommendation of FCR as first line therapy for fit patients. Although elderly patients were included in the CLL8 trial (up to 81 y-old), the median age of the cohort was 61 y, thus at least 10 y younger than median age at CLL diagnosis. The elderly population is underrepresented in clinical trials and it is still not clear how FCR should be applied in this subgroup. In December 2007, the French intergroup launched the LLC 2007 SA trial (NCT00645606) in which CLL patients aged > 65 y receive an induction with abbreviated FCR followed by randomization between observation or maintenance with rituximab. We now report the safety and efficacy of the induction part in the first 200 patients enrolled in this study. Patients and methods:Stage B or C previously untreated fit (CIRS ≤ 6, CCR ≥ 60 ml/min, PS ≤ 1) CLL patients aged > 65 y needing treatment (NCI criteria) were included. Patients with del17p and/or Matutes scoring < 4 were excluded. From these 200 first patients included, 6 were removed because of incorrect inclusion (n=4) or consent withdrawal (n=2). In total, 194 patients (included between Dec/07 and Feb/10) were analyzed. FCR consisted of four monthly cycles of oral FC (F 40 mg/msq/d and C 250 mg/msq/d, × 3d) and iv R (375 mg/msq d1 cycle 1, 500 mg/msq d14 cycle 1, d1 and 14 of cycle 2, and d1 of cycles 3 and 4). Response was assessed by NCI criteria. MRD analysis was done using 6-color FCM in PB and BM. No later than 90 d after the last FCR, patients were further randomized as per protocol. Disease outcome after randomization remains completely blinded to date. Results:The median age was 71 y (range 65–85) and 65% were males. 83% had CIRS between 0 and 3. Binet stage was B in 127 (65.5%) and C in 67 (34.5%). Median (n=143) Beta-2-microglobulin was 4 mg/L (range 2–8). Fifty-six % had unmutated IgVH and FISH revealed 18% with del11q, 15% with trisomy 12, and 57% with del13q. Karyotype (ODN+IL2-stimulated) was abnormal in 67%. Balanced and unbalanced translocations were seen in 16% and 17%, respectively. Complex (>2 abn) karyotype occurred in 14% of the patients. Toxicity:167 (86%) received all four cycles of FCR. Only 4.6% and 3.2% of patients did not receive d14 rituximab at cycle 1 and 2, respectively. 158 patients (81%) could proceed to the randomization (the main reason for failure was insufficient marrow recovery). Dose delay (by ≥ 1 w) and dose reduction (by ≥ 25% of F and C) for cycles 2, 3, and 4 were 12% and 7%, 14% and 8%, 15% and 11%, respectively. Neutropenia g3/4 occurred after cycle 1, 2, 3 and 4, in 46% (19% g4), 50% (21% g4), 53% (29% g4), and 46% (26% g4) of the patients. G-CSF was given in 32%, 46%, 48%, and 52% of them after cycles 1, 2, 3, and 4. G4 thrombocytopenia occurred in less than 2% of the cycles. G3/4 anemia was seen in 11%, 7%, 6%, and 3% of the patients after cycle 1, 2, 3, and 4, respectively. G 3/4 infectious events occurred in 6.2%, 4.8%, 7.6%, and 6.2% of the patients after each of the 4 cycles. Seventy SAE (including 46 febrile neutropenia and/or documented infection) were declared in 53 patients during the induction and the period of recovery prior to randomization. In total, 6.3% of the 732 cycles were followed by febrile neutropenia or infection qualified as SAE. Six deaths (all infections) occurred during induction, corresponding to a 3.1% (6/194) death rate from immediate toxicity. Efficacy:Among 188 evaluable patients, complete responses (CR) were observed in 19.7%, nodular partial response (PR) in 2.7%, and PR in 73.9%, for an ORR of 96.3%, using stringent criteria. According to the updated guidelines of 2008 (Hallek), CR, CRi, and PR rates were 19.7%, 13.3%, and 63.3%, respectively. Conclusion:Four cycles of oral FC combined with 6 doses of R appear feasible in elderly patients with CLL; only 14% cannot receive the 4 courses and only 19% cannot proceed to randomization planned at day 90 post FCR4. Dose reduction and treatment interruption are unusual despite strict stopping criteria. Grade 3/4 neutropenia is frequent but rarely translates into serious infection. The response rate is high, and further analysis of MRD eradication is ongoing and will be presented. In conclusion, this approach could enable the safe administration of FCR to elderly fit CLL patients in first line. Long-term toxicity, occurring after randomization, will be scrutinized. Disclosures:Dartigeas:Roche: Consultancy. Van Den Neste:Roche: Consultancy. Leblond:Mundipharma: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria.

Overview of recent developments in chronic lymphocytic leukemia

Multiple advances have been made in our understanding of pathobiology of chronic lymphocytic leukemia (CLL). These developments in the laboratory include new prognostic markers, risk stratification of the disease and newer therapeutic agents in CLL. These advances in CLL have come a long way in the past three decades since the development of Rai and Binet clinical staging systems. Important strides in the pathobiology, from defining mutational status of IGHV, to B-cell receptor (BCR) signaling pathways and CLL microenvironment have made a major difference in our understanding of this disease. Mutational status of immunoglobulin heavy chain genes (IGHV), CD38 and Zap-70, chromosomal aberrations and newer mutations, are the most clinically relevant prognostic markers. Chemoimmunotherapy (CIT) has become the treatment of choice for young and fit CLL patients. Various inhibitors of BCR signaling pathways and immunomodulatory drugs have shown efficacy in clinical trials. The most recent advance is the use of chimeric antigen receptor therapy (CAR) based on autologous T-lymphocytes. Nevertheless, CLL remains an incurable disease today. Coordinated developments between laboratory and clinic will hopefully translate into a cure for CLL. This short review focuses on advances in prognostication and therapy in CLL.

Bendamustine for treatment of chronic lymphocytic leukemia

Introduction: Chronic lymphocytic leukemia (CLL) often has an extended disease course. With a median age at diagnosis of 72 years, newer treatment options with less toxicity than standard nucleoside analogue-based regimens are needed. Historically, few therapy options are available once CLL has become refractory to nucleoside analogues. Bendamustine has emerged as a feasible therapy for older and less fit CLL patients, with clinical efficacy in previously untreated and refractory CLL.Areas covered: This paper reviews several of the pivotal clinical trials that established the clinical activity of bendamustine in previously untreated and relapsed/refractory CLL. The toxicity profile of bendamustine, primarily myelosuppression and infections, is reviewed and compared across different CLL populations. A review of the clinical data focuses on potential explanations for differences in response rates and duration of remission reported across studies and how this may impact the development of therapies for CLL.Expert opinion: Bendamustine is a valuable new agent for the management of CLL. Ongoing clinical trials are comparing bendamustine with standard CLL regimens in untreated disease, and investigating bendamustine combinations with novel targeted therapies and monoclonal antibodies. These studies will help to define the optimal role for bendamustine in CLL management.

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.