First-line Treatment Of Chronic Lymphocytic Leukemia Research Articles

CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders.

NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.

Outcomes of Conservative Indication Criteria for First-Line Treatment in Chronic Lymphocytic Leukemia: Insights from the Brazilian Registry of CLL

Introduction: Chronic lymphocytic leukemia (CLL) exhibits diverse treatment requirements, with some patients receiving immediate treatment while others remain under observation. In 2008, the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) established criteria for treatment indications, widely adopted in clinical practice and trials. The Brazilian Group of CLL (BGCLL) has been evaluating a more conservative approach to treatment indication performed in multiple centers, which avoids predefined cutoff levels for cytopenias and refrains from considering progressive lymphocytosis, extranodal involvement, or disease-related symptoms as isolated criteria. However, the safety and potential different outcomes of this conservative approach compared to the strict IWCLL criteria remain uncertain. Objective: This study aims to compare the outcomes of CLL patients without indication for treatment according to the BGCLL criteria, who were either treated or not based on the center's decision. Methods: We conducted a retrospective analysis of CLL patients enrolled in the Brazilian Registry of CLL, observed between January 2009 and March 2023, meeting the minimum data availability criteria for analysis and following IWCLL inclusion guidelines. Results: A total of 2396 patients from 41 centers were included. Among them, 1313 patients (55%) met the IWCLL criteria for treatment indication, while only 558 patients (23%) fulfilled the more conservative BGCLL indication. Of the 1240 untreated patients, 247 (20%) had a treatment indication based on IWCLL guidelines. Common indications for treatment initiation included cytopenias in 159 patients (64%), disease-related constitutional symptoms in 41 patients (17%), and symptomatic lymphadenopathy in 22 patients (9%). Non-treatment despite having an indication was attributed to BGCLL's more conservative criteria in 67% of cases, severe comorbidities in 6%, and death during follow-up in 27%. Among the 1156 treated patients, 90 patients (8%) received treatment despite lacking a treatment indication according to the IWCLL criteria. According to BGCLL's conservative criteria, 600 (48%) treated patients did not have a treatment indication. After a median follow-up of 58 months (range: 3-506), the overall survival (OS) was 70% at 8 years. Among patients without an indication for treatment according to BGCLL's conservative criteria, OS was significantly worse in treated patients (79%) compared to untreated patients (64%, P<0.0001, figure 1). Conclusion: These real-world data demonstrate that a conservative approach in indicating first-line treatment for CLL is safe and associated with improved survival, possibly by mitigating toxicities and treatment-related complications such as clonal selection. Furthermore, this strategy may conserve resources, enhancing drug accessibility for a larger number of patients in clear need of treatment, particularly in low-income countries.

Outcomes in patients with chronic lymphocytic leukemia and TP53 aberration who received first-line ibrutinib: a nationwide registry study from the Italian Medicines Agency

In this analysis we describe the effectiveness of first-line ibrutinib in 747 patients with chronic lymphocytic leukemia (CLL) and TP53 aberrations in a nationwide study with a 100% capture of patients who received the study drug. Median age was 71 years (range 32–95). An estimated treatment persistence rate of 63.4% (95% CI 60.0%-67.0%) and survival rate of 82.6% (95% CI 79.9–85.4%) were recorded at 24 months. Disease progression or death were the reasons for discontinuation in 182/397 patients (45.8%). A higher risk of treatment discontinuation was found to be associated with age, ECOG-PS and pre-existing heart disease, whereas ECOG ≥ 1, age ≥ 70 years and male sex were associated with an increased risk of death. Median post-progression overall survival (OS) was 12.2 months (95% CI 9.2–22.0). Post-discontinuation median OS in patients who discontinued ibrutinib for other reasons was not reached (95% CI 42.3 months – NA). Ibrutinib was an effective first-line treatment for CLL and TP53 aberrations in patients treated at large academic centers and community practice hospitals. Clinical characteristics at baseline may influence the effectiveness of ibrutinib, whereas the experience of prescribing centers and multi-hit or single-hit TP53 aberrations had no impact on outcome in this high-risk population.

Selecting initial therapy in CLL

Targeted therapy is a powerful treatment option in chronic lymphocytic leukemia (CLL) that has outperformed conventional chemoimmunotherapy in most clinical settings. Except for selected young, fit patients with a mutated immunoglobulin heavy chain variable region gene, most patients benefit from targeted therapy with either a continuous BTK inhibitor or 1-year fixed-duration venetoclax-obinutuzumab as first-line treatment of CLL. Treatment selection is driven by patient-, treatment-, and disease-related factors, encompassing patient preference, concomitant medications, comorbidities, safety profile of the regimen, and TP53 aberration. Clinical trials are actively investigating the simultaneous inhibition of Bruton's tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) proteins with or without a CD20 monoclonal antibody, which can achieve deep response in most patients (52%-89% undetectable minimal residual disease in bone marrow).

Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort

AbstractCAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.

Improvements in Health-Related Quality of Life and Symptoms in Patients with Previously Untreated Chronic Lymphocytic Leukemia: Final Results from the Phase II GIBB Study of the Combination of Obinutuzumab and Bendamustine

Introduction: Longitudinal changes in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an open-label, single-arm phase II study of obinutuzumab (GA101; G) in combination with bendamustine (G-Benda) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with G-Benda (Sharman et al. J Clin Oncol 2017). Here we report the final HRQoL data over 3 years from the GIBB study. Methods: Enrolled patients received G-Benda by intravenous infusion over six 28-day cycles: G 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle (C)1, then 1000mg on D1 of C2-6; benda 90mg/m2 on D2-3 of C1, and on D1-2 of C2-6. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries). Both questionnaires were completed by patients on C1D1 (baseline), C3D1, and C6D1, at the end of induction (EOI) treatment (defined as +28 days from C6D1 or early treatment termination visit), at the response visit (defined as 2-3 months after the EOI treatment for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits for up to 2 years. In total, there were 14 timepoints where data were collected. HRQoL scores were linear transformed to a 0-100-point scale. Mean baseline scores and mean score changes from baseline at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. For symptoms, negative change scores from baseline reflect an improvement in symptom burden. For global health status and functioning, positive change scores from baseline reflect improvements. Results: The trial enrolled 102 patients. Median age was 61 years and 68.4% of patients were male. Ninety-eight patients (96%) completed a questionnaire at baseline and at least 1 other questionnaire during a follow-up visit. Questionnaire completion rates at 14 time points ranged from 96% at baseline to 66% at 27 months follow-up (Table 1). According to the EORTC QLQ-C30 (Figure 1), improvements were observed for global health status at all follow-up visits, and clinically meaningful improvements were observed at the response visit, 3 months follow-up, and 27 months follow-up. Clinically meaningful improvements in role functioning were observed at EOI and persisted throughout the 27-month follow-up. For fatigue, clinically meaningful improvements were observed at every visit starting from the end of treatment (EOT) visit. Improvements were also observed for insomnia with mean reductions from baseline ≥10 points at various time points during follow-up. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the EOT and/or throughout the follow-up. The largest improvement was observed for fatigue (-24.7) at the 24-month follow-up and future health worries (-25.4) at the 27-month follow-up. Conclusions: We previously reported that G-Benda is an effective regimen for first-line treatment of CLL with no unexpected safety signals. The HRQoL data from the GIBB trial suggest that G-Benda treatment consistently improved patient HRQoL over time. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries. Disclosures Danilov: AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; MEI: Research Funding; Bristol-Meyers Squibb: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Takeda Oncology: Research Funding; Aptose Biosciences: Research Funding; Aptose Biosciences: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Gilead Sciences: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Curis: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy; Abbvie: Consultancy. Yimer:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria; Celgene: Honoraria; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Amgen: Consultancy. Boxer:Gerson Lerman: Consultancy; Best Doctors: Consultancy; Takeda: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Babu:Genentech: Research Funding. Li:Genentech: Employment; Roche: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Trask:Genentech: Employment, Equity Ownership. Masaquel:Roche: Equity Ownership; Genentech: Employment. Sharman:Acerta: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated: in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen

Utilization and Early Discontinuation of First-Line Ibrutinib for Patients with Chronic Lymphocytic Leukemia Treated in the Community Oncology Setting in the United States

Introduction: Ibrutinib, an orally and continuously administered Bruton tyrosine kinase inhibitor, allows for targeted, non-chemotherapy based treatment for chronic lymphocytic leukemia (CLL). While the initial US marketing approval for ibrutinib in CLL was for relapsed disease (February 2014), several trials have since shown favorable efficacy in the first-line setting. Ibrutinib was well tolerated in these pivotal studies, with discontinuation occurring in less than 9% at 12 months (O'Brien et al., Am J Hemato. 2019). Most early ibrutinib discontinuations in the first-line setting are due to adverse events (Tedeschi et al., EHA 2019), and optimal strategies to manage ibrutinib-related toxicities are not well defined. We hypothesized that ibrutinib is increasingly utilized for first-line treatment of CLL during routine management in the US, but that ibrutinib discontinuation rates for the real-world population are greater than those reported in clinical trials. Further, we expected to find greater odds of discontinuation in older adults and those with poor performance status, two groups underrepresented in clinical trials. Methods: We conducted a retrospective cohort study of CLL patients treated at community oncology practices using the nationwide Flatiron Health database. The Flatiron Health database is a longitudinal, demographically and geographically diverse database derived from de-identified electronic health record data from over 280 cancer clinics in the US. All patients initiated CLL therapy in the first-line setting between March 1, 2014 and February 28, 2019. We first assessed trends in the use of first-line ibrutinib (i.e., ibrutinib with/without an anti-CD20 antibody). We then focused on patients who received ibrutinib and had at least 180 days of available follow up or had died within this period. We used multivariable logistic regression to assess the association of patient characteristics with early discontinuation (defined as stopping within 180 days of initiation). Covariates included in our model were patient age, sex, race, insurance type, ECOG performance status, year of treatment, time from CLL diagnosis to ibrutinib initiation, chromosome 17p status, and geographical region. Results: We identified 5,634 individuals initiating first-line treatment for CLL, of whom 1,639 (29.1%) received an ibrutinib-based regimen. Use of ibrutinib in the first-line setting increased over time (Cochrane-Armitage test for trend, p &amp;lt;.001; Figure 1), making up approximately 40% of first-line CLL initiations by late 2018. Of the 1,497 individuals with adequate follow up, early discontinuation of ibrutinib occurred in 16.2%. Early discontinuation of ibrutinib was more common in individuals aged ≥80 years (26.2% vs. 9.4% for individuals 60-70 years old), those requiring treatment within 1 year of their CLL diagnosis (22.1% vs. 14.8% for those with CLL diagnosis ≥5 years prior to ibrutinib initiation), and those with ECOG performance status of 2 or greater (33.8% vs. 10.2% for ECOG = 0). On multivariable logistic regression, older age (≥80 years vs. 60-70 years, adjusted odds ratio (aOR) = 2.94, 95% confidence interval (CI) 1.79 - 4.76, p &amp;lt;.001) and worse performance status (ECOG ≥2 vs 0, aOR = 3.45, 95% CI 2.16-5.53, p &amp;lt;.001) remained independently associated with increased odds of early ibrutinib discontinuation. Conclusion: While ibrutinib was increasingly utilized in the first-line setting for CLL within our large representative US community patient cohort, early discontinuation was more common than reported in pivotal trials. Given the complexity of the rapidly changing CLL treatment landscape, clinical decision support tools and other modern cancer care delivery approaches should be explored to improve administration of novel CLL therapies in the real-world setting. Disclosures Huntington: Genentech: Consultancy; Bayer: Consultancy, Honoraria; AbbVie: Consultancy; Celgene: Consultancy, Research Funding; DTRM Biopharm: Research Funding; Pharmacyclics: Honoraria. Barr:Merck: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding. Jacobs:Genentech: Speakers Bureau; AstraZeneca: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; AbbVie: Consultancy, Speakers Bureau; JUNO: Consultancy; Gilead: Consultancy. Davidoff:PhRMA: Research Funding; Celgene: Research Funding. Gross:Johnson and Johnson: Research Funding; 21st Century Cancer: Research Funding; Pfizer: Research Funding.

Cost-effectiveness of ibrutinib as first-line therapy for chronic lymphocytic leukemia in older adults without deletion 17p

AbstractIbrutinib is a novel oral therapy that has shown significant efficacy as initial treatment of chronic lymphocytic leukemia (CLL). It is a high-cost continuous therapy differing from other regimens that are given for much shorter courses. Our objective was to evaluate the cost-effectiveness of ibrutinib for first-line treatment of CLL in patients older than age 65 years without a 17p deletion. We developed a semi-Markov model to analyze the cost-effectiveness of ibrutinib vs a comparator therapy from a US Medicare perspective. No direct comparison between ibrutinib and the best available treatment alternative, obinutuzumab plus chlorambucil (chemoimmunotherapy), exists. Therefore, we compared ibrutinib to a theoretical treatment alternative, which was modeled to confer the effectiveness of an inferior treatment (chlorambucil alone) and the costs and adverse events of chemoimmunotherapy, which would provide ibrutinib with the best chance of being cost-effective. Even so, the incremental cost-effectiveness ratio of ibrutinib vs the modeled comparator was $189 000 per quality-adjusted life-year (QALY) gained. To reach a willingness-to-pay threshold (WTP) of $150 000 per QALY, the monthly cost of ibrutinib would have to be at most $6800, $1700 less than the modeled cost of $8500 per month (a reduction of $20 400 per year). When the comparator efficacy is increased to more closely match that seen in trials evaluating chemoimmunotherapy, ibrutinib costs more than $262 000 per QALY gained, and the monthly cost of ibrutinib would need to be lowered to less than $5000 per month to be cost-effective. Ibrutinib is not cost-effective as initial therapy at a WTP threshold of $150 000 per QALY gained.

Improvements in Health-Related Quality of Life and Symptoms in Patients with Previously Untreated Chronic Lymphocytic Leukemia: Results from the Phase II GIBB Study of the Combination of Obinutuzumab and Bendamustine

Introduction: Maintenance and/or improvements in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an ongoing, open-label, single-arm Phase II study of the combination of obinutuzumab (GA101; G) and bendamustine (B) (BG) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with BG (Sharman et al. ASCO 2017). Here, we present the HRQoL data from GIBB.Methods: In the GIBB trial, patients received BG by intravenous infusion over six 28-day cycles: obinutuzumab 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle 1, then 1000mg on D1 of Cycles 2-6; B 90mg/m2 on D2-3 of Cycle 1, and on D1-2 of Cycles 2-6. The European Organisation for Research and Treatment of Cancer Quality of Life - Core (EORTC QLQ-C30) questionnaire includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries; EORTC website, accessed July 25, 2017). Both questionnaires were completed by patients on D1 of Cycles 1 (baseline), 3, and 6, at the end of induction treatment (defined as +28 days from D1 of Cycle 6 or early treatment termination visit), at the response visit (defined as 2-3 months after the end of induction treatment, for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits. HRQoL scores were linear transformed to a 0-100 point scale. Mean baseline scores and mean score changes at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference.Results: Of 102 patients enrolled in the trial, 98 completed a questionnaire at baseline and at least one other questionnaire during a follow-up visit. Questionnaire completion rates were 86.7%, 77.6%, 80.6%, and 86.7% at Cycles 3, 6, at the end of induction treatment, and at the response visit, respectively. Median age was 61 years and 68.4% of patients were male. According to the EORTC QLQ-C30 (Figure 1), clinically meaningful improvements were observed for global health status at the response visit, and for role functioning at the end of induction treatment and at the response visit. A trend was observed for improvement in emotional functioning. The greatest improvement in HRQoL score was observed for fatigue (mean baseline score: 37.64), with mean changes from baseline of −4.01, −5.48, −11.67, and −16.34 at Cycles 3, 6, at the end of induction treatment, and at the response visit, respectively. Improvements were also observed for insomnia (mean baseline score: 33.33), with mean changes from baseline of −6.59, −9.09, −9.7, and −10.98, respectively. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the end of induction treatment and/or at the response visit. The greatest change at the response visit was observed for fatigue (−21.23) and future health worries (−20.24). A positive trend was also observed for improvements in the social activities scale.Conclusions: We previously reported that BG is an effective regimen for first-line treatment of CLL with no unexpected safety signals. In addition, the HRQoL data from the GIBB trial suggest that BG treatment improves patient HRQoL. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries at the time of the response visit. [Display omitted] DisclosuresSharman:Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Other: GIBB is sponsored by Genentech Inc. Third-party editorial support, under the direction of Anthony Masaquel, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Yimer:Juno pharma: Equity Ownership; Bellucum Pharma: Equity Ownership. Babu:Alexion: Speakers Bureau; Abbvie: Consultancy. Li:Genentech: Employment, Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Trask:Genentech: Employment, Other: stock. Masaquel:Genentech Inc.: Employment, Other: I Receive Roche stock options. Reyes:Genentech Inc.: Employment, Equity Ownership.

Comparative Safety Analysis of Currently Approved Anti-CD20 Monoclonal Antibodies for First Line Treatment of Chronic Lymphocytic Leukemia (CLL)

Introduction:Treatment of CLL has advanced tremendously in the past decade with significant extension of life expectancy in patients diagnosed with the disease. Three anti-CD20 monoclonal antibody (mAB) combinations approved for previously untreated chronic lymphocytic leukemia (CLL) patients are obinutuzumab-chlorambucil (OBI-CHL), ofatumumab-chlorambucil (OFA-CHL), and rituximab-chlorambucil (RTX-CHL), have comparable efficacy but varying safety profiles in pivotal trials. Grade 3-4 adverse events (AEs), including infusion-related reactions (IRRs), neutropenia, thrombocytopenia, anemia, and infections differ by each mAB. Grade 3-4 AEs, defined as requiring hospitalization or life-threatening, result in reductions in patient quality of life (QoL) and bear cost implications. We sought to compare the safety of the IV-administered anti-CD20 mABs in the first-line treatment of CLL and to evaluate the respective QoL and economic implications of these AEs.Methods:A systematic literature review was conducted in PubMed, Embase, and Cochrane library for the time period of 2010-2016 and in conference proceedings of ASH, the American Society of Clinical Oncology (ASCO), and the European Hematology Association (EHA) for 2014-2016. Search was limited to clinical trials conducted on humans and published in English language. The IRRs were compared directly as CHL is administered orally. A Bayesian network meta-analyses (NMA) was conducted with data from phase 3 trials using SAS® (v9.3) to compare grade 3-4 neutropenia, thrombocytopenia, anemia, and infections associated with the three anti-CD20 mABs. A pooled analysis of data from phase 2 trials and cohort studies was conducted using MedCalc® version 16.2.1. Analyses were also conducted to estimate the potential impact of the AEs of respective anti-CD20 mABs on QoL and cost of care based on the NMA results and previously published estimates of utilities associated with CR (0.780), PR (0.790), SD/PD (0.760); disutilities associated with IRR (-0.11), neutropenia (-0.09), thrombocytopenia (-0.05), anemia (-0.09), and infections (-0.20); and costs associated with episodes of IRR ($4,482), neutropenia ($5,406), thrombocytopenia ($12,621), anemia ($8,894), and infections ($7,163) in CLL.Results:Of the 86 studies screened, 10 studies were included. Direct comparison showed that the rate of IRRs in OBI-CHL, OFA-CHL, and RTX-CHL were 21%, 10%, and 4%, respectively. Risks for neutropenia were lower for OFA-CHL compared to OBI-CHL (OR = 0.74; 95% CI: 0.12-4.59) and similar to RTX-CHL (1.08; 0.20-5.82); for thrombocytopenia were lower for OFA-CHL compared to OBI-CHL (0.16; 0.02-1.33) and to RTX-CHL (0.49; 0.06-4.15); for anemia were lower for OFA-CHL compared to OBI-CHL (0.80; 0.21-3.06) and similar to RTX-CHL (1.08; 0.24-4.64); and for infections OFA-CHL, OBI-CHL (1.00; 0.15-6.74) and RTX-CHL (0.86; 0.15-4.43) were similar. The pooled analyses of AEs observed in phase 2 / cohort studies revealed similar trends when assessed. The mean pre-progression QoL utilities associated with OBI-CHL, OFA-CHL, and RTX-CHL weighted by rates of AEs, utilities associated with respective response rates to treatments, and disutilities of the respective AEs were 0.772, 0.761, and 0.748 respectively. The total cost of treating AEs per 1,000 patients on OFA-CHL, OBI-CHL and RTX-CHL were $3.9M, $8.0M and $4.2M, respectively.Conclusion:The safety profile was most desirable for OFA-CHL, followed by RTX-CHL and OBI-CHL. Though RTX-CHL had the lowest rate of grade 3-4 IRR, OFA-CHL had the better grade 3-4 hematologic safety profile compared to OBI-CHL and RTX-CHL. As efficacy of CLL treatments has improved substantially, safety of treatments is increasingly important particularly on the impact of QoL. In addition, in the cost-conscious payer environment, selecting drugs with a better safety profile and lower cost implications is vital. Our findings demonstrate that better safety profile is associated with less impact on QoL and lower costs. We found that for every 1,000 patients covered by a payer, safety alone can save an excess of $4M based on regimen choice. Fewer incidences of AEs also results in better adherence and reduction in treatment interruption or discontinuation. Safety with the QoL and cost implications should be taken into consideration to maximize the overall benefits of the treatment to CLL patients. DisclosuresMwamburi:Novartis Pharmaceuticals: Consultancy. Bal:Novartis Pharmaceuticals: Employment. Cascella:Novartis Oncology: Employment. Shah:Novartis Pharmaceuticals: Consultancy. Nanavaty:Novartis Pharmaceuticals: Consultancy. Gala:Novartis Pharmaceuticals: Consultancy.

A canadian perspective on the first-line treatment of chronic lymphocytic leukemia.

Despite important advances in the treatment of first-line chronic lymphocytic leukemia (CLL) over the past decade, CLL remains an incurable disease with significant unmet needs. The combination of rituximab with fludarabine and cyclophosphamide (FCR) significantly improved overall survival and progression-free survival compared with fludarabine and cyclophosphamide alone in first-line treatment of CLL. However, because of its high toxicity, FCR is only recommended for younger, fit patients who can tolerate the treatment. This excludes a large fraction of CLL patients who are elderly and/or who have comorbidities. Thus, determining the appropriate treatment choices for this group of patients who are unfit for FCR treatment is a significant challenge in CLL. Current treatment choices in Canadian practice include bendamustine with rituximab, fludarabine with rituximab, and chlorambucil with rituximab. Two novel monoclonal antibodies, ofatumumab and obinutuzumab, have also recently received Health Canada approval for the first-line treatment of CLL patients in combination with chlorambucil. In addition, the Bruton tyrosine kinase inhibitor, ibrutinib, has recently been approved by Health Canada for the first-line treatment of CLL patients with deletion 17p. In the coming years, several other novel agents that are being developed are likely to change the CLL treatment landscape dramatically, however, because these novel agents are currently unavailable, the purpose of this review is to recommend the best treatment approaches in Canada using currently available therapies.

A Phase 2 Study of Alemtuzumab-Ofatumumab (A+O) Combination in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL)

BackgroundCurrent standard immunochemotherapy is highly effective as frontline treatment of CLL but has several limitations including poor tolerability in older patients with comorbidities, potential long-term marrow toxicity, and limited efficacy in high risk CLL. Therapy with monoclonal antibodies alone may offer an alternative, non-stem cell toxic treatment option. Our prior study of alemtuzumab-rituximab in previously untreated CLL showed promising results with good tolerability although lymph node responses were suboptimal (Frankfurt et al., Leuk Lymphoma 2014). Ofatumumab showed improved complement-mediated cytotoxicity over rituximab for CLL in vitro and significant clinical activity in refractory CLL. In this study we aim to test safety and effectiveness of alemtuzumab-ofatumumab (A+O) combination as a frontline treatment for CLL.MethodsThis phase 2 study of A+O first-line treatment for CLL is conducted at Northwestern University in Chicago and Karolinska University Hospital in Stockholm with an accrual goal of 60 patients. Eligibility requires symptomatic, previously untreated CLL, and PS ≤ 2. There was no exclusion for baseline cytopenia or upper age limit. Alemtuzumab (Alem) is given subcutaneously tiw for up to 18 weeks (dose escalation 3mg-10mg-30mg for week 1 and 30mg per dose for subsequent weeks). Starting week 3, ofatumumab (Ofa) is added intravenously q2 weeks up to 8 doses at 300mg for dose 1 and 2000mg for doses 2-8. All patients received anti-herpes, anti-fungal and anti-PCP prophylaxis. Cytomegalovirus (CMV) was monitored by PCR every other week. Bone-marrow biopsy and CT scans are required for response assessment (IWCLL 2008 criteria). Minimal residual disease (MRD) was assessed in bone-marrow using 6-color flow. Hematologic toxicity was assessed using IWCLL 2008 criteria and non-hematologic toxicity graded by CTCAE 4.0.ResultsTo date the study has enrolled 41 patients among whom 31 patients have completed treatment and are reported here in this interim analysis. Median age was 63 (45-77) years; 58% had Rai stage III/IV; 48% had unmutated IgHV, and 7/31 were 17p- and/or had TP53 mutation.During initial safety run-in period to assess dose-limiting toxicity (DLT), one patient after 18 weeks of therapy developed prolonged cytopenia and died of sepsis, and another patient after 14 weeks of therapy developed grade 4 neutropenia which resolved after 16 days. Both patients achieved MRD-negative complete bone-marrow response with hypocellularity. It was speculated that the cause may be continued treatment with Alem beyond the point of MRD-negative CR in bone-marrow. Early stopping rules were implemented using BM biopsy after 9 and 12 weeks of treatment. Alem is stopped if CR in the bone-marrow is achieved, or if cellularity <10%. Ofa is stopped if CR in lymph-nodes on CT after achieving bone-marrow CR. Since this protocol modification after the initial 9 patients, no further DLT was observed and the safety committee approved continued enrollment.The most frequent treatment-emergent AE included neutropenia, anemia, thrombocytopenia, Alem-related local injection-site reaction, Ofa-related infusion-symptoms, pyrexia, and fatigue. Grade 3-4 hematologic AEs included neutropenia (39%), thrombocytopenia (26%). The most frequent Grade 3-4 non-hematologic AE was febrile neutropenia (23%). CMV-reactivation occurred in 16 cases successfully treated with oral valganciclovir or IV ganciclovir.All patients achieved blood lymphocyte response within 4 weeks. Of 31 patients evaluable for response, 11 met early stopping criteria after achieving MRD-negative bone marrow CR (8/11 overall CR) with a median of 10 weeks of Alem and 5 doses of Ofa. The remaining patients (except one with PD) completed all 18 weeks of Alem and 8 doses of Ofa treatment.Overall response rate (ORR) was 97% with 42% CR and 55% PR. MRD by bone marrow flow-cytometry was negative in 12/13 CR patients and 4/17 PR patients. All but one patient remain alive at follow-up and three required subsequent treatment due to progressive disease.ConclusionsThe combination of alemtuzumab-ofatumumab as first-line CLL treatment produced high response rates, including MRD-negative CR, and had acceptable safety. Early stop after achieving CR prevented late-onset cytopenia. DisclosuresMa:GlaxoSmithKline: Research Funding; National Comprehensive Cancer Network (NCCN) Oncology Research Program: Research Funding. Off Label Use: Alemtuzumab and ofatumumab used in combination. Österborg:GlaxoSmithKline: Research Funding. Lundin:GlaxoSmithKline: Research Funding.

Characterising the Burden of Chronic Lymphocytic Leukemia in Fludarabine-Ineligible Patients in Spain, Italy, and the United Kingdom (UK): A Retrospective Observational Study

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world, accounting for approximately 30% of adult leukemias. The majority of CLL patients are elderly and have co-existing medical conditions. This limits therapeutic options and precludes many from receiving the recognized standard of care regimen, fludarabine, cyclophosphamide and rituximab (FCR). A number of recent studies have evaluated alternative chemoimmunotherapies for these patients. The objective of this study was to describe patient characteristics, treatment patterns, and resource utilization for patients who are unfit for a standard fludarabine-based regimen as first-line treatment for CLL in Spain, Italy, and the UK.A retrospective chart review was undertaken at 18 sites in Spain, 16 in Italy, and 17 in the UK, to identify CLL patients who initiated treatment between January 2011 and December 2012, with a target sample size of 150 per country. Eligible patients were defined as those who initiated first-line CLL treatment that did not include fludarabine (UK and Spain) or standard-dose fludarabine (Italy) which ensured that elderly patients with comorbidities were included. The variability in definitions was due to increased use of reduced-dose fludarabine regimens in Italy for patients not otherwise suitable for a standard dose of fludarabine. Data on demographic and disease-related characteristics, treatment patterns, and health resource utilization were abstracted from diagnosis until December 2013.Among eligible patients (Spain, n=127, Italy, n=121, UK, n=94), the mean age at treatment initiation was 75.9, 73.8, and 76.8 years, respectively. In the UK, 89.4% had 2 or more comorbidities compared to 74.8% in Spain and 65.3% in Italy. In all countries, chlorambucil monotherapy was the single most common regimen, prescribed to 59.6% of patients in the UK, 38.6% in Spain, and 30.6% in Italy. Bendamustine plus rituximab was the next most common regimen in the UK (17.0%) and Italy (23.1%). In Spain, the second-most common regimen was chlorambucil plus rituximab (18.9%). In Italy, 9.9% of patients received the reduced-dose fludarabine regimen, FCR-Lite.In both Spain and the UK, 40% of patients were hospitalized during the follow-up period, compared to 27% in Italy. Emergency room use ranged from 2% in the UK to 40% in Spain. A large majority of patients in all countries utilized outpatient services and laboratory monitoring, with more frequent of visits in Spain and Italy relative to the UK. Hospitalization costs were the largest cost driver (€3284 in Spain, €1312 in Italy, €10291 in the UK). Observed differences in hospital costs across countries were due to variation in: the proportion of individuals being hospitalized, with hospitalizations less common in Italy; length of hospital stay, with a minority of long and costly hospital stays in the UK; and hospital per diem costs. In Spain, outpatient visits comprised the second largest category of costs, while in Italy the second largest category was laboratory tests. In the UK, the second largest category was hospice care, although this was heavily influenced by a small number of individuals with very lengthy hospice stays. For the majority of UK patients, outpatient care was the second-highest category of costs.In conclusion, CLL patients who initiated first-line therapy during 2011 and 2012, with a regimen that did not include fludarabine (UK and Spain) or did not contain standard-dose fludarabine (Italy), were elderly, with 2 or more comorbidities. The most frequently administered treatment was chlorambucil monotherapy. Resource utilization patterns varied across countries; while some differences may have resulted from differences in patient and disease characteristics, they likely also reflect variation in management strategies between these countries. These results provide valuable baseline data to understand the potential impact of future treatments for this patient population. Abstract 2646. Table 1SpainItalyUK% with utilizationMean annual cost per patient (€)% with utilizationMean annual cost per patient (€)% with utilizationMean annual cost per patient (€)Hospitalization40.5328426.9131240.410291Hospice008.42055.36380Emergency room40.311515.01072.24Laboratory95.052899.052687.178Outpatient95.0116794.021968.8874Transfusions25.25117.04330.1226 DisclosuresDelgado:Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria. Rossi:Amgen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Raine:GSK: Employment. Haiderali:GSK: Employment.

Comparison of Outcomes in Chronic Lymphocytic Leukemia (CLL) with the Addition of Rituximab to Initial Treatment: A Comparative Effectiveness Analysis in the Province of British Columbia (BC), Canada

Background: Clinical trials report that chemoimmunotherapy with rituximab (R) improves overall survival (OS) and progression-free survival in the treatment (tx) of symptomatic CLL patients (pts). R has been available for first-line CLL tx in BC, population 4.5 million, since 2004. We compared clinical outcomes with and without addition of R to chemotherapy in a large unselected provincial cohort of pts treated for CLL, to determine the "real world" effectiveness of addition of R to standard chemotherapy.Methods: Three large provincial databases (db) were used to identify eligible pts: the BC Provincial CLL db, the BC Lymphoid Cancer db, and the Providence Hematology CLL db. All pts who received minimum 1 cycle of first-line tx for confirmed CLL were included. Pts with > 1 hematologic malignancy (n=8) were excluded. Baseline features of pts treated with (+R) or without R (No R) were compared using Chi-squared for categorical and Kruskal-Wallis test for continuous variables. OS was calculated from date of initial tx to date of death from any cause. Treatment-free survival (TFS) was calculated from date of initial tx to date of next tx/death from any cause. Multivariate analysis (MVA) was performed using Cox proportional hazard models to evaluate the effect of R on OS/TFS, after controlling for covariates including age (³60 yrs vs <60 yrs), Rai stage (3-4 vs 0-2), CD38 status (pos vs neg), presence of 17p (17p-) and 11q (11q-) deletions, and first-line tx with purine analogs (PAs).Results: A total of 1784 pts diagnosed with CLL from 1973-2014 were identified, of which 726 pts (41%) received tx in follow-up. Of treated pts, 393 (54%) received R and 333 (46%) received chemotherapy alone. Among the No R group, tx included: chlorambucil 56%; fludarabine (F) 34%; cyclophosphamide (C)-based 8%; cladrabine 2%. Among the +R group, tx included: FR 75%; C-based + R 17%; FCR 7%; chlorambucil + R 1%. 103 pts underwent bone marrow transplant (BMT) during their tx course (19% No R vs 10% +R, P=.002). Median age at diagnosis (dx) and tx between groups were not statistically different (No R vs +R: 60.6 vs 60.8 yrs and 64.7 vs 63.9 yrs, respectively). There were no clinically significant differences in diagnostic parameters including % with elevated LDH, lymphocyte count >20x109/L , Rai stage 3-4. Median follow-up time in survivors was longer in the No R group (13.0 vs 6.8 yrs, P<.001). Among 467 pts with known CD38 status, CD38 pos was more common in +R vs No R groups (47 vs 36%, P=.02). FISH was performed in 586 pts, with no significant differences in abnormalities between tx groups. Poor-risk FISH, 17p- or 11q-, were present in 29% (No R) and 27% (+R).Median time from dx to initial tx was 2.8 yrs (range 0-20.6) in No R vs 2.5 yrs (range 0-22.7) in +R groups (P=.84). OS was longer in the +R cohort (median OS 11.8 vs 7.1 yrs, P<.001), Fig. 1. Significant improvements in OS were also seen in pts <60 yrs of age at tx (median OS 11.3 vs 3.1 yrs, P<.0001), without 17p- (median OS 9.3 vs 5.2 yrs, P<.0001), and treated with PAs (median OS 9.4 vs 6.4 yrs, P=.0001). Median TFS was longer in pts treated with R (3.3 vs 2.3 yrs, P= .004), Fig. 2, and in those without 17p- (median TFS 3.1 vs 1.3 yrs, P<.001).MVA confirmed that the addition of R to chemotherapy remained a strong independent predictor of mortality (HR 0.66, 95% CI: 0.44-0.98, P=.04) and TFS (HR 0.6, 95% CI: 0.46-0.79, P<.001) after controlling for covariates. Other independent predictors of OS included age ³60 yrs (HR 2.77, 95% CI 1.87-4.10, P<.001) and presence of 17p- (HR 1.23, 95% CI 1.62-3.76, P<.001), whereas for TFS, presence of 17p- (HR 2.08, 95% CI: 1.49-2.91, P<.001) and CD38+ (HR 1.32, 95% CI: 1.03-1.68, P=.025) were independent negative predictors.Conclusion: In this large, population based cohort of pts treated for CLL, we confirm that the addition of R to chemoimmunotherapy as initial tx significantly improves OS, resulting in a 44% lower risk of overall mortality (95% CI, 2% to 66%) after controlling for covariates. We have also demonstrated that the addition of R to first-line therapy significantly delays the time to subsequent therapy, a finding not previously reported in a population based setting to our knowledge. This study complements clinical trial [Hallek, Lancet 2010] and US Registry data [Danese, Blood 2011], demonstrating benefit of the addition of R to standard therapy for first-line treatment of CLL and shows the generalizability of such results in a real world setting. [Display omitted] DisclosuresGerrie:Roche: Honoraria, Research Funding. Ramadan:Roche: Honoraria, Research Funding.

Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic leukemia

We conducted a randomized phase III trial to compare the efficacy and safety of two purine analogs, cladribine and fludarabine, with high-dose chlorambucil, in patients with previously untreated chronic lymphocytic leukemia (CLL). Between 1997 and 2004, 223 patients with CLL were randomly assigned to cladribine, fludarabine or chlorambucil, for six cycles of therapy with frequent health-related quality of life assessments. There was no statistical difference for the primary endpoint of overall response with cladribine (70%), fludarabine (67%) and chlorambucil (59%), or complete remission (12%, 7% and 8%), respectively. However, the median progression-free survival (25, 10, 9 months) and median time to second treatment (40, 22, 21 months) were superior with cladribine. There was no significant difference in overall survival (96, 82 and 91 months), nor in toxicity or HRQoL assessments. Monotherapy with cladribine gives superior PFS and longer response duration than fludarabine and chlorambucil as first-line treatment of CLL.

Making Advances in First-Line Chronic Lymphocytic Leukemia Treatment

Bendamustine was developed in East Germany as a potent alkylating agent. Bendamustine monotherapy was US Food and Drug Administration approved for both first-line and salvage treatment of patients with chronic lymphocytic leukemia (CLL) as a result of superior progression-free survival (PFS) compared with that seen with chlorambucil monotherapy in first-line treatment of CLL. Although CD20 monoclonal antibody (mAB) monotherapy has limited activity in CLL, the German CLL Study Group (GCLLSG) confirmed in their CLL8 trial that the addition of rituximab to chemotherapy significantly advanced treatment for CLL, with improved PFS and overall survival (OS). On the basis of these data and data from the REACH (Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia) trial, rituximab was US Food and Drug Administration approved in combination with fludarabine and cyclophosphamide (FC) for firstline and previously treated CLL. The GCLLSG reported results of a phase II trial of bendamustine combined with rituximab (BR) for relapsed and refractory CLL, and in the article that accompanies this editorial, Fischer et al, on behalf of the GCLLSG, report results of a first-line, multicenter phase II clinical trial of BR for CLL. They report an overall response rate of 88%, complete remission (CR) rate of 23%, and estimated median PFS of 34 months for 117 previously untreated patients with CLL. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in 20%, 22%, and 20% of patients, respectively. Randomized first-line phase III clinical trials that evaluated chlorambucil versus fludarabine, then fludarabine versus FC, and most recently, FC versus FC plus rituximab (FCR), established FCR as a standard chemoimmunotherapy (CIT) regimen that provides excellent PFS and OS. Other agents have been evaluated in phase III trials as monotherapy compared with chlorambucil, such as alemtuzumab and bendamustine, and have garnered US Food and Drug Administration approval on the basis of superior PFS, but hardly represent significant therapeutic advances. Several phase II trials have aimed to improve outcomes by modifying FCR, but without obvious success. Examples include increasing the dose of rituximab, adding mitoxantrone, adding alemtuzumab, or adding a granulocytemacrophage colony-stimulating factor to the FCR regimen. These first-line phase II BR trial results can be compared with standard first-line CD20 mAb–containing CIT regimens like FCR, FR, or pentostatin, cyclophosphamide, and rituximab (Table 1). The difficulty in comparing outcomes between clinical trials is that

Bendamustine in Combination With Rituximab for Previously Untreated Patients With Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group

We investigated the safety and efficacy of bendamustine and rituximab (BR) in previously untreated patients with chronic lymphocytic leukemia (CLL). In all, 117 patients, age 34 to 78 years, 46.2% of patients at Binet stage C, and 25.6% of patients age 70 years or older received BR chemoimmunotherapy for first-line treatment of CLL. Bendamustine was administered at a dose of 90 mg/m(2) on days 1 and 2 combined with 375 mg/m(2) rituximab on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses. Overall response rate was 88.0% (95% CI, 80.7% to 100.0%) with a complete response rate of 23.1% and a partial response rate of 64.9%. Ninety percent of patients with del(11q), 94.7% with trisomy 12, 37.5% with del(17p), and 89.4% with unmutated IGHV status responded to treatment. After a median observation time of 27.0 months, median event-free survival was 33.9 months, and 90.5% of patients were alive. Grade 3 or 4 severe infections occurred in 7.7% of patients. Grade 3 or 4 adverse events for neutropenia, thrombocytopenia, and anemia were documented in 19.7%, 22.2%, and 19.7% of patients, respectively. Chemoimmunotherapy with BR is effective and safe in patients with previously untreated CLL.

Flavopiridol Treatment of Patients Aged 70 or Older with Refractory or Relapsed Chronic Lymphocytic Leukemia Is Feasible and Not Associated with Adverse Outcome When Compared to Younger Patients

AbstractAbstract 1378Although the most rapidly growing portion of the United States population is the elderly (Yancik R and Ries L, Semin Oncol 2004), they are consistently underrepresented in cancer clinical trials (Hutchins L et al, N Engl J Med 1999). The incidence of chronic lymphocytic leukemia (CLL) is markedly increased in older people, with a median age at diagnosis of 72 years (Ries L et al, SEER Clinical Statistics Review 2008). In contrast, an age range of between 58 and 66 years has been noted in patients (pts) enrolled in key trials to evaluate the first-line treatment for CLL (Eichhorst B et al, Leuk Lymphoma 2009). Both fludarabine and chemoimmunotherapy with rituximab have not demonstrated much promise in the older subset of patients. Developing new therapeutics that have clinical benefit and also demonstrate feasibility of administration to this patient population is of great interest. Flavopiridol, is a pan-cyclin-dependent kinase inhibitor, that has demonstrated significant clinical activity in relapsed and refractory CLL pts including those with del(17p13.1)(Christian B et al, Clin Lymphoma Myeloma 2009). We sought to determine the feasibility and impact of treating patients over the age of 70 with flavopiridol by reviewing outcomes of two clinical trials using single-agent flavopiridol in patients with relapsed or refractory CLL at our institution (Byrd J et al, Blood 2007; Lin T et al, J Clin Oncol 2009). Pts were divided into categories based on age [≥70 years old (n = 21) and <70 years old (n = 95)]. Of the 21 pts aged 70 or older, all but one (95%) presented with Rai Stage III/IV compared with 76% of the younger pts (<70 years old; P = 0.07). Older age was also associated with complex karyotype (63% vs. 37%; P = 0.04). No significant difference was observed in response rates, with 43% of older pts achieving response vs. 47% of younger pts (P = 0.81). The estimated median progression free survival (PFS) for both age groups was 0.8 years (P = 0.9). In multivariable analyses, there remained no significant differences in response rates or PFS when controlling for treatment schedule, Rai stage and presence of complex karyotype (P = 0.76 and P = 0.89, respectively). Although overall survival tended to be worse in the older pts compared with the younger pts (estimated medians of 2.1 and 2.4 years, respectively), following adjustment for other variables in a multivariable analysis, this difference was no longer significant (P = 0.54, hazard ratio = 1.20 [95% CI: 0.7 – 2.1]). With respect to toxicities, no significant difference in occurrence of tumor lysis syndrome (TLS) or cytokine release syndrome (CRS) was observed between the two age groups, TLS occurred in 48% of older pts and 45% of younger pts (P = 1.00), while CRS occurred in 33% of older pts and 36% of younger pts (P = 1.00). As for infection, only 29% of older pts experienced this toxicity compared to 62% of younger pts (P = 0.007). In multivariable pharmacokinetic (PK) analyses of a patient subset (n=56), there were no significant associations observed between PK parameters and age when controlling for age, bilirubin level, alanine transaminase level, platelet count, white blood cell count, BUN, and 14 distinct single nucleotide polymorphisms. These data demonstrate that flavopiridol administration to older CLL patients is both feasible, acceptably tolerated, and has similar efficacy as compared to younger patients. Future development of treatment approaches with both single-agent and combination strategies of flavopiridol should be considered for older CLL patients. Disclosures:Off Label Use: The efficacy of the cyclin dependent kinase inhibitor, flavopiridol is under investigation in CLL. Jones:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbott Laboratories: Research Funding.

Bendamustine Combined with Rituximab (BR) in First-Line Therapy of Advanced CLL: A Multicenter Phase II Trial of the German CLL Study Group (GCLLSG).

Abstract 205 Introduction:Bendamustine has shown considerable activity in monotherapy for lymphoid malignancies including chronic lymphocytic leukemia (CLL). In vitro studies have demonstrated synergistic pro-apoptotic effects of bendamustine and the CD20 antibody rituximab (BR) in primary CLL cells. Encouraging results have also been obtained using the BR combination treatment in previously treated CLL. This multicenter phase II trial (CLL2M) is the first study assessing the efficacy and toxicity of bendamustine in combination with rituximab in previously untreated CLL patients (pts). Patients and Methods:Between March 2007 and September 2008 117 pts with untreated CLL requiring therapy were enrolled into the protocol. Bendamustine was given at a dose of 90 mg/m2 on day 1 and 2, combined with 375 mg/m2 rituximab for the first cycle and 500 mg/m2 for subsequent cycles. BR treatment was administered every 28 days for up to 6 courses. Blood samples were taken for analysis by fluorescence in situ hybridization (FISH), the IgVH mutational status and expression of ZAP70/CD38. Minimal residual disease (MRD) was evaluated in peripheral blood and bone marrow by 4-color flow cytometry. Results:Data on the entire study population of 117 pts (median age 64 years) with a total of 583 treatment cycles are available. As of June 2009 the median observation time was 15.4 months (mo). 11.1% of the pts presented with stage Binet A, 41.0% with Binet B and 47.9% with Binet C disease. A mean number of 5.0 courses were delivered. 114 pts were evaluable for toxicity, 110 for response and 113 for progression free survival (PFS). The most frequent adverse events based on 583 treatment cycles were myelosuppression and infections: grade 3/4 anemia occurred in 4.9%, grade 3/4 leukopenia in 14.6%, grade 3/4 neutropenia and thrombocytopenia in 6.5% and 6.1% of all given courses, respectively. 29 episodes of CTC grade >3 infections were documented (5.1% of all courses). Treatment related mortality occurred in 2.6% of the pts: one liver failure after attempt of suicide with antihistamines, one fatal pneumonia and one sepsis in neutropenia. The overall response rate was 90.9% with 32.7% (36 pts) clinical complete remissions (CR). A nodular partial remission (nPR) was achieved in 2.7% (3 pts) and a partial response (PR) in 55.5% of the pts (61 pts), respectively. 9.1% of the pts (10 pts) had stable disease (SD) whereas none of the pts was progressive (PD). After 18 mo 75.8% of the pts were still in remission, median PFS has not been reached. An MRD level below 10E-4 was observed after completion of therapy in 29 of 50 evaluable pts in peripheral blood, while 7 of 25 pts achieved MRD negativity in bone marrow. Differences in response were observed among the genetic subgroups: 19 of 21 pts with 11q- achieved a remission with 10 PR and 9 CR (ORR: 90.5%). Accordingly, 17 of 19 patients with +12 responded (14 PR, 3 CR, ORR: 89.5%). In the high-risk group with 17p-, 3 of 7 pts showed a partial response (ORR: 42.9%). 56 of 63 pts (ORR: 88.9%) with unmutated IgVH status responded to BR. Conclusion:Bendamustine plus rituximab (BR) is effective and safe in the first-line treatment of CLL. Major side effects (myelosuppression and infections) were infrequent. Based on these encouraging phase II data the German CLL Study group is presently investigating the efficacy of BR in comparison to fludarabine-based immunochemotherapy (FCR) in the first-line treatment of CLL within a randomized phase III trial (CLL10 protocol). Disclosures:Fischer:Roche: travel expenses. Cramer:Roche: travel grants. Stilgenbauer:Bayer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Fink:Roche: . Boettcher:Roche: Research Funding. Ritgen:Roche: Research Funding. Kneba:Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Döhner:Roche: Research Funding. Eichhorst:Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Hospira: Honoraria. Hallek:Roche: Consultancy, Honoraria, Research Funding. Wendtner:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Schering: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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▪▪This icon denotes an abstract that is clinically relevant. 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-naïve 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<0.001), respectively. 74% (FCR) and 67% (FC) of pts received 6 cycles (p=0.02). The total median cumulative dose applied per pt was 775 mg for F and 7712 mg for C, with no statistically significant difference among the two treatment arms. Pts in Binet stages A and B received more treatment cycles (5.31) than Binet C pts (4.52; p<0.001). Only 57.1% (FC) and 60.3% (FCR) Binet C pts received 6 cycles. Dose reductions by more than 10% were observed in 49% of FCR pts (vs 28% FC (p=0.001). 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<0.001). Median PFS was 32.8 mo for FC and 51.8 mo for FCR pts (p<0.001, Hazard Ratio (HR) 0.56, CI 95% 0.460-0.689). The largest benefit for FCR was observed in Binet stage A and B for CR, ORR and PFS (Binet A: p=0.08, HR 0.423 CI 95%, 0.157-1.135, Binet B: p<0.001 HR: 0.504 CI 95%, 0.390-0.651, Binet C: p=0.08, HR 0.732 CI 95%, 0.514-1.041). In Binet C, the median PFS was 14 mo for pts treated with up to 3 courses FC, but 44 mo for pts that received 4 courses or more (p<0.001). Median PFS for pts treated with up to 3 cycles FCR was 12.5 mo, while for pts with 4 cycles or more, median PFS has not been reached (p<0.001). Statistically significant differences were observed in OS between the two treatment arms. The OS rate at 37.7 mo was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01). In both arms, the median OS has not been reached. Only patients in Binet stages A and B showed a superior OS after FCR treatment (Binet A: HR 0.19, CI 95%, 0.023-1.613 p=0.09; Binet B: HR 0.45, CI 95%, 0.296-0.689, p<0.001; Binet C HR1.4, CI 95%, 0.843-2.620, p=0.168).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 entity's 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 entity's 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 entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Berrebi:Roche: travel grants. Jaeger:Roche: Consultancy, Honoraria, Membership on an entity's 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.