scholarly journals Lenalidomide and Rituximab Maintenance Therapy after Front-Line Induction Chemoimmunotherapy in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5470-5470
Author(s):  
Julie E Chang ◽  
Vaishalee P. Kenkre ◽  
Christopher D. Fletcher ◽  
Aric C. Hall ◽  
Natalie Scott Callander ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Second Malignancies ◽  
Front Line ◽  
First Line ◽  
11Q Deletion ◽  
Line Chemotherapy

Introduction: Chronic lymphocytic leukemia (CLL) is incurable with standard therapy. With first-line chemotherapy, some patients (pts) may achieve durable remissions of many months/years. Lenalidomide (LEN) has improved progression-free survival (PFS) when given as maintenance (MNT) therapy after front-line chemotherapy (CALGB10404, CLLM1). The combination of LEN + rituximab (LR) has activity in relapsed CLL, hypothesizing benefit as MNT therapy after first-line chemotherapy. Methods: Adult pts ≥18 years with previously untreated CLL received induction bendamustine (B) 90 mg/m2 IV days 1 & 2 and rituximab (R) IV day 1 (375 mg/m2 cycle 1, then 500 mg/m2 cycles 2-6) for 6 treatment cycles (as few as 4 cycles allowed). MNT therapy with LR was initiated within 12 weeks after cycle 6, day 1 of BR. Criteria to start LR MNT included: neutrophils ≥1000/microliter (uL), platelets ≥75 K/uL, and creatinine clearance ≥40 mL/min. LEN was administered in 28-day cycles for 24 cycles, initially 5-10 mg daily continuous dosing, later modified to 5-10 mg on days 1-21 of each 28-day cycle in 6/2018 due to neutropenia and second malignancy risk. LEN was reduced to 5 mg every other day for toxicities at 5 mg/day. R 375 mg/m2 IV was given every odd cycle (total of 12 doses). Patients discontinuing LEN for any reason were allowed to continue R MNT per protocol. The primary endpoint is PFS with LR MNT therapy, calculated from the first day of MNT therapy until progressive disease (PD), death, or start of a new therapy. Secondary endpoints are response rate and overall survival. Results: Thirty-four pts have enrolled beginning 11/2013, with follow-up through 6/2019. Median age is 64 years, with 8 pts ≥70 years; 8 women and 26 men. CLL FISH panel is available on all pts: 14 with 13q (as sole abnormality), 9 with 11q deletion, 6 with trisomy 12, 4 with normal FISH panel and 1 with 17p deletion. Heavy chain mutation analysis is available on 11 pts: 8 unmutated, 2 mutated, 1 indeterminate. Thirty-one pts completed 4 (n=2) or 6 cycles of induction BR; 3 pts are receiving induction BR. Twenty-four pts have received MNT LR; 7 did not receive LR for reasons of PD during induction (n=2), infection (n=1), pt preference (n=2), renal insufficiency (n=1), and new carcinoma (n=1). MNT LR was completed in 7 pts; 9 pts are still receiving LR. Fourteen subjects have discontinued protocol therapy, 3 during induction due to PD (n=2) and infection (n=1), and 8 during MNT. Toxicities that led to discontinuation of LR were recurrent infections in 7 pts, including 2 events of PJP pneumonia; 4 pts had recurrent neutropenia with infections; 1 pt had neutropenia without infections. Response is assessable in 31 patients using the International Working Group Consensus Criteria. Best responses to treatment were: partial response 65% (22/34), complete response (CR)/unconfirmed CR 24% (8/34). The median number of MNT cycles received is 16. The dose intensity of LEN across total cycles received (n=278): 5 mg every other day (52.5%), 5 mg/day (43.9%), and 10 mg/day (3.6%). The most common reason for dose reduction or dose holding was neutropenia. Most common Gr 3/4 toxicities (reported as events Gr3/Gr4) during MNT therapy were: neutropenia (20/20), leukopenia (19/4), febrile neutropenia (3/1), and infections (11/-). The majority of Gr3 infections were pneumonia/respiratory (n=5). One event of disseminated herpes zoster occurred. Second malignancies during MNT included: basal cell CA (n=1), squamous cell carcinoma (n=5), and colon cancer (n=1). No unexpected second malignancies were observed in pts receiving LR. Two-year PFS (defined from day 1 of MNT therapy) is 90% (95% confidence interval [CI] 0.78-1), and the median follow-up for 24 patient who started maintenance therapy is 1.79 years (95% CI 1.53-2.7). There have been no deaths. Conclusion: The combination of LR is effective in sustaining remissions after a BR induction in previously untreated CLL, but with frequent neutropenia and infections even at low doses of LEN. Most patients discontinuing MNT did so due to neutropenia and/or infections. A shorter planned interval of MNT LR (i.e., 6-12 months) may confer similar benefit to extended dosing that is more tolerable. Pts at high risk for short remissions after front-line chemotherapy (e.g., unmutated heavy chain status, 11q deletion and/or failure to achieve minimal residual disease after induction) may be the populations for which LR MNT therapy is most appropriate. Disclosures Chang: Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Lenalidomide administered as maintenance therapy for first treatment of CLL/SLL.

A Phase II Trial of Ofatumumab for Older Patients and Patients Who Refuse Fludarabine-Based Regimens with Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3912-3912
Author(s):  
Ian W. Flinn ◽  
William N. Harwin ◽  
Inés M. Macias-Pérez ◽  
Patrick S. Tucker ◽  
David M. Waterhouse ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Maintenance Therapy ◽  
Older Patients ◽  
Research Funding ◽  
Single Agent ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Front Line ◽  
Small Lymphocytic Lymphoma ◽  
Free Survival

Abstract Abstract 3912 Background: Fludarabine (FLU), cyclophosphamide and rituximab (FCR) or other FLU-based regimens have shown improvement in response rates, progression-free survival, and in some studies overall survival in patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). However, a randomized trial of older patients demonstrated no improvement in progression-free and overall survival with FLU-based therapy (Eichhorst BF, et al: Blood 114; 3382, 2009). A recent retrospective analysis of serial CALGB trials (Woyach J, et al: ASH 2011) confirmed the lack of PFS and OS advantage of fludarabine in elderly patients but did find benefit of the anti-CD20 antibody rituximab across all age groups. Ofatumumab (OFA) is a fully human immunoglobulin G1 kappa, monoclonal antibody that targets a unique epitope on the CD20 molecule. Pre-clinical data indicate that OFA has greater NK cell and monocyte-mediated killing, complement-dependent cytotoxicity and direct killing against CLL cells. Based on pre-clinical and clinical studies indicating possible increased efficacy of OFA in patients with CLL, our aim was to develop an antibody-only regimen for older patients and patients who refuse FLU-based regimens. Methods: Eligible patients had previously untreated, symptomatic CD20+ B-cell chronic lymphocytic leukemia (B-CLL) or small lymphocytic lymphoma (SLL), ECOG PS of ≤ 2, and were either ≥ 65 years of age, or patients 18–64 years of age who had declined FLU-based regimens. All patients in this study received OFA as an IV infusion once weekly for a total of 8 weeks. To reduce the possibility of infusion reactions, the first dose of OFA was administered at a dose of 300 mg. If the initial 300-mg dose of OFA was well tolerated, without occurrence of any infusion associated AEs of ≥ grade 3, subsequent doses of OFA (i.e., Week 2 through Week 8) were given at a dose of 2000 mg. Eight weeks after the 8-week study treatment period ended, patients were assessed for response to the treatment. Patients who progressed received no further treatment. Patients who responded to the treatment or who did not have disease progression received maintenance therapy consisting of OFA at a dose of 2000 mg IV every 2 months for 2 years (for a total of 12 doses, in the absence of PD or intolerable toxicity) beginning 3 months after the last dose of OFA. Results: Between 8/2010 and 4/2011, 42 patients were enrolled and are included in this analysis. Patients were 57% male with median age 69 yrs (range: 47–88 yrs). Fourteen patients (33%) were < age 65. All but 1 patient had CLL; 1 patient had SLL. The median WBC at study entry was 41.1 (range 1.7–236.5). Rai stage at entry to study was Stage 0 = 8, Stage I = 8, Stage II – 4, Stage III – 10, Stage IV – 11. Interphase cytogenetics demonstrated 2/42 (5%) 17p-, 4/42 (10%) 11q-, 11/42 (26%) trisomy 12, 9/42 (21%) normal, 14/42 (33%) 13q-, and 2 (5%) unknown. To-date, 41 (98%) patients remain on study and 35 have completed 8 weeks of initial therapy with 24 (57%) having already begun maintenance therapy. Lymphocyte count normalized in 85% of patients at the end of the initial 8 weeks of therapy. Thirty patients have been evaluated for response according to IWCLL criteria (Hallek 2008): 13 patients (44%) achieved an objective response (CR, 0; PR, 13); 16 (53%) patients had SD; 1 patient (3%) had PD. SAEs were infrequent with 2 patients hospitalized for unrelated events: g2 fracture, g3 chest pain, g3 hematoma and g4 pulmonary emboli; 2 patients hospitalized for events possibly OFA-related had g2 fever, g3 anemia and g3 pneumonia. Only 1 patient experienced significant infusion-related toxicity that required repeat administration of the initial 300-mg dose instead of dose escalation at dose 2. Baseline FcγR polymorphisms for patients enrolled are currently being analyzed and will be presented. Conclusion: Single-agent OFA is a highly active and well tolerated front-line therapy for older patients with CLL or patients refusing FLU as evidenced by both early response and also ability of virtually all patients to proceed to maintenance therapy. A low incidence of serious infusion toxicity, infectious morbidity and other heme / non-heme toxicities was observed. Continued long-term assessment will further characterize the toxicity and efficacy of this single-agent OFA regimen in patients with CLL, as well as overall and progression-free survival rates. Disclosures: Flinn: GSK: Research Funding. Off Label Use: Ofatumumab in front-line CLL. Jones:Abbott Labs: Research Funding; GSK: Consultancy.

scholarly journals Long-Term Follow up of Front-Line Therapy with Ofatumumab, High Dose Methylprednisolone and Lenalidomide (HiLO trial) for Treatment-Naïve Chronic Lymphocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3150-3150
Author(s):  
Ariel Felipe Grajales-Cruz ◽  
Julio C. Chavez ◽  
Elyce P. Turba ◽  
Lisa Nodzon ◽  
Francisco Perez Leal ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Treatment Phase ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Front Line ◽  
High Dose Methylprednisolone ◽  
Treatment Naïve ◽  
Grade 3

Abstract Background: New targeted therapies continue to show improved efficacy in various stages of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), sparing patients from chemoimmunotherapy. However, cure remains elusive. Here, we present a front-line alternative based on a combination of high-dose methylprednisolone (HDMP) and ofatumumab, followed by consolidative therapy with lenalidomide plus ofatumumab. Methods: This is a phase II, single-center study in patients with treatment-naive (TN) CLL/SLL. During the first treatment phase (cycles 1-3) patients received HDMP 1000 mg/m2 IV and ofatumumab 2000 mg (300 mg given week 1 then 2000 mg for a total of 12 doses) IV infusions weekly x 4 doses in cycle 1 of a 28 day cycle, then every 2 weeks for cycles 2 and 3. During the second treatment phase (cycles 4-12), patients received renally adjusted lenalidomide 5-10 mg daily and ofatumumab 2000mg IV once every 8 weeks. Growth factor support was permitted at the discretion of treating physician. Prophylactic medications included allopurinol for tumor lysis syndrome (TLS) 3 days before C1D1 through C1; and trimethoprim/sulfamethoxazole and fluconazole through cycle 4, and acyclovir through C12. Patients received aspirin 81 mg/day as thrombosis prophylaxis while on lenalidomide. Patients were assessed for response by iwCLL 2008 criteria (including imaging assessment) after completion of cycles 3 and 12. The study allowed continuation of lenalidomide if patients achieved complete (CR), partial (PR) response or stable disease (SD). Primary endpoints were efficacy, adverse events (AEs) profile, and time-to-treatment failure (TTF). Results: Between January 2012 and September 2015, the study enrolled a total of 45 patients. Median follow-up was 50.4 (5.6-72.8) months. The median age was 62.6 (48.2-86.1) years. Chromosomal analysis by FISH demonstrated Del17p in 8 (17.8%), Del11q (+/- others, except Del17p) in 10 (22.2%), Trisomy 12 (+/- others, except Del17p and Del11q) in 8 (17.8%), Del13q in 10 (22.2%), no mutations in 9 (20%) patients. The IGHV status was unmutated in 34 (75.6%) cases. Indications to start treatment were: symptomatic lymphadenopathy, symptomatic splenomegaly, anemia, and thrombocytopenia in 5 (11.1%), 10 (22.2%), 12 (26.7%), and 18 (40%), respectively. The median duration of treatment was 35.6 (2.7-66.9) months. Reasons for treatment discontinuation were: progressive disease (PD) in 9 (20%), AEs in 15 (33.3%), transplantation in 3 (6.7%), consent withdrawal in 1 (2.2%), and secondary malignancies in 2 (4.4%) cases. The overall response rates (PR+CR) at 3, 12, 24, 36, and 48 months were 75.6%, 77.8%, 66.7%, 44.4%, and 37.8%, respectively. The CR rates at 3, 12, 24, 36, and 48 months were 2.2%, 11.1%, 20%, 17.8%, and 13.3% respectively. Fifteen patients remain in PR/CR and on treatment at the time of this analysis. The intention-to-treat median TTF was 45.2 (2.9-69.7) months, and was not different among high risk groups such as Del17p, Del11q and/or unmutated IgHV. In patients who discontinued for reasons other than PD the median duration of response without treatment was 30.7 (9.8-69.7) months. Three (6.7%) patients underwent allogeneic hematopoietic cell transplantation after a median of 3 (3 - 4) treatment cycles. Treatment was well tolerated with grade 3/4 infusion reaction in 1 (2.2%) patient. Grade 3/4 treatment-related hematological AEs were neutropenia, thrombocytopenia, and anemia in 33 (73.3%), 5 (11.1%), and 1 (2.2%), respectively. Grade 3/4 infections occurred in 6 (13.3%) patients. No grade 3/4 tumor flares were observed, and there were no cases of TLS or thrombosis. Conclusion: The combination of ofatumumab, HDMP and lenalidomide is effective and well tolerated in treatment-naive CLL/SLL, even when poor prognostic features are present. Disclosures Komrokji: Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Locke:Novartis Pharmaceuticals: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Kite Pharma: Other: Scientific Advisor. Kharfan-Dabaja:Seattle Genetics: Speakers Bureau; Incyte Corp: Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau. Sokol:Spectrum Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Mallinckrodt Pharmaceuticals: Consultancy.

scholarly journals Long-Term Sustained Responses Following Ibrutinib Discontinuation after Frontline Therapy with Obinutuzumab Plus Ibrutinib in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Paula A. Lengerke Diaz ◽  
Michael Y. Choi ◽  
Eider F. Moreno Cortes ◽  
Jose V. Forero ◽  
Juliana Velez-Lujan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Side Effects ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Grade 3

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (&gt;5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as &lt;10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

scholarly journals 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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3491-3491 ◽  
Author(s):  
Alexey Danilov ◽  
Habte A Yimer ◽  
Michael Boxer ◽  
John M Burke ◽  
Sunil Babu ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Health Status ◽  
Chronic Lymphocytic Leukemia ◽  
Global Health ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Future Health ◽  
Equity Ownership

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

Is Chronic Lymphocytic Leukemia Still Incurable?

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3929-3929
Author(s):  
Michael J. Keating ◽  
Constantine S Tam ◽  
William G. Wierda ◽  
Susan O'Brien ◽  
Deborah A. Thomas ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Cell Transplant ◽  
Second Malignancies ◽  
Mutation Status ◽  
Richter’S Transformation ◽  
Richter's Transformation

Abstract Abstract 3929 Introduction Up until now, Chronic Lymphocytic Leukemia (CLL) has been considered incurable except with an allogeneic stem cell transplant. In the last 10 years, evidence has demonstrated that chemo-immuotherapy with fludarabine, cyclophosphamide, and rituximab, (FCR) has significantly improved CR rates, overall survival (OS), and progression free survival 1. Long term follow up data for FCR at MDACC demonstrated that a significant proportion of patients (pts.) were free at 8 years2 raising the question of whether pts. are potentially cured. Definition of cure in a chronic disease such as CLL has not been addressed. To investigate this possibility we evaluated the outcome characteristics of 222 of the 300 patients (who commenced FCR more than 10 years ago) in our previously reported study of initial therapy with FCR in CLL2. Seventy eight (35%) pts were free of relapse and 127 (58%) were alive at 10 years (Fig. 1). Thirty three patients died in CR/PR of infection (5), second malignancies (8), Richter's transformation (8). MDS (9), and other causes (3). One hundred and sixty three pts. (73%) achieved CR, 22 pts. (10%) a nodular PR (nPR), 27 pts. (12%) a PR, and 10 (5%) failed treatment. The 10 year PFS correlates strongly with response, CR (41%), nPR+PR (15%) (Fig. 2). None of these patients were transplanted in remission. FISH analysis was not available at the time of this study. Conventional karyotyping demonstrated +12 (24 pts), del 11q (15), del 17p (4), other abnormalities (15), diploid (105), and in 59 patients the test was not done or had no metaphases. The worst outcomes were del 17p and del 11q each significantly inferior to diploid (+12) patients had the best time-to-treatment failure (TTF) with P<.09 compared to diploid. The 10-year TTF was significantly higher for Rai <3 versus 3 – 4 (P=.02), serum beta-2-microglobulin (β2M) value of ≤ 4 mg/L (p<.001), mutation status of IgVh (P<.001) and number of courses of FCR received. (Table 1) The causes for receiving <6 courses of FCR were persistent cytopenia (15), infections (6), resistance (5), Richter's transformation and other malignancies (9), autoimmune hemolysis (5), and other causes and lost to follow-up (16). Of the 77 patients who are still in remission at 10 years, two have relapsed and one developed Richter's transformation. Four of 21 patients checked had no residual disease in their blood at 10 years by 4-parameter flow cytometry. All other 10 yr. TTF patients are being contacted to provide blood for 4-parameter flow residual disease. Conclusion The present data suggest that one-third of patients treated with chemoimmunotherapy are potentially cured of CLL. The characteristics most strongly associated with 10 yr. TTF were Rai stage, serum β2M level, mutation status, and tolerance of chemotherapy. Second malignancies and transformations are emerging as significantly impairing the likelihood of cure. Disclosures: No relevant conflicts of interest to declare.

Heritable Predisposition To Richter Syndrome In Patients With Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2867-2867 ◽  
Author(s):  
Sameer A. Parikh ◽  
Susan L Slager ◽  
Kari G. Rabe ◽  
Neil E. Kay ◽  
James R Cerhan ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Chromosome 18 ◽  
Richter Syndrome ◽  
Increased Risk ◽  
Translocation Breakpoints

Abstract Background Approximately 2-8% patients with chronic lymphocytic leukemia (CLL) will transform to diffuse large B-cell lymphoma (DLBCL, Richter syndrome [RS]). Clinical characteristics and molecular markers at the time of CLL diagnosis are associated with the risk of RS; however, there are no data regarding germline genetic variations and the risk of RS. Genomewide association studies (GWAS) have shown several single-nucleotide polymorphisms (SNPs) that are associated with a higher risk of familial CLL. It is not known whether any of these polymorphisms also predispose to RS. Methods Since 2002, all consecutive patients with newly diagnosed (<9 months diagnosis) CLL at Mayo Clinic were offered enrollment into a prospective genetic epidemiology study. Patients completed extensive epidemiologic questionnaires and baseline clinical, laboratory, and biologic data were abstracted using a standard protocol. Genotyping of germline tissue at diagnosis was performed using an Illumina iSelect panel and Affymetrix 6.0 SNP chip. All patients were prospectively and longitudinally followed at defined time-points with systematic collection of data on treatments, second cancers, and RS. All patients with biopsy-proven DLBCL during follow-up were considered to have undergone transformation into RS. Time to RS was calculated from CLL diagnosis date until RS or until last follow-up date for those with no RS. SNPs were modeled in two ways: ordinal and dominant. Cox regression was used to estimate hazard ratio (HR) for individual SNPs with time to transformation. Results Thirteen of the GWAS-discovered SNPs associated with risk of developing CLL were available and genotyped on 620 CLL patients. Median age at diagnosis of CLL was 62 years (range 27-88), and 428 (69%) were male. Three hundred and ten (51%) patients were low (0) Rai stage, 271 (45%) were intermediate (I-II) Rai stage, and 22 (4%) were advanced (III-IV) Rai stage. The immunoglobulin heavy chain gene was unmutated in 189 (40%) patients; 157 (32%) patients expressed ZAP-70, 163 (29%) expressed CD38 and 104 (31%) expressed CD49d. Fluorescence in-situ hybridization (FISH) revealed that 210 (41%) patients had del13q, 90 (18%) patients had trisomy 12, 37 (7%) had del11q, 23 (5%) had del17p and 141 (28%) had no detectable FISH abnormalities. As of last follow-up, 239 (39%) patients received therapy for CLL. After a median follow-up of 5.9 years (range 0-11), 15 (2.4%) patients developed biopsy-proven RS. The median time to RS in these 15 patients was 4.5 years (range 1.0-8.7 years). The ordinal HR for the 13 SNPs tested, their corresponding genes, and p-values are shown in Table 1. Germline polymorphisms in a single SNP, rs4987852, encoding for BCL2 (chromosome 18), was significantly associated with an increased risk of RS (ordinal HR=3.9; 95% CI=1.6-9.8; p-value=0.004). This allele was present in 48/605 (8%) non-transformed CLL patients compared to 4/15 (27%) of patients with RS. Time to RS according to the Kaplan-Meier analysis for rs4987852 is shown in Figure 1. This SNP is located in a region in which t(14;18) translocation breakpoints commonly occur in follicular lymphoma and overexpression of BCL2 leads to an increased incidence of B-cell lymphomas in mice. Conclusion Our results suggest that inherited genetic polymorphisms predispose CLL patients to develop RS. Specifically, SNP (rs4987852) present on the BCL2 gene on chromosome 18 in CLL is associated with an increased risk of transformation to RS. These observations require replication in other CLL cohorts. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.

Renal Disease In Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5302-5302 ◽  
Author(s):  
Tait D Shanafelt ◽  
Kari G. Rabe ◽  
Curtis A Hanson ◽  
Timothy G. Call ◽  
Susan Schwager ◽  
...  
Keyword(s):  
Renal Function ◽  
Chronic Lymphocytic Leukemia ◽  
Renal Insufficiency ◽  
Serum Creatinine ◽  
Research Funding ◽  
Univariate Analysis ◽  
Lymphocytic Leukemia ◽  
Disease Course ◽  
To Receive

Abstract Background Chronic lymphocytic leukemia (CLL) can effect renal function in a variety of ways including direct infiltration of the kidney, ureteral obstruction by lymphadenopathy, and treatment related tumor lysis syndrome (uric acid nephropathy). Rarely, CLL has also been reported to be associated with light chain nephropathy, renal amyloidosis, membranoproliferative glomerulonephritis (MPGN), granulomatous interstitial nephritis (GIN), and minimal change disease (MCD). Nearly all the data on the effects of CLL on renal function is at the case report level. We systematically evaluated the prevalence of renal insufficiency at diagnosis as well the incidence of acquired renal insufficiency during follow-up in a large cohort of patients with newly diagnosed CLL to more accurately define the effects of CLL on the kidney and its impact on clinical outcomes. Methods Between January 1995 -February 2013, previously untreated CLL patients seen in the Division of Hematology at Mayo Clinic at diagnosis (<12 months) and who had baseline assessment of serum creatinine were included in this analysis. Patients with serum creatinine (Cr) ≥1.5 mg/dL at baseline were classified as having renal insufficiency at diagnosis. Patients who initially had baseline creatinine <1.5 mg/dL but who developed a Cr≥1.5 mg/dL during the course of their disease were considered to have acquired renal insufficiency. Results Existing renal insufficiency at the time of CLL diagnosis: Of 2047 patients who met the eligibility criteria, 153 (7.5%) patients had renal insufficiency (Cr≥1.5 mg/dL) at the time of CLL diagnosis including 15 (0.7%) with a Cr≥3 mg/dL. Renal insufficiency was also more common among men (9.3% vs. 3.9%; p<0.00001), those with advanced stage disease (Rai 0=7.0%; Rai I-II=6.4%, Rai III-IV=20.2%; p<0.0001), and CD49d positive patients (6.8% vs. 3.8%; p<0.038). Patients with renal insufficiency at diagnosis were also older (median age 72.2 vs. 63.9; p<0.0001). No difference in the prevalence of renal insufficiency at diagnosis was observed based on cytogenetic abnormalities detected by FISH or CD38, ZAP-70 or IGHV gene mutation status. Although renal insufficiency at diagnosis was strongly associated with OS on univariate analysis (p<0.001), no association was observed between renal insufficiency and TTT or OS on multi-variate analysis adjusting for age, sex, and Rai stage. Acquired renal insufficiency during CLL disease course: Among the 1894 patients with normal renal function at diagnosis, 304 (16.1%) acquired renal insufficiency (Cr≥1.5 mg/dL) during the course of their CLL disease course including 43 (2.3%) with peak Cr≥3 mg/dL. In addition to age (older) and male sex, a number of CLL disease characteristics were associated with a higher likelihood of acquired renal insufficiency including: IGHV UM (OR=2.0; p=0.0001), unfavorable FISH (del17p- or 11q-; OR=2.0; p=0.001), and being CD49d+ (OR=1.8; p=0.002), ZAP-70+ (OR=1.6; p=0.004), or CD38+ (OR=1.4; p=0.0.032),. Shorter TTT (p<0.001) and OS (P<0.001) was observed among patients with initially normal creatinine who acquired renal insufficiency (Figure 1A and 1B). On MV analysis adjusting for age, sex, and stage at diagnosis, acquired renal insufficiency remained an independent predictor of TTT (OR=1.77; p=0.001) and OS (OR=2.67; p<0.001). Renal insufficiency and therapy selection After median follow-up of 4.5 years (range 0-18.0), 620 of 2047 (30.3%) patients have progressed to require treatment. Patients with renal insufficiency prior to treatment were less likely to receive purine nucleoside analogue based therapy and more likely to receive single agent alkylator based treatment. Conclusions Approximately 1 in every 13 patients (7.5%) with CLL has renal insufficiency at the time of diagnosis and an additional 16.1% acquire renal insufficiency during the course of the disease. The risk of developing renal insufficiency is associated with a variety of CLL B-cell characteristics and is associated with TTT and OS. Data on causes of acquired renal insufficiency is being abstracted and will be presented at the meeting. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Off Label Use: MK2206 in a phase 1 trial of CLL.

Outcome of Second Line Treatment in Patients with Chronic Lymphocytic Leukemia Did Not Improve 2002-2013: A Population-Based Study from a Well-Defined Geographic Region

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4166-4166
Author(s):  
Anna Asklid ◽  
Agnes Mattsson ◽  
Einar Björgvinsson ◽  
Maria Winqvist ◽  
Sandra Eketorp Sylvan ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Line Treatment ◽  
Second Line ◽  
Phase 2 ◽  
Line Therapy ◽  
Time Period ◽  
Grade 3

Abstract Background: Treatment of relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) remains challenging. Major progress has been achieved with new agents such as ibrutinib and idelalisib. However relapses still occur with these agents or the treatment has to be withdrawn (Byrd et al, Blood 2015). Several new drugs have been or are currently tested in pivotal, non-controlled phase 2 trials on R/R CLL patients, with the majority of patients on 2nd line therapy following chemoimmunotherapy. Thus, reliable and matching historical data are required for comparison. We have previously reported on the outcome of heavily pretreated refractory patients (Eketorp Sylvan et al, Leuk Lymphoma 2014). The aim of the this study was to specifically investigate the outcome of 2nd line treatment prior to the access of small molecule-based treatment options, in consecutive patients from a well-defined geographical region, where almost complete follow-up exists and external referrals are minimal. Methods: Patients diagnosed with CLL were identified from the Cancer Registry in Stockholm (Nov 2002- Dec 2013) and patient files were reviewed individually to identify R/R patients. Efficacy and toxicity of 2nd line and later salvage therapies were recorded as well as long term follow-up. Patients were also grouped into treated in the early (Nov 2002-2007) and late time period (2008-2013) and compared regarding outcome. A multivariate cox proportional hazards model was perform to explore risk factors for outcome. Results: Chart review of 979 patients identified 148 consecutive, non-referred patients with R/R CLL undergoing various types of 2nd line salvage therapy. Median age was 73 years and 53% had Binet stage C. Del17p testing was available in 46% of patients of which 20.6% had del17p. Most frequently initiated treatments in 2nd line were chlorambucil (27.7%), FC (23.6%) and FCR (13.5%). The overall response rate (ORR) was 48.6% (3.4% CR). Median overall-survival (OS) from start of second line therapy was 37.9 months. Shorter OS was significantly associated with ECOG higher than 0, male sex, and age > 80 years. There was no difference in OS, PFS or ORR between those treated in the first vs the second time period of this study, despite that 2nd line use of chlorambucil decreased from 39% to 23% and use of FCR or BR increased from 0% to 26% from 2002-2007 to 2008-2013. However, median duration of response was significantly longer during the later time period (20.9 vs 10.3 months, p=0.035). During treatment, 50.7% of patients were hospitalized and 32.4% of patients experienced grade III-IV infections. Other AEs ≥ grade 3 occurred in 10.1% and 7.4% had bleeding events. Grade 3/4 hematological toxicity, according to IWCLL-criteria, occurred in 0.7%/0.7% (Hb), 11.5%/8.8% (platelets) and 16.9%/36.5% (neutrophils). Toxicity was similar in both time periods. Conclusion: Our study describes the outcome of 2nd line treatment in R/R CLL in consecutive patients from a geographically well defined region with almost complete follow-up and without influence on the results from external referrals. Almost no improvement was observed in the outcome of 2nd line treatment during the 10 year period. Such real-world results may be used for comparison with data obtained in non-controlled phase 2 trials on new orphan drugs. Keywords: Chronic lymphocytic leukemia, Relapsed, Refractory, Clinical outcome Disclosures Asklid: Janssen Cilag: Research Funding. Mattsson:Janssen Cilag: Research Funding. Björgvinsson:Janssen Cilag: Research Funding. Winqvist:Janssen Cilag: Research Funding. Eketorp Sylvan:Janssen Cilag: Research Funding. Søltoft:Janssen Cilag: Employment. Repits:Janssen Cilag: Employment. Diels:Janssen: Employment. Österborg:Janssen Cilag: Research Funding. Hansson:Jansse Cilag: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document