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 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.

Detection and impact of minimal residual disease on outcome of chronic lymphocytic leukemia

2012 ◽  
Vol 153 (41) ◽  
pp. 1622-1628
Author(s):  
Márk Plander ◽  
Judit Skrapits ◽  
Tünde Bozsó ◽  
Tamás Szendrei ◽  
János László Iványi
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Minimal Residual

Introduction: Minimal residual disease is associated with longer overall survival in patients with chronic lymphocytic leukemia. Aim: The aim of the authors was to determine the clinical significance of remission and minimal residual disease on the survival of patients with chronic lymphocytic leukemia. Methods: Data from 42 first-line treated patients with chronic lymphocytic leukemia were analyzed. Minimal residual disease was determined by flow cytometry. Results: Overall response and complete remission was achieved in 91%, 86%, 100% and 87%, 0%, 60% of patients with fludarabine-based combinations, single-agent fludarabine and cyclophosphamide + vincristin + prednisolone regimen, respectively. Minimal residual disease eradication was feasible only with fludarabine-based combinations in 60% of these cases. The ratio of minimal residual disease was 0.5% on average. During a median follow-up period lasting 30 months, the overall survival of patients with fludarabine-resistant disease proved to be significantly shorter (p = 0.04), while complete remission without minimal residual disease was associated with significantly longer progression free survival (p = 0.02). Conclusion: Only fludarabine-based combinations were able to eradicate minimal residual disease in patients with chronic lymphocytic leukemia. Complete remission without minimal residual disease may predict longer progression free survival in these patients. Orv. Hetil., 2012, 153, 1622–1628.

Final Analysis From the International Trial of Single-Agent Ofatumumab In Patients with Fludarabine-Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 921-921 ◽  
Author(s):  
William G. Wierda ◽  
Thomas J. Kipps ◽  
Jiri Mayer ◽  
Tadeusz Robak ◽  
Martin JS Dyer ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Primary Endpoint ◽  
Interim Analysis ◽  
Research Funding ◽  
Single Agent ◽  
Early Death ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Lymphocytic Leukemia ◽  
Grade 3

Abstract Abstract 921 Background: Patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab (FA-ref) or refractory to fludarabine with bulky (>5 cm) lymphadenopathy (BF-ref) have poor prognosis with salvage regimens (Tam et al. Leuk Lymphoma 2007). Ofatumumab, a human CD20 monoclonal antibody, was recently approved by the US FDA and EMEA for treatment of CLL refractory to fludarabine and alemtuzumab based on the interim analysis of the pivotal international clinical trial, which included data from 138 patients with FA-ref and BF-ref CLL. At the interim analysis, the overall response rate (ORR; primary endpoint) with single-agent ofatumumab was 58% (99% CI: 40, 74) in the FA-ref group and 47% (99% CI: 32, 62) in the BF-ref group (Wierda et al. J Clin Oncol 2010). Here, we report the final result for the primary endpoint in 206 patients with FA-ref or BF-ref CLL enrolled in this study. Methods: Patients with FA-ref or BF-ref CLL received 8 weekly doses of ofatumumab followed by 4 monthly doses (dose 1, 300 mg; doses 2–12, 2000 mg). Premedication included acetaminophen, antihistamine and glucocorticoid. The primary endpoint (ORR, 1996 NCI-WG criteria) was evaluated over the 24-week treatment period by an Independent Endpoint Review Committee (IRC). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS) and safety. Results: Baseline characteristics are summarized in the Table; 89% and 50% of patients completed 8 and 12 ofatumumab doses, respectively. The ORR (95% CI) by IRC evaluation was 51% (40, 61) for the FA-ref group and 44% (35, 64) for the BF-ref group. Two patients in the BF-ref group achieved complete remission (Table). Results for time-to-event analyses are shown in the Table. Infusion-related AEs occurred in 63% of patients, which primarily occurred during doses 1 and 2, and diminished with subsequent doses. Infusion-related reactions were grade 1–2 events in 95% of patients; no fatal reactions were reported. The most common (≥5% of all patients) grade ≥3 adverse events (AEs) that occurred from start of treatment until 30 days after the last infusion were infections (24%), neutropenia (12%) and anemia (5%). The most common grade ≥3 infection was pneumonia (8% of patients). Fatal infections occurred in 8% of patients (13% in FA-ref; 5% in BF-ref groups). Grade 3–4 thrombocytopenia occurred in 8 patients (4%), febrile neutropenia in 4 patients (2%) and autoimmune hemolytic anemia in 2 patients (1%). Early death (within 8 weeks from start of treatment) occurred in 5 patients (5%) in the FA-ref group (infections, n=5) and 4 patients (4%) in the BF-ref group (infections, n=2; myocardial infarction, n=1; pulmonary edema, n=1). Conclusions: These final results from the pivotal trial clearly demonstrate the efficacy and safety of ofatumumab monotherapy in this heavily pretreated patient population with FA-ref and BF-ref CLL. Additional data analyses are ongoing, and efficacy outcomes for patient subgroups will be presented. Disclosures: Wierda: GlaxoSmithKline: Honoraria, Research Funding. Kipps:GlaxoSmithKline: Research Funding. Mayer:GlaxoSmithKline: Consultancy, Research Funding. Robak:GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Furman:GlaxoSmithKline: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Cephalon, Inc.: Speakers Bureau; Celegene: Consultancy; Calistoga: Consultancy. Stilgenbauer:Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Cartron:GlaxoSmithKline: Honoraria; Roche: Honoraria. Padmanabhan:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chan:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Gorczyca:GlaxoSmithKline: Employment. Davis:GlaxoSmithKline: Employment. Losic:Genmab A/S: Employment, Equity Ownership. Lisby:Genmab A/S: Employment. Österborg:GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck KGaA: Research Funding.

Second-Line Therapies After Treatment with Fludarabine, Cyclophosphamide, and Rituximab (FCR) or Fludarabine and Cyclophosphamid Alone (FC) for Chronic Lymphocytic Leukemia (CLL) within the CLL8-Protocol of the German CLL Study Group (GCLLSG)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2863-2863 ◽  
Author(s):  
Paula Cramer ◽  
Anna-Maria Fink ◽  
Raymonde Busch ◽  
Barbara Eichhorst ◽  
Clemens-Martin Wendtner ◽  
...  
Keyword(s):  
Research Funding ◽  
Rating Scale ◽  
Single Agent ◽  
Progression Free Survival ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Line Treatment ◽  
Second Line ◽  
Free Survival ◽  
Line Therapy

Abstract Abstract 2863 Introduction: The CLL8-trial is the first study that has shown not only an increase in complete remission rates and progression-free survival, but also an improved overall survival (OS) in physically fit, treatment-naúve CLL-patients (pts) with FCR-chemoimmunotherapy in comparison to FC alone [Hallek et al., Lancet 2010]. Despite this remarkable progress, CLL remains an incurable disease and virtually all pts will eventually relapse. So far, little is known about the efficacy of 2nd-line therapies of these pts. Patients and Methods: Between July 2003 and March 2006 817 pts in good physical fitness as defined by a cumulative illness rating scale (CIRS) score of ≤6 and creatinine clearance 70 ml/min were randomized within the trial and received 6 courses FC (n=409; F: 25mg/m2 i.v. d1–3 and C: 250 mg/m2 i.v. d1–3; q 28 days) without or with rituximab (n=408; 375 mg/m2 i.v. d0 cycle 1, 500 mg/m2 d1 of all subsequent cycles; q 28 days) for 1st-line treatment. Results: As of March 2009, 65% of the patients who had received FCR were free of progression compared to 45% of those who were treated with FC (p<0, 0001) [Hallek et al, Lancet, 2010]. Until July 2010, 232 pts were treated for relapsed CLL, among them 91 of 408 (22%) initially treated with FCR and 141 of 409 (35%) initially treated with FC. In 2nd-line treatment after FCR and FC, the drugs most frequently used either alone or in combination were rituximab (R, 52% of all 2nd-line therapies), fludarabine (F) and bendamustine (B) (21% each), as well as alemtuzumab (A, 12%). The combination of cyclophosphamide, doxorubicin, vincristine, prednisolone and rituximab (CHOP-R) was the most common treatment (35 pts, 15% of all 2nd-line therapies), applied mainly in cases with a relapse ≤24 months after FC/FCR, whereas FCR or BR were administered predominantly in case of relapse >24months (32 and 27 pts, 14% and 12%). Other prevalent 2nd-line therapies were single agent A (20 pts) or B (17 pts), CHOP and FC (11 pts respectively), chlorambucil (9 pts) as well as R monotherapy (7 pts). 9 pts underwent stem cell transplantations. Second-line therapies with FC+/−R and B+/−R were found to be more effective with regard to treatment-free survival (TFS, time to 2nd relapse) and OS when compared to A or CHOP-R and CHOP-like chemotherapies. However, the outcome of 2nd-line therapies seemed to be influenced by the 1st-line treatment. In pts initially treated with FC, FCR was found to be the most effective 2nd-line therapy (TFS: 23 months, OS: not reached), whereas in pts initially treated with FCR, a substitution of the chemotherapeutic agents FC by B seemed justified, as TFS was superior after 2nd-line treatment with B+/−R (16 and 18 months respectively) when compared to FC+/−R (11 and 8 months). Furthermore, in pts who had received FCR for 1st-line treatment, chemotherapy with FC or B was found to be at least equally or even more effective in prolonging OS than FCR or BR (OS calculated from beginning of 2nd-line therapy: FC: not reached, B: 45, FCR: 19, and BR 18 months). Conclusion: Second-line treatments of pts with a relapse after FC or FCR were found to be surprisingly heterogeneous even though the patient collective examined is comparatively homogenous due to the inclusion/exclusion criteria of a clinical trial. As the majority of CLL8-patients is still in remission and has not yet received a 2nd-line treatment, the therapies captured in this analysis are predominantly 2nd-line therapies for earlier relapses. Therefore and because of the short follow-up time, the results ought to be considered as preliminary and descriptive trends. The worse outcome of CHOP-like regimen and A-based therapies in comparison to more established CLL-therapies such as FC+/−R and B+/−R might be related to the fact, that these therapies were administered more often in case of an early relapse after FC/FCR, which is known to be related to other poor prognostic factors [Fink et al, ASH 2010]. Nevertheless, the observation of favorable TFS and OS times after 2nd-line treatment with FC+/−R and B+/−R supports the recommendation to repeat chemoimmunotherapy in case of a relapse >24 months after 1st-line treatment. Further analyses are needed to confirm the observation that chemotherapy (FC or B) without rituximab might be sufficient for for 2nd-line treatment after FCR. Disclosures: Cramer: Mundipharma: Travel Grants. Fink:F. Hoffmann La Roche:. Eichhorst:Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Wendtner:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Pflug:Hoffmann La Roche:. Hallek:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria. Fischer:Hoffmann La Roche:.

A Dose Escalation Study of Ibrutinib with Lenalidomide for Relapsed and Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1987-1987 ◽  
Author(s):  
Daniel A. Pollyea ◽  
Steven Coutre ◽  
Lia Gore ◽  
Nichole Adler ◽  
Pamela Harris ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
Bcr Signaling ◽  
Expansion Cohort

Abstract Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is dependent upon dysregulated signaling through the B-cell receptor (BCR) pathway. Bruton’s tyrosine kinase (BTK) mediates BCR signaling, and inhibition of BTK with ibrutinib, a selective, irreversible BTK inhibitor, is effective and well tolerated for patients (pts) with relapsed/refractory CLL/SLL. However, complete remissions (CRs) are infrequent, mechanisms of resistance to single-agent ibrutinib have been identified, and the duration of response beyond 3 years is unknown. Lenalidomide, a multi-functional immunomodulatory agent, is active in CLL/SLL, but limited by tumor flare reactions, which occur secondary to B-cell activation. Ibrutinib and lenalidomide modulate several key overlapping factors involving the CLL tumor microenvironment, and therefore a phase 1 combination study with lenalidomide dose escalation was undertaken. Methods: The primary objective was to determine the maximum tolerated dose (MTD) of lenalidomide in combination with ibrutinib. Secondary objectives included assessments of efficacy, PK/PD, and other mechanistic correlative studies. A 1-month (cycle 0) period of 420 mg of daily oral ibrutinib was administered as a single agent to decrease BCR signaling and mitigate lenalidomide-associated tumor flare. Beginning with the second month (cycle 1), ibrutinib was given concomitantly with lenalidomide. Four dose escalation cohorts of lenalidomide were planned using a 3+3 design; 2.5, 5, 7.5 and 10 mg. After the 2.5 mg cohort, intra-patient dose escalation was employed: in cohort 2, pts received 2.5 mg in week 1 followed by 5 mg subsequently; pts in cohort 3 received 2.5 mg in week 1, 5 mg in week 2 and 7.5 mg subsequently; pts in cohort 4 will receive 2.5 mg in week 1, 5 mg in week 2, 7.5 mg in week 3 and 10 mg subsequently. Ibrutinib was not dose escalated (420 mg). Pts receive 12 cycles of the combination, after which lenalidomide is discontinued and ibrutinib continues until unacceptable toxicity or disease progression. Eligible pts had relapsed/refractory CLL/SLL with adequate organ and bone marrow function. Pts who relapsed after stem cell transplantation were excluded. Results: To date, 11 pts were enrolled; 9 are evaluable (1 voluntarily withdrew consent prior to completing 3 cycles, the protocol-defined minimum to be evaluable, and 1 was a screen fail). The median age was 65 (49-81). Eight were male and 8 had CLL. Median Rai stage was 1 (1-4). The median number of prior therapies was 2 (range 1-8); 3 were purine analog resistant. Six had bulky (>5 cm) disease. Two had del(17p13.1) and 4 had del(11q22.3). The median number of cycles completed was 8 (range 1-13). Adverse events (AEs) were reported according to the NCI CTCAE v4.0. Possibly related grade 1/2 AEs that occurred in >1 patient included: rash (n=4), muscle cramps (n=3) and abdominal discomfort (n=2). Possibly related grade 3 AEs included neutropenia (n=4), lymphocytosis (n=2), neutropenic fever (n=1), anemia (n=1) and thrombocytopenia (n=1). There was 1 possibly related grade 4 AE, neutropenia, which was pre-defined as DLT, in the 7.5 mg lenalidomide cohort. One patient experienced grade 2 tumor pain, thought to be due to a lenalidomide-associated tumor flare reaction. Four pts required a lenalidomide dose reduction, for neutropenia (n=2) and fatigue (n=2). Six required a treatment hold, of either lenalidomide or both agents, for a median 7 days (2-28), for neutropenia (n=2), anemia (n=1), fatigue/diarrhea (n=1), atrial fibrillation (n=1) and to obtain a lymph node biopsy (n=1). Lymphocytosis was noted in 5 pts, peaking at a median of 22.5 days. The ORR is 100% (9/9), with all responders experiencing PRs. One progressed with Richter’s transformation during cycle 7, 4 months after achieving a PR. All 9 remain alive with a median follow up of 263 days (range 97-391). The 7.5 mg dose cohort is currently being expanded to 6 pts; after the MTD is determined, a 10 patient dose expansion cohort will commence. Conclusions: Ibrutinib with lenalidomide appears to be well tolerated, although lenalidomide dose reductions were common. Tumor flare reactions were rare. Response assessments at higher dose cohorts of lenalidomide are ongoing. Completed phase 1 data, preliminary data from the expansion cohort and correlative findings will be presented. Disclosures Pollyea: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide for CLL/SLL. Byrd:Genentech: Research Funding; Pharmacyclics: Research Funding.

Low-Dose FCR Is a Safe and Effective Treatment Option for Elderly/Comorbid Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Updated Results of Project Q-Lite By Czech CLL Study Group

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4670-4670 ◽  
Author(s):  
Lukas Smolej ◽  
Yvona Brychtova ◽  
Michael Doubek ◽  
Eduard Cmunt ◽  
Martin Spacek ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Study Group ◽  
Free Survival ◽  
Grade Iii

Abstract Background: Combination of fludarabine, cyclophosphamide and rituximab (FCR) is the current gold standard for physically fit patients (pts) with chronic lymphocytic leukemia (CLL). Nevertheless, many CLL patients cannot tolerate this intensive regimen owing to advanced age and/or serious comorbidities. Combination protocols based on dose-reduced fludarabine demonstrated promising results in pilot studies. Therefore, the Czech CLL Study Group initiated Project Q-lite, an observational study to assess efficacy and safety of low-dose FCR regimen used in elderly/comorbid patients with CLL/SLL. Updated results including progression-free survival (PFS), overall survival (OS) and multivariate analysis are presented. Patients and Methods: Between March 2009 and July 2012, a total of 207 pts with active disease (CLL, n=196, SLL, n=11) were treated by low-dose FCR at 16 centers cooperating within Czech CLL Study Group. Dose reductions of chemotherapy compared to full-dose FCR were: 50% of fludarabine (12 mg/m2 i.v. or 20 mg/m2 orally on days 1-3) and 60% of cyclophosphamide (150 mg/m2 i.v./p.o. on days 1-3). Rituximab was administered in standard schedule (375mg/m2 i.v. day 1 in 1st cycle, 500mg/m2 i.v. day 1 from 2nd cycle). Treatment was repeated every 4 weeks; antimicrobial prophylaxis with sulfamethoxazol/trimethoprim and aciclovir or equivalents was recommended. The basic characteristics are summarized in Table 1. Results: Based on intention-to-treat principle, the overall response rate / complete responses including clinical CR (without bone marrow biopsy) and CRi were 81/37% in 1st line and 63/30% in relapsed/refractory (R/R) disease. Serious (CTCAE grade III/IV) neutropenia was frequent (56 and 50%) but grade III/IV infections were only 15 and 18%. The most common causes of death were CLL progression and infections. At the median follow-up of 25 months, median progression-free survival (PFS) for previously untreated and R/R patients was 28 and 15 months; median overall survival (OS) has not been reached in previously untreated pts (75 % at 30 months) and was 30 months in R/R pts. Multivariate analysis identified del 11q, del 17p, bulky lymphadenopathy (1st line) and del 17p (R/R) as independent predictors of shorter PFS; absence of therapeutic response was the only factor associated with shorter OS (both in 1st line and R/R pts). Conclusions: Low-dose FCR appears to be an effective treatment for elderly/comorbid patients with CLL/SLL in first-line as well as R/R setting. Toxicity was acceptable and manageable. In historical comparison, efficacy of low-dose FCR compares favourably with chlorambucil monotherapy and is similar to obinutuzumab-chlorambucil combination from German CLL11 study. Interestingly, neither CIRS score nor creatinine clearance were predictive of PFS/OS. The study is registered at www.clinicaltrials.gov (NCT02156726). Fig 1. Fig 1. Disclosures Smolej: Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Travel grants, Travel grants Other; GlaxoSmithKline: Consultancy, Honoraria, Travel grants, Travel grants Other; Roche: Consultancy, Honoraria, Research Funding, Travel grants Other. Brychtova:Roche: Travel grants Other. Doubek:Roche: Consultancy; GlaxoSmithKline: Research Funding; Janssen: Consultancy. Spacek:Roche: Consultancy, Travel grants Other. Belada:Celgene: Research Funding; Roche: Consultancy, Research Funding, Travel grants, Travel grants Other; GlaxoSmithKline: Research Funding. Motyckova:Roche: Travel grants Other. Prochazka:Roche: Honoraria, Travel grants Other; Takeda: Speakers Bureau. Kozak:Roche: Honoraria, Travel grants Other.

Bendamustine + Rituximab (BR) Chemoimmunotherapy and Maintenance Lenalidomide in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): A Wisconsin Oncology Network (WON) Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3647-3647
Author(s):  
Julie E. Chang ◽  
Chong Zhang ◽  
KyungMann Kim ◽  
Rachel Kirby ◽  
Lynn Volk ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Stable Disease ◽  
Research Funding ◽  
Progressive Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Minor Response ◽  
Grade 3

Abstract Abstract 3647 Introduction: BR chemoimmunotherapy was shown to have an overall response rate (ORR) of 59%, a median progression-free survival (PFS) of 14.7 months, and an acceptable toxicity profile in R/R CLL (Fischer K, et al. J Clin Oncol 2011). Given the single-agent activity of lenalidomide in R/R CLL/SLL, we hypothesized that maintenance lenalidomide after BR induction could improve PFS. Methods: Thirty-four patients requiring therapy for R/R CLL/SLL were treated with bendamustine 90 mg/m2 IV on days 1 & 2 and rituximab 375 mg/m2 IV on day 1 every 28 days for a maximum of 6 cycles. Growth factor support was permitted. Patients achieving at least a minor response (objective improvement even if not meeting criteria for partial response) were eligible to proceed with 12 cycles of maintenance therapy with lenalidomide 5–10 mg/day orally given continuously in each 28-day cycle. Patients were eligible if they had histologically proven CLL/SLL and had received >1 but ≤5 prior cytotoxic chemotherapy regimens (retreatment with an identical regimen was not counted as a separate treatment). The primary endpoint was PFS. Results: Baseline characteristics include median age 67 (range 38–86), 25 men/9 women, 26 CLL/8 SLL, and median of 2 prior therapies (range 1–4). Cytogenetic profiling by FISH analysis was available in 22 patients (65%), with 11/22 demonstrating presence of 17p and/or 11q deletions. Twenty-five patients (74%) completed 6 cycles of induction BR. Two patients died from toxicities of pneumonia and heart failure during cycle 1; 7 patients received <6 cycles due to toxicities (n=4), progressive disease (n=2), and stable disease (n=1). Dose modifications were required in 14 (41%) patients, most commonly for neutropenia (12/14), thrombocytopenia (3/14), and weight loss/failure to thrive (3/14). Grade 3/4 toxicities were primarily hematologic, with neutropenia in 20 patients, anemia in 1, and thrombocytopenia in 7. Febrile neutropenia occurred in 4 patients. Infections with or without neutropenia were common; grade 2 infections in 16 patients, grade 3 in 7 patients. Grade 2 rash occurred in 4 patients. Eleven deaths have been observed, 7 events due to progressive disease (including 2 events of transformed lymphoma). Responses were evaluable in 31/34 patients. The ORR was 65%, with 6 complete (18%) and 16 partial (47%) responses. An additional 7 patients achieving stable disease were eligible to proceed to maintenance therapy. With a median follow up of 20.1 months, the median PFS and overall survival are 24.3 months and 27.9 months, respectively. Conclusions: In our multicenter trial for patients with R/R CLL/SLL, the BR induction produced an ORR that is comparable to historical observations (65% vs 59%). However, the median PFS is longer (24.3 vs 14.7 months), suggesting maintenance lenalidomide may be contributing to an improved response duration. Based upon these promising results, we have initiated a successor study in which patients will receive lenalidomide plus rituximab maintenance after a BR induction. Disclosures: Chang: Celgene: Research Funding; Genentech: Research Funding. Off Label Use: Lenalidomide as maintenance therapy for CLL after induction rituximab + bendamustine chemoimmunotherapy. Fenske:Spectrum Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kahl:Millennium: Consultancy, Research Funding; Roche: Consultancy; Genentech: Consultancy, Research Funding.

scholarly journals A Prospective Economic Analysis of Canadian Cancer Trials Group Clc.2/Alliance A041202: A Randomized Phase III Comparison of Bendamustine-Rituximab Versus Ibrutinib-Based Regimens in Untreated Older Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-30
Author(s):  
Matthew C. Cheung ◽  
Nicole Mittmann ◽  
Carolyn Owen ◽  
Nizar Abdel-Samad ◽  
Graeme Fraser ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Economic Analysis ◽  
Ambulatory Care ◽  
Research Funding ◽  
Time Horizon ◽  
Progression Free Survival ◽  
Medical Costs ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Direct Medical Costs

CCTG CLC.2/Alliance A041202 demonstrated superior progression-free survival at 2 years with ibrutinib alone (87%; HR 0.39) or ibrutinib-rituximab (IR 88%; HR 0.38) compared to chemo-immunotherapy with bendamustine-rituximab (BR 74%) in treatment-naïve patients (pts) with chronic lymphocytic leukemia (CLL) who were 65 or older (Woyach NEJM 2018). We hypothesized that ibrutinib-based therapies would be more costly than BR but that costs would be offset by less toxicity and improved quality of life (QOL). We completed a prospective trial-based economic analysis to study the direct medical costs and quality-adjusted benefit associated with ibrutinib-based therapies compared to BR in the Canadian (CDN) subset of patients enrolled in CLC.2/Alliance 041202. All CDN pts were invited to participate in the companion analysis. Health utilities were collected using the EuroQOL EQ-5D and calculated using CDN population valuations (Bansback PLOS One 2012). Resource utilization forms were administered to collect off-protocol health care encounters. The planned analysis was a cost-utility analysis from the perspective of a public healthcare system, examining the costs and outcomes (quality-adjusted life years or QALYs) of ibrutinib-based therapy compared to BR. Unit costs were applied to resource data based on publicly available provincial/national databases; all costs were expressed in 2019 US dollars (1 CDN = 0.75 US dollar). Total and disaggregated direct medical costs are presented descriptively. Mean survival was calculated using the restricted mean survival method from randomization to the study time-horizon of 24 months; derived utilities were used to calculate QALYs. A discount rate for costs and benefits (r=0.05) was applied. The analysis was based on estimation (with bootstrapping) of an incremental cost-effectiveness ratio (ICER) and/or direct medical costs. A total of 55 pts were enrolled; two pts who did not receive any treatment were censored at day 1 and 3 after randomization and excluded from analysis. Of the 53 analysed, pt demographics were well balanced between treatments and were reflective of the entire population: mean age was 71.6 (SD 6.34) in pts receiving ibrutinib alone (n=17), 72.2 (SD 3.85) in pts receiving IR (n=18), and 71.7 (SD 4.1) in pts receiving BR (n=18). A total of 3 pts, one in each arm, had 17p deletion. Progression-free survival at 2 years for CDN pts was 94% (95% CI 65-99%) for ibrutinib, 100% (95% CI 100-100%) for IR, and 72% (95% CI 45-87%) for BR (Figure 1). At 24 months, 1 pt on the BR arm had crossed over to ibrutinib (as per protocol); there was no overall survival difference between the three arms. On-protocol costs (including protocol treatment, ambulatory care, and imaging) and off-protocol costs (including hospitalizations, concomitant medications, and ambulatory care) are highlighted in Figure 2. On-protocol costs were higher for pts receiving ibrutinib (mean $142,001 USD; SD 48,417) and IR ($164,931; SD 46,208) compared to BR ($38,509; SD 10,351), driven by higher drug acquisition costs associated with ibrutinib (list price $6422 for 420mg/30 days). In contrast, off-protocol costs were modestly higher for pts on BR (mean $3050; SD 3812) compared to the ibrutinib ($2460; SD 3863) or IR ($2890; SD 4206); hospitalizations were the key off-protocol cost drivers and were highest for pts on IR and BR. Overall mean costs over the 2-year time horizon were $144,461 (SD 47,910) for pts on ibrutinib, $167,820 (SD 46,830) for pts on IR, and $41,560 (SD 11,849) for pts on BR. Discounted QALYs were similar between the three treatment arms: 1.66 (0.16) for ibrutinib alone, 1.65 (0.24) for IR, and 1.66 (0.17) for BR. Given the similar quality-adjusted survival between arms at the time of this analysis, a formal ICER was not calculated. Direct medical costs are substantially higher for pts receiving continuous ibrutinib-based therapies, compared to chemo-immunotherapy of fixed duration, in frontline CLL management; the key cost driver is the cost of ibrutinib. The PFS benefit with ibrutinib-based therapy has not translated into an advantage in quality-adjusted survival to date; further follow-up may be required to demonstrate any cost or QOL benefits associated with fewer progression events for those on ibrutinib. Support: U10CA180821, U10CA180882; U10CA180863 and #704970 CCTG. https://acknowledgments.alliancefound.org ClinicalTrials.gov: NCT01886872 Figure Disclosures Owen: AbbVie, F. Hoffmann-La Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva: Honoraria. Lam:Roche: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Crump:Servier: Consultancy; Kite/Gilead: Consultancy; Roche: Consultancy. Sperlich:Lundbeck Canada: Honoraria. Woyach:Pharmacyclics, Janssen, Morphosys, Karyopharm, Verastem, Abbvie, Lox: Research Funding; Janssen, Pharmacyclics, AstraZeneca, Abbvie, Arqule: Consultancy; Pharmacyclics LLC, an AbbVie Company, AbbVie, Janssen, AstraZeneca, ArQule: Honoraria. Prica:astra zeneca: Honoraria; seattle genetics: Honoraria; Gilead: Honoraria. Hay:Roche: Research Funding; Janssen: Research Funding.

Ibrutinib for Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: A Meta-Analysis of Randomized Controlled Trials

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5596-5596
Author(s):  
Shijia Zhang ◽  
Larysa Sanchez ◽  
Jieqi Liu ◽  
Victor Chang ◽  
Stuart L. Goldberg
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Controlled Trials ◽  
Small Lymphocytic Lymphoma ◽  
Bulky Disease ◽  
Free Survival ◽  
Randomized Controlled

Background: Ibrutinib, a Bruton's tyrosine kinase inhibitor, was approved by FDA for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This study aims to evaluate the efficacy and safety data from randomized controlled trials (RCT) of ibrutinib-based therapy in patients with CLL or SLL. Methods: PubMed, ASH, and ASCO databases (2008-2016) were searched for randomized control trials of ibrutinib therapy (either single-agent or combination) for chronic lymphocytic leukemia or small lymphocytic lymphoma through June 30, 2016. Study endpoints included overall survival (OS), progression-free survival (PFS), and adverse events (AE). Pooled hazard ratios (HR) for survival outcomes and relative risks (RR) for dichotomous data with 95% confidence interval (CI) were calculated with a random effect model using MedCalc. Results: Four randomized controlled trials (RESONATE-1, RESONATE-2, HELIOS, and CLL12) were identified, but CLL12 trial was excluded from this study since the efficacy data were not available at the time of this meta-analysis. Pooled data from the 3 RCTs (1238 patients) showed that ibrutinib-based therapy improved overall survival (HR 0.419; 95% CI 0.242-0.725, P = 0.002) and progression-free survival (HR 0.201; 95% CI 0.162-0.251, P < 0.001) compared to regimens without ibrutinib. Subgroup analysis showed that the PFS benefits were independent of sex (male: HR 0.188, 95% CI 0.143-0.249, P < 0.001; female: HR 0.225, 95% CI 0.154-0.331, P < 0.001), Rai stage (0-II: HR 0.154, 95% CI 0.109-0.217, P < 0.001; III-IV: HR 0.235, 95% CI 0.167-0.333, P < 0.001), bulky disease (<5 cm: HR 0.219, 95% CI 0.155-0.309, P < 0.001; ≥5 cm: HR 0.179, 95% CI 0.135-0.238, P < 0.001) or chromosome 11q deletion (positive: HR 0.099, 95% CI 0.060-0.163, P < 0.001; negative: HR 0.261, 95% CI 0.212-0.322, P < 0.001). Ibrutinib-based therapy significantly increased the risk of developing all-grade diarrhea (RR = 2.135, 95% CI = 1.437-3.174, p < 0.001), pyrexia (RR = 1.265, 95% CI = 1.011-1.583, p = 0.040), and arthralgia (RR = 1.863, 95% CI = 1.101-3.152, p = 0.020), but not anemia (RR = 0.955, 95% CI = 0.694-1.313, p = 0.777), neutropenia (RR = 1.048, 95% CI = 0.760-1.446, p = 0.774), fatigue (RR = 0.897, 95% CI = 0.746-1.078, p = 0.247), or nausea (RR = 0.951, 95% CI = 0.600-1.506, p = 0.829). Conclusions: Ibrutinib-based therapy significantly improves OS and PFS (independent of sex, Rai stage, bulky disease or chromosome 11q deletion) in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, but increases the risks of all-grade adverse events including diarrhea, pyrexia, and arthralgia. Disclosures Chang: Johnson and Johnson: Other: Stock; Amgen: Other: Research; Boehringer Ingelheim: Other: Research. Goldberg:Neostem: Equity Ownership; Bristol Myers Squibb, Novartis: Speakers Bureau; COTA Inc: Employment; Pfizer: Honoraria; Novartis: Consultancy.

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