A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2048-2048 ◽  
Author(s):  
Carlos I. Amaya-Chanaga ◽  
Michael Y. Choi ◽  
Natalie Nguyen ◽  
Elizabeth DeVore ◽  
Colin MacCarthy ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Response Assessment ◽  
Lymphocytic Leukemia ◽  
Multiparameter Flow Cytometry ◽  
Phase Ib ◽  
Overall Response ◽  
Grade 3

Abstract Standard treatment for patients (pts) with chronic lymphocytic leukemia (CLL) is rapidly evolving and gradually has incorporated the use of monoclonal antibodies (mAbs) and targeted therapy with small molecules. Single agent Ibrutinib (a first-in-class BTK inhibitor) has shown to be effective in previously untreated (PU) pts including those that are older than 65 or considered unfit to receive chemotherapy-based combinations. The response rate could be higher in pts receiving ibrutinib (overall response of 71% and complete response of 13%) but the mobilization of lymphocytes, which is typically asymptomatic, decreases the response rate due to lack of complete fulfillment of iwCLL criteria. Ibrutinib-induced lymphocytosis could be ameliorated by using mAbs like rituximab or obinutuzumab-Gazyva (G), a third-generation anti-CD20 mAb, and consequently increased the overall response rate. However, there are no data available assessing the combination of ibrutinib and G in the elderly population (> 65 years old) or in those pts < 65 years old where chemotherapy based agents are not indicated. Accordingly, we initiated an open-label phase Ib/II clinical study of Ibrutinib in combination with G for therapy of PU pts with CLL. The study will enroll 32 PU pts with CLL. Pts receive G administered based on FDA dosing recommendations for 6 cycles (28 days/cycle) and Ibrutinib 420mg po. qd for up to 3 years. All pts receive prophylactic medications (acyclovir, allopurinol and low dose glucocorticoids). Pts will undergo response assessment two months after completion of the study treatment by iwCLL criteria, and will be followed for survival during 3 years until initiation of new treatment for CLL, disease progression, consent withdrawal or death, whichever occurs first. Here we present a preliminary analysis of safety / tolerability with the first 9 pts treated with this regimen. The median age of the pts was 63 years ± 8.6. 78% of the pts had a CIRS > 6, 44% had a Rai stage III-IV and 33% had an ECOG performance >2. The median baseline absolute lymphocyte count (ALC) was 96.6 ± 20.2 x103/mm3. Pts showed the following cytogenetic abnormalities: del(13q) in 67%, trisomy 12 in 22% and del(11q) in 11%. None of these pts showed del(17p). Most adverse events (AEs) were grade 1-2 (94%) without development of dose-limiting toxicities. Only one pt (11%) had a grade 1 G-infusion-related reaction (IRR). We did not observe grade 3-4 IRR. We observed neutropenia (all grades: 33%, grade 3-4: 22%), thrombocytopenia (all grades: 78%, grade 3-4: 11%) and anemia (all grades: 44%). 78% of the pts had a decrease in ALC during the first cycle of treatment and two pts had persistent lymphocytosis up to cycle three. There were no cases of febrile neutropenia. Two pts (22%) had grade 1-2 bleeding (one pt with asymptomatic lower gastrointestinal bleeding and the second pt with epistaxis) that resolved spontaneously without requirement of blood transfusion or study treatment discontinuation. One pt (11%) developed community-acquired pneumonia requiring inpatient treatment with IV antibiotics; the study treatment was held until resolution of symptoms and re-initiated at full dose. The most frequent non-hematological AEs were diarrhea, transaminitis, hyperbilirubinemia, hyperglycemia, and electrolyte alterations (grade 1-2). Two pts were evaluable for response assessment by iwCLL criteria. One pt achieved a complete remission with MRDpositivein the bone marrow by multiparameter flow cytometry and the other pt had a partial response due to small residual lymph nodes > 1.5 cm. Overall, Ibrutinib-G combination has been well tolerated. All 9 pts have had favorable clinical and hematological responses. We observed a resolution of the lymphocytosis in 78% of the pts during the first cycle of treatment. We did not observe unexpected AEs with this regimen allowing all 9 pts to continue in the study. The most important finding thus far has been the very low rate of IRR, only one pt (11% - grade 1), and the absence of grade 3-4 IRR, suggesting that ibrutinib can strongly mitigate the incidence and severity of IRR with G. Pt enrollment continues and updated information will be presented at the meeting. Disclosures Hilger-Rolfe: Pharmacyclics: Employment; AbbVie: Employment. Kipps:AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria.

A Phase Ib/II Study of Combined Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) As Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2051-2051 ◽  
Author(s):  
Januario E. Castro ◽  
Michael Y. Choi ◽  
Carlos I. Amaya-Chanaga ◽  
Natalie Nguyen ◽  
Colin MacCarthy ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
High Dose ◽  
Free Survival ◽  
Phase Ib ◽  
High Dose Methylprednisolone ◽  
Grade 3

Abstract High-dose methylprednisolone (HDMP) and rituximab (R) is an effective non-myelosuppressive treatment regimen for patients (pts) with chronic lymphocytic leukemia (CLL). Also, this combination has shown activity even in pts who have adverse leukemia-cytogenetics, such as del17p. Phase III studies have demonstrated that CLL pts treated with chlorambucil and obinutuzumab-Gazyva (G), another anti-CD20 mAb, had a superior outcome than comparable pts treated with R-chlorambucil. We hypothesized that G-HDMP is well-tolerated and effective in the treatment of pts with CLL. Accordingly, we initiated an open-label phase Ib/II clinical study. A total of 40 pts were enrolled in two cohorts of 20 pts each (previously untreated (PU) and relapsed/refractory (RR) CLL) and treated with HDMP 1 g/m2on Day 1-3 of cycles 1-4 (28 days/cycle) and G administered based on FDA dosing recommendations for 6 cycles. The pts had a median age of 67 years + 9.1 in the RR cohort and 63 years + 8.3 in the PU cohort. The median baseline absolute lymphocyte count was 30.7 + 7.3 x1,000/mm3 for pts in the RR cohort and 47.6 + 19.7 x1,000/mm3for pts in the PU cohort. Pts showed the following cytogenetic abnormalities: del(17p) in 30% RR vs. 0% PU, del(13q) in 60% RR vs. 70% PU, del(11q) in 20% RR vs. 35% PU, and trisomy 12 in 15% RR vs. 20% PU. Most AEs were grade 1-2 (RR=87%; PU=93%) without development of dose-limiting toxicities. Only two pts needed therapy discontinuation. One pt due to pulmonary embolism and the second pt due to asymptomatic gastrointestinal bleeding that required blood transfusion and resolved spontaneously. Grade 1-2 G-infusion-related reactions (IRR) were observed in 40% and 80% of pts in the RR and PU cohorts, respectively. Grade 3-4 IRR were observed in 10% of pts in the PU cohort only. We observed cytopenias (neutropenia grade 3-4: RR=55%, PU=40%; thrombocytopenia grade 3-4: RR=35%, PU=20%; and anemia grade 3-4: RR=0%, PU=0%). There were no cases of febrile neutropenia. Two pts (10%) in the RR cohort and one pt (5%) in the PU cohort developed infection grade 1-2 that was treated with oral antibiotics but did not require study treatment discontinuation. The most frequent non-hematological adverse events (AEs) were transaminitis, hyperglycemia, and electrolyte alterations (grade 1-2). There were no treatment related deaths in either cohort. The response assessment was performed in all 40 pts by iwCLL criteria. The ORR was 100% in the PU cohort and 95% in the RR cohort. 70% of the pts in the PU cohort and 85% of the pts in the RR cohort achieved a PR. CR was observed in 30% and 10% of the pts in the PU and RR cohorts, respectively. One pt (5%) in the RR cohort and four pts (20%) in the PU cohort achieved MRDneg status (<0.01% CLL in the bone marrow by multiparameter flow cytometry). Only one pt in the RR cohort achieved SD. At a median follow-up of 12.2 months, the RR cohort had a median Progression Free Survival (PFS) of 13.6 months and median Treatment Free Survival (TFS) of 14.7 months; the median Overall Survival (OS) has not been reached. In the PU cohort, the median PFS, TFS and OS have not been reached. One pt from the RR cohort and one pt from the PU cohort died during the follow-up period due to disease progression. G-HDMP was well tolerated and all 40 pts showed hematological and clinical responses during the study treatment without development of unexpected AEs. In both cohorts, most of IRR were grade 1-2 and severe IRR (grade 3-4) were much less compared with previously published data (G-chlorambucil / CLL-11 study). Compared to pts in the CLL-11 study, cytopenias appeared to be more frequent, however, the rate of infection and need for IV antibiotics or hospitalizations was lower. Of note, the eligibility criteria allowed pts with severe cytopenias and transfusion requirement to participate in our study. Response in PU pts were higher in terms of ORR, CR and CR-MRDnegativecompared with the data from the CLL-11 study and suggests a possible synergistic activity between G and HDMP. Overall, G-HDMP was well tolerated in the PU and RR CLL pts with a lower rate of IRR making this regimen more manageable in the outpatient setting. Responses were higher than previously reported in PU pts. Responses in RR pts appear to be comparable to our previous studies using R-HDMP. Our data supports G-HDMP as an alternative combination regimen for the treatment of CLL pts. Disclosures Kipps: Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria.

Five-Year Experience with Single-Agent Ibrutinib in Patients with Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 233-233 ◽  
Author(s):  
Susan M. O'Brien ◽  
Richard R. Furman ◽  
Steven E. Coutre ◽  
Ian W. Flinn ◽  
Jan Burger ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Over Time

Abstract Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton's tyrosine kinase inhibitor, is approved by the US FDA for treatment of patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including pts with del17p. The phase 1b/2 PCYC-1102 trial showed single-agent efficacy and tolerability in treatment-naïve (TN; O'Brien, Lancet Oncol 2014) and relapsed/refractory (R/R) CLL/SLL (Byrd, N Engl J Med 2013). We report efficacy and safety results of the longest follow-up to date for ibr-treated pts. Methods: Pts received 420 or 840 mg ibr QD until disease progression (PD) or unacceptable toxicity. Overall response rate (ORR) including partial response (PR) with lymphocytosis (PR-L) was assessed using updated iwCLL criteria. Responses were assessed by risk groups: unmutated IGVH, complex karyotype (CK; ≥3 unrelated chromosomal abnormalities by stimulated cytogenetics assessed by a reference lab), and in hierarchical order for del17p, then del11q. In the long-term extension study PCYC-1103, grade ≥3 adverse events (AEs), serious AEs, and AEs requiring dose reduction or discontinuation were collected. Results: Median age of the 132 pts with CLL/SLL (31 TN, 101 R/R) was 68 y (range, 37-84) with 43% ≥70 y. Baseline CK was observed in 41/112 (37%) of pts. Among R/R pts, 34 (34%) had del17p, 35 (35%) del11q, and 79 (78%) unmutated IGVH. R/R pts had a median of 4 prior therapies (range, 1-12). Median time on study was 46 m (range, 0-67) for all-treated pts, 60 m (range, 0-67.4) for TN pts, and 39 m (range, 0-67) for R/R pts. The ORR (per investigator) was 86% (complete response [CR], 14%) for all-treated pts (TN: 84% [CR, 29%], R/R: 86% [CR, 10%]). Median progression-free survival (PFS) was not reached (NR) for TN and 52 m for R/R pts with 60 m estimated PFS rates of 92% and 43%, respectively (Figure 1). In R/R pts, median PFS was 55 m (95% confidence intervals [CI], 31-not estimable [NE]) for pts with del11q, 26 m (95% CI,18-37) for pts with del17p, and NR (95% CI, 40-NE) for pts without del17p, del11q, trisomy 12, or del13q. Median PFS was 33 m (95% CI, 22-NE) and NR for pts with and without CK, and 43 m (95% CI, 32-NE) and 63 m (95% CI, 7-NE) for pts with unmutated and mutated IGVH, respectively(Figure 2). Among R/R pts, median PFS was 63 m (95% CI, 37-NE) for pts with 1-2 prior regimens (n=27, 3 pts with 1 prior therapy) and 59 m (95% CI, 22-NE) and 39 m (95% CI, 26-NE) for pts with 3 and ≥4 prior regimens, respectively. Median duration of response was NR for TN pts and 45 m for R/R pts. Pts estimated to be alive at 60 m were: TN, 92%; all R/R, 57%; R/R del17p, 32%; R/R del 11q, 61%; R/R unmutated IGVH, 55%. Among all treated pts, onset of grade ≥3 treatment-emergent AEs was highest in the first year and decreased during subsequent years. With about 5 years of follow-up, the most frequent grade ≥3 AEs were hypertension (26%), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%). Study treatment was discontinued due to AEs in 27 pts (20%) and disease progression in 34 pts (26%). Of all treated pts, 38% remain on ibr treatment on study including 65% of TN pts and 30% of R/R pts. Conclusions: Single-agent ibrutinib continues to show durable responses in pts with TN or R/R CLL/SLL including those with del17p, del11q, or unmutated IGVH. With extended treatment, CRs were observed in 29% of TN and 10% of R/R pts, having evolved over time. Ibrutinib provided better PFS outcomes if administered earlier in therapy than in the third-line or beyond. Those without CK experienced more favorable PFS and OS than those with CK. Ibrutinib was well tolerated with the onset of AEs decreasing over time, allowing for extended dosing for 65% of TN and 30% of R/R pts who continue treatment. Disclosures O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Furman:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Coutre:Janssen: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Burger:Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses. Sharman:Gilead: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Wierda:Abbvie: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luan:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses. James:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Chu:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership.

Bendamustine in Combination with Rituximab (BR) for Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): A Multicentre Phase II Trial of the German CLL Study Group (GCLLSG)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 330-330 ◽  
Author(s):  
Kirsten Fischer ◽  
Stephan Stilgenbauer ◽  
Carmen D Schweighofer ◽  
Raymonde Busch ◽  
Jasmin Renschler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Lymphocytic Leukemia ◽  
Study Group ◽  
Overall Response ◽  
Grade 3

Abstract Introduction: Bendamustine, an alkylating agent with additional properties of a purine analogue, has shown considerable activity in monotherapy for solid and 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 clinical results have been obtained using BR combination treatment in relapsed/refractory and previously untreated Non-Hodgkin’s lymphoma. This phase II trial represents the first study evaluating the efficacy and toxicity of bendamustine in combination with rituximab in patients (pts) with relapsed or refractory CLL. Patients and Methods: 81 pts with a median number of 2 (1–3) pretreatments were enrolled between March 2006 and June 2007. Patients received 70 mg/m² bendamustine on day 1 and 2 combined with 375mg/m² rituximab for the first cycle and 500 mg/m² for the second and subsequent cycles. BR treatment was administered every 28 days for up to 6 courses. Blood samples were taken for molecular cytogenetics by fluorescence in situ hybridization (FISH) and analysis of the immunoglobulin heavy chain (IgVH) mutational status prior to the first treatment course. Assessment for minimal residual disease (MRD) was performed by four-colour flow cytometry of peripheral blood and bone marrow. Primary endpoint of the trial was the overall response rate (ORR). Secondary endpoints included toxicity, duration of response, event-free survival, MRD response rate and overall response rate in biological defined risk groups. Results: 81 pts (mean age 66.7 years) received a total of 328 treatment cycles. A mean number of 4.5 courses was administered. In total 123 CTC grade 3/4/5 adverse events were reported, most frequently on myelosuppression and infections: grade 3/4 anemia occurred in 6.1%, grade 3/4 leukopenia/neutropenia and thrombocytopenia in 11.9% and 9.1% of all given courses, respectively. 16 episodes (4.9%) of CTC grade ≥3 infections were documented, most of them could be successfully managed. However, treatment related mortality occurred in 3.7% of pts: three pts died due to severe infections associated with treatment related neutropenia including 1 fatal pneumonia, one sepsis after diagnosis of Richter’s syndrome and 1 urosepsis. In 62 pts data for response assessment were available: 19 pts were not evaluable for response due to withdrawal or missing of consent, violation of enrolment criteria or early discontinuation of therapy. The overall response was 77.4% with complete remissions (CR) in 14.5% (9 pts) and a partial response (PR) in 62.9% of pts (39 pts). An MRD level below 10E-4 was measured after completion of therapy in 2 of 30 evaluable pts in peripheral blood, while none of the pts achieved MRD negativity in bone marrow. Stable disease (SD) was achieved in 17.7% (11 pts) whereas 3 pts (4.8%) had progressive CLL (PD). Differences in response were observed among genetic subgroups: 12 of 13 pts with 11q- achieved a remission with 11 PR and 1 CR (ORR: 92.3%). Accordingly, 8 of 8 patients with +12 responded (7 PR, 1 CR). In the high-risk group with 17p-, four of nine pts showed a partial remission (ORR: 44,4%). 29 of 39 pts (ORR: 74.4%) with unmutated IgVH status were responsive to BR. Conclusion: Bendamustine plus rituximab is an effective treatment regimen for pts with relapsed and/or refractory CLL and has notable activity in high-risk CLL disease. Major but tolerable treatment toxicities were myelosuppression and infections. Ongoing trial follow-up analysis will define response duration and long-term safety. In a forthcoming trial the German CLL Study group will investigate the efficacy of BR in comparison to fludarabine-based immunochemotherapy (FCR) for first-line treatment of CLL.

The Combination of Lenalidomide and Rituximab Induces Complete and Partial Responses In Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1395-1395 ◽  
Author(s):  
Alessandra Ferrajoli ◽  
Xavier Badoux ◽  
Susan O'Brien ◽  
William G. Wierda ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Cytotoxic T Cell ◽  
Tumor Lysis ◽  
Significant Difference ◽  
Grade 3

Abstract Abstract 1395 Lenalidomide is an immunomodulatory drug with single-agent activity in untreated and relapsed patients (pts) with chronic lymphocytic leukemia (CLL). Lenalidomide may potentiate the activity of rituximab through enhancement of NK and cytotoxic T-cell activity and antibody-dependent cytotoxicity. As lenalidomide is active as single-agent in relapsed/refractory CLL, we designed a trial to evaluate the combination of lenalidomide and rituximab in pts with previously treated CLL. Between 09/2008 and 10/2009, 59 pts with relapsed or treatment-refractory CLL were enrolled in this Phase II trial. Pts were eligible if they had relapsed disease requiring treatment and had received prior fludarabine-based therapy. Pts were required to have adequate performance status (WHO <3) and adequate renal and liver function (serum Cr or bilirubin <2mg/dl). Pts with an unrelated malignancy or with HIV, hepatitis B or C infection were excluded. Rituximab 375 mg/m2 was given intravenously weekly × 4 from Day 1 in Cycle 1 then every 4 weeks during cycles 3 – 12. Oral lenalidomide 10 mg/day was started on Day 9 of cycle 1 on a continuous dosing schedule. Cycles were 28 days with intention to continue therapy for 12 cycles or longer if the patient experienced a clinical response. Dose reductions were made following grade 3 or 4 lenalidomide-related toxicity. Allopurinol 300mg daily was prescribed during the first 2 weeks as tumor lysis prophylaxis. Response evaluation was performed with after cycles 3, 6 and every 6 cycles thereafter using 2008 IWCLL response assessment guidelines. Toxicity was graded according to CTC-v3.0 criteria. All 59 pts are evaluable for response and clinical outcome. Patient pre-treatment characteristics are shown in Table 1. All pts had prior rituximab therapy and 52 (88%) pts had prior chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR). The overall response rate was 64% with 5 complete responses (CR, 8%), 3 CR with incomplete hematological recovery (CRi, 5%), 7 nodular partial remissions (nPR, 12%) and 23 PR (39%). Most response (32/38, 84%) occurred by 3 cycles of therapy, but the majority of CR/CRi (7 of 8, 88%) occurred after 6 cycles of therapy. At a median follow-up of 14 months, the estimated treatment failure rate was 42% and estimated overall survival (OS) was 90%. There was no significant difference in responses or TTF for pts with deletion 17p when compared to other FISH subgroups. Two deaths occurred while on study therapy, one due to ischemic stroke and one to infectious exacerbation of chronic obstructive pulmonary disease. Six deaths occurred after progression of disease during subsequent therapies. Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 40 (68%), 13 (22%) and 6 (10%) pts, respectively. Grade 3/4 infections occurred in 18 pts (31%), mostly lower respiratory tract. Seventy-three % of pts required a dose reduction of lenalidomide with a median tolerated daily dose of 5mg (2.5mg – 10mg). One patient experienced a grade 3 tumor lysis syndrome and 22 pts had grade 1–2 tumor flare reactions. In conclusion, combination therapy with lenalidomide and rituximab induces both complete and partial responses as salvage therapy in CLL. The addition of rituximab to lenalidomide appears to improve responses relative to single agent lenalidomide (Ferrajoli 2008, Chanan-Khan 2006) despite all pts having received prior rituximab-based therapies. This treatment was well tolerated with the most common toxicity being myelosuppression. Disclosures: Ferrajoli: Celgene: Research Funding; Genentech: Research Funding. Off Label Use: The use of lenalidomide in the treatment of chronic lymphocytic leukemia. O'Brien:Celgene: Consultancy; Genentech BioOncology: Consultancy. Wierda:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Advisory Board, Consultancy, Speakers Bureau. Estrov:Celgene: Consultancy. Keating:Celgene: Consultancy; Genentech: Consultancy.

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.

Preliminary Results of a Phase II Open-Label, Randomized Study of the BH3 Mimetic Protein Navitoclax (ABT-263) with or without Rituximab for Treatment of Previously Untreated B-Cell Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 190-190 ◽  
Author(s):  
Herbert Eradat ◽  
Sebastian Grosicki ◽  
John Catalono ◽  
Walter Cosolo ◽  
Irina Dyagil ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rate ◽  
Response Assessment ◽  
Lymphocytic Leukemia ◽  
Preliminary Results ◽  
Binet Stage ◽  
Bh3 Mimetic

Abstract Abstract 190 Introduction: Overexpression of Bcl-2 in Chronic Lymphocytic Leukemia (CLL) is associated with enhanced CLL-cell resistance to spontaneous or chemotherapy-induced apoptosis. The BH3 mimetic protein navitoclax (ABT-263) specifically inhibits Bcl-2, and related proteins Bcl-xL and Bcl-w, and can induce apoptosis of CLL cells in vitro. Phase I evaluation in relapsed/refractory CLL patients demonstrated 35% overall response rate (Roberts, 2012). Dose-limiting thrombocytopenia due to Bcl-xL inhibition was mitigated using a lead-in dosing schedule to allow the bone marrow to achieve a compensatory increase in platelets prior to dose escalation to the MTD of 250 mg. Based on the promising single-agent data, a Phase II trial randomized trial compared the safety, pharmacokinetics, and biologic activity of treatment with navitoclax and rituximab (RTX) versus RTX alone. Methods: Patients with CLL who required initial treatment according to iwCLL criteria (Hallek et al, 2008) were stratified by Binet stage and high-risk cytogenetic features (17p deletion and/or 11q deletion), and randomized 1:1:1 to receive RTX weekly for 8 wks (375 mg/m2 wk 1, 500 mg/m2 wks 2–8) (Arm A), or RTX for 8 wks plus navitoclax daily for 12 wks (250 mg/day following a 7–14 day lead-in period of 100 mg/day) (Arm B), or RTX for 8 wks plus navitoclax daily as in Arm B, but continued treatment with navitoclax until disease progression, relapse, or unacceptable toxicity (Arm C). Arm A to Arm B crossover was permitted. Response rate was assessed by iwCLL CLL response criteria at week 12, and every 12 weeks during follow-up. The study was stopped after the last patient had completed ≥ 12 weeks of treatment and week-12 response assessment. Results: Baseline characteristics and prognostic factors for the 118 randomized patients were generally balanced among the three treatment arms. Median age was 63 years (range 38–94), and 55% were Binet stage B+C. Median baseline lymphocyte count was 53,000 mm3 (range 7,000–552,000/mm3). FISH analyses identified higher than expected rates of deletion of 11q or 17p in the CLL cells of 32% or 28% of patients, respectively. Median time on study was 32 weeks overall (24 wks for Arm A, 33 wks Arm B, and 44 wks Arm C). AEs of Grade 3–4 that were more common (> 5% greater) in a navitoclax-treated arm compared with the RTX arm included thrombocytopenia, neutropenia, leukopenia, anemia, GI symptoms (diarrhea, abdominal pain), chills, fatigue, ALT/AST/bilirubin elevations, and infusion-related reactions (to RTX). Thrombocytopenia, neutropenia, and hepatic enzyme elevations were generally reversible when navitoclax was stopped and/or dose-reduced; however, 12 patients (15%) discontinued navitoclax due to laboratory abnormalities (9 due to ALT elevations). Neutropenia responded to growth factors. One serious event of epistaxis occurred related to the thrombocytopenia. Two deaths occurred on study, one on the RTX-only arm due to a pulmonary embolus and one on Arm B due to hypotension and dyspnea related to a severe RTX infusion reaction. Investigator-assessed objective response (CR and PR) rate was 35% for Arm A, 55% for Arm B (p=0.19 vs A), and 70% for Arm C (p=0.0034 vs A). All responses were PRs except for 2 CRs in Arm C. All responses were confirmed by CT (and BM for CR) ≥ 8 wks after clinical response assessment. While the presence of 17p deletion appeared to result in a lower response rate to RTX alone (Arm A, ORR 18%, 2/11 pts), it did not appear to affect the response to ABT-263 and RTX (Arm B, ORR 73%, 8/11 pts); Arm C, ORR 50%, 5/10 pts. Limited PFS results appeared consistent with the responses by arm, with a longer PFS associated with the longer duration of ABT-263 treatment on Arm C; however, the magnitude of PFS differences could not be precisely quantified due to the limited follow-up and patient number. Preliminary pharmacokinetic analysis did not detect any drug interaction between navitoclax and RTX. Conclusions: Navitoclax in combination with RTX weekly × 8 was generally well-tolerated as initial therapy for CLL patients and demonstrated greater clinical activity than treatment with RTX alone as well as responses in patients with 17p deletion. The preliminary results of this study indicate that a BH3-mimetic inhibitor of Bcl-2 could be highly effective when used in combination with RTX for treatment of patients with CLL. Disclosures: Eradat: Genentech: Research Funding. Off Label Use: BH3 Mimetic Protein Navitoclax (ABT-263). Catalono:Genentech: Consultancy. Kipps:Genentech: Research Funding. Zheng:Genentech: Employment. Yalamanchili:Genentech: Employment. Sahasranaman:Genentech: Employment. Hurst:Genentech: Employment. Ho:Genentech: Employment.

Long-Term Follow-up of a Phase 2 Study of Single Agent Lenalidomide in Previously Untreated, Symptomatic Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 718-718
Author(s):  
Christine Chen ◽  
Harminder Paul ◽  
Trina Wang ◽  
Lisa W Le ◽  
Vishal Kukreti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3

Abstract Abstract 718 Introduction: In a previously reported phase 2 study of single agent lenalidomide in 25 untreated CLL patients (pts), we reported an overall response rate (ORR) of 56% (14 pts), 40% SD (10 pts) and no CR at a median follow-up of 20.7 months (Chen et al. JCO 2010;29:1175). Although an amended protocol with conservative lenalidomide dosing was used to mitigate tumor lysis and severe myelosuppression observed in the first 2 accrued pts, we continued to observe frequent toxicities of grade 3–4 neutropenia (72%) and tumor flare (TF 88%). We now report long-term efficacy and toxicity from this study at a median follow-up of 47 months (mos). Methods: Patients were eligible if previously untreated and symptomatic (cytopenias, symptomatic adenopathy/organomegaly, constitutional symptoms, lymphocyte doubling count <12 mos). The amended starting dose for lenalidomide was 2.5mg daily on days 1–21 of a 28 day cycle, with slow monthly dose escalations (2.5mg cycle 1, 5mg cycle 2, 10mg cycle 3 and if required for response, further 5mg increments to a maximum of 25mg daily were allowed). Results: Longterm toxicities: Hematologic toxicities were common: grade 3–4 neutropenia (76%), thrombocytopenia (28%), anemia (20%). With longer term use, neutropenia tended to recur (12% of all cycles) and 10 pts required GCSF support (5 routinely during each cycle). Most common non-hematologic toxicities (all grades) were TF (88%), fatigue (76%), rash (60%), muscle cramping (40%), diarrhea (40%). All non-hematologic toxicities were mild (grade 1–2), except for 1 pt each with grade 3 rash and diarrhea. Although TF was most common during cycle 1, repeat flare symptoms upon resuming lenalidomide after the 7 day rest period of each cycle were noted in 16% of all 898 cycles administered, and as late as at cycle 28. Infections were mild (most respiratory, skin) with only 2 grade 3 events (disseminated zoster, S.pneumoniae bacteremia). Other malignancies: 2 pts developed transformed large cell lymphoma 7 and 18 mos after study discontinuation, 1 pt developed squamous cell carcinoma of skin at cycle 51, and 1 pt developed recurrence of remote non-small cell lung cancer at cycle 34. Dose modifications/discontinuation: The median highest dose achieved for all 25 pts was 15 mg (range 2.5–25 mgs); 8 pts were able to escalate to the maximal 25mg dose. Ten pts (40%) required dose reductions for grade 3 cytopenias [neutropenia (2), thrombocytopenia (2), both (2)], febrile neutropenia (2), and diarrhea (2). Of all 25 pts, the median duration on therapy was 31.1 mos (range 28 days – 60.6 mos). Twelve pts (52%) currently remain on study, receiving a median of 59 cycles of therapy (range 48–66). Causes of discontinuation for 13 pts included: treatment-related toxicity (8), lack of response/progressive disease (4), and recurrence of remote lung cancer (1). Toxicities leading to discontinuation included: prolonged cytopenias (3), recurrent infections (1), atrial fibrillation (1), disseminated herpes zoster (1), persistent grade 2 diarrhea (1), and grade 3 skin rash (1). Efficacy: With extended median follow-up from 20.7 to 47 mos, the ORR improved from 56% (14 pts) to 72% (18 pts), with 3 pts in PR upgrading to CR, and 1 SD to PR. Although the median time to response was 7.7 mos, responses occurred as quickly as 1.8 mos to as late as 27.0 mos of therapy. For the 3 CR pts, prolonged therapy with an additional 14.9, 28.3 and 40.6 mos beyond the time of first response was required to achieve CR. To date, 7 pts have progressed with 3-year PFS 68.8% (95% CI:52–91%) and OS 85.3% (95% CI:71.1–100%). Correlatives: Cereblon (CRBN), recently identified as a direct protein target of lenalidomide, was evaluated by gene expression profiling and Western blot and found to be uniformly expressed in all 19 evaluable day 1 pt samples regardless of lenalidomide response. Thus, baseline CRBN expression does not appear to be a useful predictive biomarker of response in this population. The mechanism by which CRBN is linked to response is reported by Trudel et al, ASH 2012. Conclusions: Long-term followup of this study demonstrates that when using low doses of single agent lenalidomide in CLL, prolonged therapy is feasible and may be required for the achievement of durable, high quality responses. Maximal daily doses of 25mg can be reached and may also be needed for optimal response, though recurrent myelosuppression remains limiting. Disclosures: Chen: Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Lundbeck: Consultancy; Janssen: Consultancy, Research Funding. Off Label Use: Lenalidomide is not approved for use in chronic lymphocytic leukemia. Kukreti:Roche: Honoraria; Celgene: Honoraria; Janssen Ortho: Honoraria. Trudel:Celgene: Honoraria, Research Funding, Speakers Bureau.

scholarly journals A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1863-1863
Author(s):  
Juliana Velez Lujan ◽  
Michael Y. Choi ◽  
Chaja Jacobs ◽  
Colin McCarthy ◽  
Alaina Heinen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Grade 3

Abstract Standard treatment for patients with chronic lymphocytic leukemia (CLL) is rapidly evolving and gradually has incorporated the combined use of monoclonal antibodies (mAbs) and targeted therapy with small molecules. Single agent Ibrutinib (Ibr), a first-in-class BTK inhibitor, is effective in previously untreated patients including those that are older than 65 or considered unfit to receive chemotherapy-based combinations. The complete response rate in patients receiving single agent Ibr is relatively low (overall response rate of 86% and complete response of 4% based on 2008 iwCLL criteria), though most patients have durable remissions. The combination of Ibr with mAbs like Obinutuzumab-Gazyva (G), a third-generation anti-CD20 mAb, can ameliorate the Ibr-induced lymphocytosis and increase the overall and complete response rates. Accordingly, we initiated an open-label phase Ib/II clinical study of Ibr in combination with G for first-line therapy of previous untreated pts with CLL. The study completed enrollment of 32 previously untreated patients with CLL. Patients received G administered based on FDA dosing recommendations for 6 cycles (28 days/cycle) and Ibr 420mg po (1-3 hours before starting G infusion), and daily for up to 3 years. All patients received prophylactic medications. Patients were assessed for response by 2008 iwCLL criteria two months after completion of G, as the primary efficacy endpoint. The median age of the patients was 65 (range: 46-78) years. 84% of the patients had a CIRS >6, 45% had a Rai stage III-IV and 19% had an ECOG performance ≤2. The median baseline absolute lymphocyte count (ALC) was 79x103/mm3(range: 1.4-412.4). Patients showed the following FISH/cytogenetic abnormalities: del(13q) in 55%, trisomy 12 in 23% and del(11q) in 19%. Only 2 (6%) of these patients showed del(17p). From the patients with IGVH mutational status available (n=17), 11 (65%) were unmutated (>98% homology). Most adverse events (AEs) were grade 1-2 (74%). Six patients (19%) had grade 1-2 G-infusion-related reaction (IRR) and only one patient (3%) showed grade 3 IRR (without the need for G discontinuation). We observed neutropenia (all grades: 52%, grade 3-4: 23%), thrombocytopenia (all grades: 71%, grade 3-4: 19%) and anemia (all grades: 26%). There were no cases of febrile neutropenia. Two patients (6%) had grade 1 bleeding (one patient with asymptomatic lower gastrointestinal bleeding and the second patient with epistaxis) that resolved spontaneously without requirement of blood transfusion or study treatment discontinuation. Two patients (6%) developed pneumonia, one was community-acquired pneumonia requiring inpatient treatment with IV antibiotics; the study treatment was held until resolution of symptoms and re-initiated at full dose. The most frequent non-hematological AEs were diarrhea, transaminitis, hyperbilirubinemia, hyperglycemia, and electrolyte alterations (grade 1-2). Three patients (9%) discontinued Ibr due to atrial fibrillation grade 1 (n=1), rash and headaches grade 2 (n=1), and persistent grade 4 thrombocytopenia (n=1). Twenty-three patients were evaluable for response assessment by 2008 iwCLL criteria (median follow-up of 11 months). 84% of the patients showed a rapid decrease in ALC from baseline during the first cycle of treatment and only four patients (13%) required more than 3 cycles of treatment to achieve an ALC response. The overall response rate was 100%. The majority of pts had a partial response and six of 23 evaluable patients (26%) achieved a complete remission with detectable Minimal Residual Disease in the bone marrow by multiparametric flow cytometry. In summary, Ibr-G combination has been generally well tolerated. AEs have been consistent with the known safety profiles of Ibr and G individually. The patients that discontinued Ibr remain in follow-up without disease progression. 100% of evaluable patients achieved response after 6 months of combination therapy, and 26% of patients met CR criteria. One important finding thus far has been a very low rate of IRR, (19% grade 1-2 and 3% grade 3-4), suggesting that Ibr can strongly mitigate the incidence and severity of G associated IRR. Disclosures Choi: AbbVie, Inc: Consultancy, Speakers Bureau; Rigel: Consultancy; Gilead: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Speakers Bureau. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Kipps:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy; Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Genentech Inc: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Castro:F. Hoffmann-La Roche: Consultancy; Genentech, Inc: Consultancy; Pharmacyclics, LLC, an AbbVie Company:: Consultancy.

Clinical Efficacy of Lenalidomide in Fludarabine-Refractory Chronic Lymphocytic Leukemia Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3108-3108 ◽  
Author(s):  
Asher A. Chanan-Khan ◽  
Myron S. Czuczman ◽  
Swaminathan Padmanabhan ◽  
Michael J. Keating ◽  
Susan M. O’Brien ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
Phase Ii ◽  
Clinical Efficacy ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Refractory Disease ◽  
Overall Response

Introduction: Fludarabine treatment has been shown to be beneficial for patients with Chronic Lymphocytic Leukemia (CLL), and fludarabine-based combinations may even further improve outcomes in patients with CLL. However, most CLL patients eventually become fludarabine refractory, a state which is associated with a relatively short survival. Treatment of fludarabine-refractory patients is challenging, with a median survival of about 10 months. Recently, 2 phase II clinical trials (Chanan-Khan et al. JCO 2006 and Ferrajoli et al. ASH 2006) demonstrated the clinical efficacy of lenalidomide, an immunomodulatory agent, in relapsed/refractory CLL patients. We conducted a subset analysis to examine the efficacy of lenalidomide in patients who are fludarabine refractory. Methods: All patients enrolled on the 2 phase II single agent lenalidomide clinical trials were evaluated and patients with fludarabine-refractory disease (progressed while on or within 6 months of fludarabine-based therapy) were assessed for clinical efficacy of lenalidomide. Lenalidomide was given orally either at 10 mg daily for 28 days followed by 5 mg increments every 28 days to a maximum dose of 25 mg or given at 25 mg on days 1–21 of each 28-day cycle. Response was assessed using the NCI-WG 1996 criteria. Results: A total of 80 patients were collectively enrolled in these clinical studies. Among these, 29 were identified to have fludarabine-refractory disease. Important clinical characteristics of these patients are reported in Table 1. The overall response rate in fludarabine-refractory patients was 34.5% (10/29). Complete remission was observed in 2 (6.8%) patients. Conclusion: Lenalidomide is a novel agent with immunomodulating properties demonstrating clinical efficacy in relapsed or refractory CLL patients. Interestingly, clinical responses to single agent lenalidomide were noted despite refractoriness to fludarabine (a subset of CLL patients with poor survival and limited therapeutic options). This observation of the clinical benefit of lenalidomide independent of responsiveness to prior fludarabine is encouraging and warrants further evaluation. Table 1 Ferrajoli et al. Chanan-Khan et al. Fludarabine-refractory (N=12) Fludarabine-refractory (N=17) ORR, overall response rate; PFS, progression-free survival; OS, overall survival. Median age, years (range) 62 (51–82) 68 (53–75) Sex, female/male 4/8 4/13 Median no. prior therapies (range) 4 (3–15) 4 (1–10) Median beta microglobulin (range) 5 (3–10) 5 (2–10) Advance Rai Stage (III/IV), n (%) 7 (58.3) 13 (76.4) ORR, n (%) 3 (25.0) 7 (41.2) Median PFS, months 12 14.9 Median OS, months All alive (range, 7–19) 23

Retrospective Analysis of the Experience with Rituximab and Methylprednisone In Elderly Patients with CLL

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4636-4636
Author(s):  
Xavier Badoux ◽  
Ali M Al-Ameri ◽  
Susan O'Brien ◽  
William G. Wierda ◽  
Jan A. Burger ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Partial Response ◽  
Elderly Patients ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Chromosome 17 ◽  
High Dose ◽  
Β2 Microglobulin ◽  
Grade 3

Abstract Abstract 4636 Background: Single agent rituximab has limited activity in chronic lymphocytic at standard doses; however, the addition of rituximab to purine analogues, monoclonal antibodies or steroids has been shown to improve responses and response duration in patients with untreated and relapsed chronic lymphocytic leukemia (CLL). The combination of rituximab and high dose methylprednisone has shown activity in patients with untreated and fludarabine-refractory CLL (Castro 2008, Castro 2009); however, there is limited reported experience with this regimen in elderly patients. These data prompted us to review our center's experience with rituximab in combination with high dose methylprednisone in elderly patients with CLL. Patients and Methods: We retrospectively identified 24 patients 65 years or older with CLL who received rituximab and methylprednisone between July 2002 and April 2010 at MD Anderson Cancer Center. Six patients received this treatment as initial therapy and 18 patients as salvage treatment. Rituximab 375–750 mg/m2 and methylprednisone 500–2000 mg were administered i.v. weekly for 4 weeks. Three patients received further maintenance treatment with rituximab 375–750 mg/m2 and methylprednisone 500 mg/m2 every month or every 3 months until failure of response. Responses were assessed according to 2008 NCI-WG criteria. Estimated progression free survival and OS were analyzed from time of treatment to progression or death using Kaplan-Meier survival curves. Results: The median age was 71 (65 – 87) years and 17 of 24 (71%) had Rai stage III or IV disease. Two patients had concomitant autoimmune hemolytic anemia (AIHA), one patient had immune thrombocytopenic purpura and AIHA was the indication for therapy in one patient. Median β2-microglobulin was 7.7 (2.3 – 21) mg/l and 5 patients had chromosome 17 abnormalities. Previously treated patients had received a median of 3 (1 – 7) prior treatments and 6 (32%) pts were refractory to fludarabine. Responses were observed in 4 of 6 untreated patients (ORR 67%) and included 3 clinical complete responses unconfirmed by bone marrow biopsy (CRu, 50%) and 1 partial response. The estimated median PFS and OS in this group were 13 and 55 months, respectively. Among patients who received rituximab and methylprednisone as salvage therapy, 7 patients achieved a partial response (ORR 39%), 10 (50%) patients failed treatment, 1 patient (6%) received another therapy after 1 cycle for lack of response and 1 patient (6%) was lost to follow-up. In the salvage group, estimated median PFS and OS were 4 and 18 months, respectively. Four deaths occurred 3, 5, 11 and 12 months after rituximab and methylprednisone without further therapy; 3 patients had progressive CLL and the cause of death was unknown in 1 patient. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in 6 (33%), 3 (14%) and 1 (5%) of evaluable patients. Four patients (17%) experienced grade 3 or 4 infections (3 pneumonia and 1 colonic abscess), 5 patients experienced minor infections and 3 patients experienced viral reactivations (1 CMV, 1 HSV, 2 VZV). There were four grade 3 or 4 non-hematological adverse events including grade 4 gastrointestinal and pulmonary hemorrhage (1), colitis (1), steroid myopathy (1) and peripheral edema (1). All grade 3 or 4 complication occurred in salvage patients. Conclusions: Based on our experience, rituximab and methylprednisone therapy can be safely administered to older patients with CLL. As previously reported by Castro et al, higher response rates were seen in untreated patients, whereas responses were less frequent and shorter lasting in patients with relapsed disease, although this group had high risk disease based on β2-microglobulin levels. Additional studies are required to explore the benefit of this regimen in elderly patients with CLL. Disclosures: Off Label Use: Ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia. O'Brien:Celgene: Consultancy; Genentech BioOncology: Consultancy. Wierda:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Advisory Board, Consultancy, Speakers Bureau. Estrov:Celgene: Consultancy. Keating:Celgene: Consultancy; Genentech: Consultancy. Ferrajoli:Celgene: Research Funding; Genentech: Research Funding.

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