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

Bendamustine Combined With Rituximab in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group

2011 ◽  
Vol 29 (26) ◽  
pp. 3559-3566 ◽  
Author(s):  
Kirsten Fischer ◽  
Paula Cramer ◽  
Raymonde Busch ◽  
Stephan Stilgenbauer ◽  
Jasmin Bahlo ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Partial Response ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Refractory Disease ◽  
Overall Response

Purpose The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL). Patients and Methods Seventy-eight patients, including 22 patients with fludarabine-refractory disease (28.2%) and 14 patients (17.9%) with deletion of 17p, received BR chemoimmunotherapy. Bendamustine was administered at a dose of 70 mg/m2 on days 1 and 2 combined with rituximab 375 mg/m2 on day 0 of the first course and 500 mg/m2 on day 1 during subsequent courses for up to six courses. Results On the basis of intent-to-treat analysis, the overall response rate was 59.0% (95% CI, 47.3% to 70.0%). Complete response, partial response, and nodular partial response were achieved in 9.0%, 47.4%, and 2.6% of patients, respectively. Overall response rate was 45.5% in fludarabine-refractory patients and 60.5% in fludarabine-sensitive patients. Among genetic subgroups, 92.3% of patients with del(11q), 100% with trisomy 12, 7.1% with del(17p), and 58.7% with unmutated IGHV status responded to treatment. After a median follow-up time of 24 months, the median event-free survival was 14.7 months. Severe infections occurred in 12.8% of patients. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 23.1%, 28.2%, and 16.6% of patients, respectively. Conclusion Chemoimmunotherapy with BR is effective and safe in patients with relapsed CLL and has notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. These promising results encouraged us to initiate a further phase II trial evaluating the BR regimen in patients with previously untreated CLL.

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.

Multicenter phase II trial of mitoxantrone in patients with advanced nasopharyngeal carcinoma in Southeast Asia: an Asian-Oceanian Clinical Oncology Association Group study.

1993 ◽  
Vol 11 (1) ◽  
pp. 70-76 ◽  
Author(s):  
M Dugan ◽  
D Choy ◽  
A Ngai ◽  
J Sham ◽  
P Choi ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Survival Duration ◽  
Median Response ◽  
Overall Response ◽  
Multicenter Phase

PURPOSE Patients with advanced nasopharyngeal carcinoma (NPC) have a high incidence of recurrence and often develop distant metastases despite local control. This prospective multicenter phase II trial was conducted to evaluate the safety and efficacy of Novantrone (mitoxantrone; Lederle Laboratories, Wayne, NJ) in the therapy of patients with advanced NPC. PATIENTS AND METHODS One hundred eight patients with advanced NPC, namely, those with recurrent or persistent disease following primary radiotherapy, or newly diagnosed metastatic disease, were treated with mitoxantrone. Mitoxantrone was administered intravenously at an initial dose of 12 mg/m2 and repeated every 3 weeks, with dose escalation to a maximum of 14 mg/m2. The distribution of histologic subtypes was representative of NPC, with the majority being (61%) undifferentiated (or anaplastic) carcinoma. RESULTS The overall response rate (complete response [CR] and partial response [PR]) was 25% (95% confidence interval, 17% to 33%). The median response duration, time to treatment failure, and survival duration were 140, 82, and 394 days, respectively. Histology (poorly differentiated squamous cell) was found to be the only important factor in predicting response (P = .04) based on a multivariate analysis of nine pretreatment characteristics. The major dose-limiting toxicity was leukopenia. The incidences of nausea/vomiting, alopecia, and stomatitis/mucositis were 34%, 6%, and 3%, respectively. None were severe. Two patients had asymptomatic, moderate Alexander-grade cardiotoxicity. CONCLUSION This study represents a large, controlled multicenter trial of single-agent mitoxantrone in the treatment of advanced NPC. Mitoxantrone was well tolerated and produced an overall response rate comparable to that of other single-agent therapies used in the treatment of advanced head and neck cancer. Combination trials with mitoxantrone for advanced disease should be considered.

A phase II study of pemetrexed and doxorubicin in patients with advanced or metastatic breast cancer (MBC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1047-1047
Author(s):  
M. Blasinska-Morawiec ◽  
M. Martin ◽  
F. Salas ◽  
S. Falcon ◽  
J. Rolski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Single Agent ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Overall Response

1047 Background: Pemetrexed has a single-agent activity in MBC while doxorubicin is an established agent in breast cancer chemotherapy. This phase II study investigated the combination in patients with advanced or MBC who had not been previously treated with anthracyclines. Primary objective was to evaluate the overall response rate. Methods: Patients received pemetrexed 500 mg/m2 (10-min intravenous infusion) followed by doxorubicin 50 mg/m2 on day 1 of six 21-day cycles. Additional cycles were permitted based upon: absence of progressive disease, adequate cardiac function, and a maximum cumulative limit of doxorubicin 450 mg/m2. Routine folic acid and vitamin B12 supplementation was given to all patients. Results: A total of 79 women with advanced or MBC were enrolled at 15 centers in 7 countries. Major racial groups were Caucasians (50.6%) and Hispanics (24.1%). Median age was 55 years (range, 26–79) and most (91.1%) had performance status of 0 or 1. Patients had either metastatic (72.2 %) or locally advanced disease (27.9%). Sixteen (20.3%) patients had received prior adjuvant chemotherapy. A median of 6 cycles (range, 1–9) was delivered. During the 438 cycles, no doses were omitted, and 7 doses were reduced (3 for pemetrexed, 4 for doxorubicin). A total of 129 doses (29.5%) were delayed, primarily due to scheduling conflicts (84 doses) and neutropenia (19 doses). The relative dose intensity for both drugs was 93%. Overall response rate was 60.8% (95% CI, 49.1–71.6) with complete response in 8 patients (10.1%), partial response in 40 patients (50.6%), and stable disease in 20 patients (25.3%). Maximum CTC grade 3 and 4 toxicities observed in >5% patients were neutropenia (19 patients, 24.1%), leukopenia (8 patients, 10.1%), and vomiting (5 patients, 6.3%). Five deaths occurred during study treatment, 2 of which had causes (diarrhea, pneumonia) possibly related to the study drugs. One patient had resting left ventricular ejection fraction decreased to <50% after 6 cycles and did not receive further treatment. Conclusions: The combination of pemetrexed and doxorubicin was well tolerated and had promising response in patients with advanced or MBC. Survival and time-to-event results are forthcoming. No significant financial relationships to disclose.

Phase II Study of Lenalidomide in Combination with Rituximab for Patients with CD5+/CD20+ Hematologic Malignancies Who Relapse or Progress After Rituximab. Interim Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2376-2376
Author(s):  
Marays Veliz ◽  
Ricardo Santana ◽  
Jeffrey E Lancet ◽  
Rami S. Komrokji ◽  
Mohamed A Kharfan-Dabaja ◽  
...  
Keyword(s):  
Phase Ii ◽  
Poor Prognosis ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Combination Regimen ◽  
Duration Of Treatment ◽  
Bone Marrow Biopsies ◽  
Overall Response ◽  
Grade 3

Abstract Abstract 2376 Poster Board II-353 Background: Patients with relapsed or refractory CLL/SLL and patients with mantle cell lymphoma (McL) have a poor prognosis. Overall response rate (ORR) to salvage therapy for refractory patients is approximately 10-30%, and survival benefit with current treatment approaches is limited. Phase II studies of single agent lenalidomide in patients with relapsed or refractory CLL revealed an ORR of 32-58% (7-17% CR), depending on treatment dose, scheduled used and duration of treatment with lenalidomide. In patients with refractory or relapsed McL, lenalidomide treatment resulted in an ORR of 53% (CR 20%, PR 33%), and a 14-month median duration of response (Habermann et al 2009). Recent in vitro studies have shown that lenalidomide enhances the rituximab-induced killing of NHL cell lines and B-CLL cells via ADCC by restoring the defective T-cell and NK-cell mediated ability to form immune synapses to exert tumor cell cytotoxicity. Methods: Patients with relapsed or refractory CLL/SLL or McL received oral lenalidomide via dose escalation as follows, 2.5 mg on days 1-7, 5mg on day 8-14 and 10mg on day 15-21 followed by 7 days of rest in 28-day cycle; for cycle 2 and beyond 20mg was given on day 1-21 on a 28 day cycle. Rituximab was dosed at 375mg/m2 IV weekly for 4 weeks starting on day 15 of cycle 1. Treatment was continued until disease progression or toxicity. All patients were given allopurinol 300mg orally twice per day starting 3 days prior to first dose of lenalidomide. CT scans, and bone marrow biopsies were done every 2 months to assess for response. Primary objectives were overall response rate (CR+PR) and safety and tolerability of the combination regimen. Results: 17 patients were enrolled on study (13 patients with CLL/SLL and 4 patients with McL). Median number of prior chemotherapies was 3 (range 1-5). Median age was 64 years (range 42-80). Among patients with CLL, the most common cytogenetic abnormalities were trisomy 12 (isolated n=3, associated with other abnormalities n=4), del11q (isolated n=1, with others n=3), isolated del13q (n=1), complex cytogenetics with 3 or more abnormalities (n=4 including 1 patient with del 17p). Responses were assessed every 2 months after initiation of therapy. Response rate for 13 evaluable patients (10 with CLL and 3 with McL) relative to months on treatment with lenalidomide are summarized in the table. Although all responses were PR, the rate of PR improved with continued therapy suggesting increased responses with a longer duration of treatment with lenalidomide. Currently, 7 patients are still receiving active treatment on study, all with CLL (3 achieved a PR and 4 have SD). Of the 4 patients with McL enrolled on study, 1 achieved a PR after 2 months of therapy; 1 achieved SD after 2 months of therapy with a sustained SD after 6 months; 1 patient achieved SD after 2 months, but progressed after 6 months on treatment. The regimen was well tolerated. Most common (>5%) toxicities include neutropenia (35% grade 3, 6% grade 4), fatigue (17% grade 1-2, 6% grade 3), tumor flare (12% grade 2, 12% grade 3), acute renal insufficiency (6% grade 1, 12% grade 3), rituximab related infusion reactions (6% grade 2, 6% grade 3), flu-like symptoms (6% grade 2, 6% grade 3), venous thromboembolic disease (6% grade 2, 6% grade 3), infections (11% including 1 patient with fatal endocarditis), and hypercalcemia (11% grade 4). Correlative studies are ongoing. Conclusions: The combination of lenalidomide with Rituximab is a promising combination regimen in CLL patients with very poor prognosis who have undergone multiple lines of therapy. This treatment combination appears tolerable with observed events consistent with the use of these two agents in other studies. Further investigation is warranted, possibly in the front line setting and in combination with other agents. Disclosures: Lancet: Celgene: Research Funding.

Final Results Of A Phase 2 Study Of Vorinostat Plus Rituximab In Newly Diagnosed, Relapsed Or Refractory Indolent Non-Hodgkin's Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4398-4398 ◽  
Author(s):  
Robert Chen ◽  
Paul Frankel ◽  
Leslie Popplewell ◽  
Tanya Siddiqi ◽  
Wei Ye ◽  
...  
Keyword(s):  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Remission Rate ◽  
Single Agent ◽  
Newly Diagnosed ◽  
Overall Response ◽  
Cytokine Analysis ◽  
Hodgkin's Lymphomas

Abstract Background Follicular (FL), marginal zone (MZL), mantle cell (MCL) lymphomas, and lymphoplasmacytic lymphomas are indolent non-Hodgkin's lymphomas (NHL) that tend to recur multiple times with decreasing intervals of remissions. Vorinostat is an orally administered histone deacetylase inhibitor. Previously, we observed a single agent overall response rate (ORR) of 29% for vorinostat and a complete remission rate (CR) rate of 14% in indolent lymphomas (Kirschbaum 2009). Preclinical data suggests enhanced activity for the combination of vorinostat plus rituximab. We report the final results of a phase II study of the combination of vorinostat plus rituximab with correlative assays. Methods This is a two-stage phase II study in patients with newly diagnosed, relapsed or refractory indolent NHL. Vorinostat was given at 200 mg PO twice daily for 14 consecutive days on a 21 day cycle. Rituximab was given on day 1 of each cycle. CT scanning and/or FDG-PET were performed after every three cycles. The primary endpoint was the overall response rate according to Revised Cheson Criteria. Immune cytokine analysis was performed on serum samples drawn on day 0 and day 14 of treatment using Luminex X-MAP bead array. Results 30 patients were accrued with 28 eligible (2 ineligible tumor types). See Table 1 for baseline characteristics. The overall response (CR+PR) rate was 46% (13/28), and CR rate was 39% (11/28). The ORR and CR for previously untreated patients was 67% (4/6, all CR). The ORR for relapsed/refractory patients was 41% (9/22), with a CR rate of 32% (7/22). By histology, the ORR was 50% (11/22) and CR was 45% (10/22) for FL, 33.3% (1/3) for MCL (PR), 50% (1/2) for MZL (CR), and 0/1 for lymphoplasmacytic lymphoma. The median PFS was 38.2 months (95% CI: 14.4, 51.0) for all patients, 21.1 months (95% CI: 8.5, 51.0) for previously treated patients, and not-reached for untreated patients. Figure 1 shows the PFS of patients in CR and PR versus others. Patients who achieved CR were allowed to discontinue treatment and return to treatment upon progression. 10/13 CRs were progression-free with a median follow-up of 14.4 months (range 4-48 months). 2/3 patients who relapsed achieved CR again after resuming therapy. Of non-responders, 8 patients achieved stable disease for at least 9 cycles with one SD for 69 cycles. The disease control rate for >9 cycles (CR+PR+SD>9 cycles) was 75% (21/28). Five patients were taken off study for reasons other than progression (2 patient's choice, 1 to transplant, 1 for violation, and 1 physician choice). The median time to treatment failure for all patients was 17.8 months, 95% CI: (6.2, 51). Treatment was well tolerated. Grade 4 toxicities possibly attributable to study drug included neutropenia (n=1), incidental asymptomatic thrombosis (n=4), and thrombocytopenia (n=2). Grade 3 possibly related toxicities >20% included fatigue (n=9, 32%) and lymphopenia (n=7, 25%). The thromboses were asymptomatic pulmonary embolism discovered incidentally on CT scan, and resulted in amending the study to include 40 mg enoxaparin as prophylaxis, resulting in no further thromboses identified. Vorinostat plus rituximab reduced the levels of pro-inflammatory cytokines such as IL-2, INF-g, TNF-a, and IL-6. 8 of the 16 cytokine markers showed statistical decrease (p<0.05) on day 14 as compared to day 0 (IL1RA, IL2R, IL12p40p70, MIG, EOTAXIN, MCP1, EGF, and FGFBasic), and none showed a significant increase. However, the cytokine measurements on the two days and the observed changes did not distinguish between responders and non-responders. Conclusions The combination of vorinostat with rituximab is well tolerated, and showed encouraging activity against newly diagnosed and relapsed/refractory indolent NHL. Durable responses can be achieved and retreatment can lead to 2nd CR. The activity observed warrants multicenter evaluation of vorinostat with rituximab in patients with indolent lymphoma. Disclosures: Off Label Use: use of vorinostat and rituximab to treat indolent NHL.

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.

Ofatumumab in combination with high-dose methylprednisolone for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7124-7124
Author(s):  
Januario E. Castro ◽  
Michael Y. Choi ◽  
Tomas Carvajal ◽  
Hongying Li ◽  
Danelle Frances James ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
High Dose ◽  
Free Survival ◽  
Overall Response ◽  
Coronary Syndrome ◽  
Grade 3

7124 Background: We performed a phase II, single-arm, clinical trial evaluating ofatumumab in combination with HDMP for the treatment of patients with relapsed or refractory CLL. Methods: Patients received ofatumumab at the dose of 1,000 mg weekly (half the conventional dose) for 12 weeks, without monthly maintenance doses. The HDMP dose was 1,000 mg/m2for 3 days of each of 3 monthly cycles. Prophylactic medications included acyclovir, bactrim, fluconazole, and allopurinol. Results: 21 patients were enrolled at a single center. The median age was 63 years (range 46–76). The median number of prior therapies was 3. 24% had unfavorable cytogenetics (Del 17p or Del 11q) and 76% had CLL cells that expressed unmutated IgVH genes or high levels of ZAP-70. 24% were fludarabine-refractory. Treatment was well tolerated. The majority of adverse events were grade 1 or 2, including insomnia, anxiety, fatigue, and infusion reactions. There were no grade 4 toxicities.19% of patients had grade 3 neutropenia, and 5% had grade 3 thrombocytopenia. Other grade 3 toxicities were hyperglycemia (71%), non-melanoma skin cancer and other skin lesions (19%), as well as acute coronary syndrome, atrial fibrillation, renal calculi, pneumonia, and hypocalcemia (1 patient each). Responses were assessed two months after completion of therapy. The overall response rate was 81% (17/21) with 5% CR (1/21), 10% nodular PR (2/21), 67% PR (14/21), 14% SD (3/21), and 5% PD. The median follow-up time was 12 months (range 5-23). The median progression-free survival (PFS) time was 9.1 months (95%CI: 7.5-NA) and the median treatment-free survival (TFS) was 11.5 months (95%CI: 10.0-NA). Patients with Del 17p or Del 11q had a significantly lower overall response rate (p-value <0.001, fisher’s exact test). Conclusions: The combination of HDMP and ofatumumab is an effective, tolerable, non-myelosuppressive treatment regimen. We observed a higher ORR and longer PFS than those previously reported with single agent mAb. This regimen may be useful for patients who are unable to tolerate more aggressive, myelosuppressive therapies, or have not responded to other treatments.

Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia

2005 ◽  
Vol 23 (30) ◽  
pp. 7697-7702 ◽  
Author(s):  
Susan M. O'Brien ◽  
Charles C. Cunningham ◽  
Anatoliy K. Golenkov ◽  
Anna G. Turkina ◽  
Steven C. Novick ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Intravenous Infusion ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Lymphocytic Leukemia ◽  
Complete Disappearance ◽  
Continuous Intravenous Infusion

Purpose To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). Patients and Methods Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. Results Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), ≥ 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and ≥ 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. Conclusion Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

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