scholarly journals A Phase II trial of Ofatumumab and Complement Replacement in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

2019 ◽  
Author(s):  
Joseph M Tuscano ◽  
Christina Poh ◽  
Aaron S Rosenberg ◽  
Brian A. Jonas ◽  
Gustavo Barisone ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Fresh Frozen Plasma ◽  
Lymphocytic Leukemia ◽  
Complement Activity ◽  
Fresh Frozen ◽  
Low Levels

Abstract Background: While many humanized monoclonal antibodies utilize complement dependent cytotoxicity, the complement depleting effects of these antibodies and the effect of complement replacement are not well-described. This study sought to examine complement levels and the effect of complement repletion after treatment with ofatumumab in patients with chronic lymphocytic leukemia (CLL). Methods: Twelve patients with relapsed or refractory CLL were treated with ofatumumab in combination with fresh frozen plasma used as complement replacement. The primary endpoint was objective response rate. Correlative endpoints included complement levels C3 and C4 and complement activity. Results: Adverse events were minimal, and efficacy was encouraging with an overall response rate of 83% and 2 patients (17%) achieving a complete response. While only 2 (17%) of patients had low complement activity at baseline, 8 (67%) developed low levels of complement activity. At a median follow-up time of 37 months the median progression-free survival was 12.5 months. Conclusions: While a minority of patients had low complement activity at baseline, a majority developed low levels of complement with ofatumumab treatment. The magnitude of complement depletion did not correlate with response. Future trials are needed to further explore complement replacement as a less toxic strategy to improve efficacy of monoclonal antibody-based regimens in CLL.

Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial

2018 ◽  
Vol 36 (19) ◽  
pp. 1973-1980 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Barbara Eichhorst ◽  
Johannes Schetelig ◽  
Peter Hillmen ◽  
John F. Seymour ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Median Time ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Free Survival

Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10−4 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Conclusion Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL. A high rate of blood MRD < 10−4 was achieved in this high-risk population.

Enhancing the Action of Rituximab in Chronic Lymphocytic Leukemia by Adding Fresh Frozen Plasma

2009 ◽  
Vol 1173 (1) ◽  
pp. 865-873 ◽  
Author(s):  
Abraham Klepfish ◽  
Lugassy Gilles ◽  
Kotsianidis Ioannis ◽  
Rachmilewitz Eliezer ◽  
Schattner Ami
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Fresh Frozen Plasma ◽  
Lymphocytic Leukemia ◽  
Fresh Frozen ◽  
Frozen Plasma

Treatment of refractory chronic lymphocytic leukemia with fludarabine phosphate via the group C protocol mechanism of the National Cancer Institute: five-year follow-up report.

1997 ◽  
Vol 15 (2) ◽  
pp. 458-465 ◽  
Author(s):  
J M Sorensen ◽  
D A Vena ◽  
A Fallavollita ◽  
H G Chun ◽  
B D Cheson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
National Cancer Institute ◽  
Response Rate ◽  
Performance Status ◽  
Treatment Protocol ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Motor Dysfunction ◽  
Hematologic Toxicity ◽  
Contributing Factors

PURPOSE To provide fludarabine to physicians for the management of patients with advanced refractory chronic lymphocytic leukemia (CLL) and to determine the response rate and duration, toxicity, and survival with this agent. PATIENTS AND METHODS This phase II protocol was open to all eligible patients whose local physicians obtained written permission from the National Cancer Institute (NCI) to register patients onto this protocol. Of 791 national and international enrolled patients, 724 with a median age of 65 years received fludarabine, of which 703 were assessable for response. RESULTS Thirty-two percent of assessable patients responded (95% confidence interval [CI], 29% to 36%), with 21 patients (3%) obtaining a complete response and 205 (29%) a partial response. The median duration of response was 13.1 months and the median survival time from registration was 12.6 months. Age, performance status (PS), and Rai stage correlated with survival (P < .01). Grade 4 hematologic toxicity was reported in 43% and was associated with infection in 22%. Neurotoxicity (primarily grade 1 motor dysfunction) was reported in 14% patients and correlated with age. CONCLUSION This study describes the toxicity and activity of fludarabine in refractory CLL in a setting that more closely resembles clinical practice than most published trials. The low response rate may be related to advanced stage (89% Rai high-risk), disease-related symptoms (63% had B symptoms), and/or degree of prior treatment. Other contributing factors inherent in a group C treatment protocol included lack of central pathology review, variable supportive care, and a tendency to use this mechanism at a later stage in the disease.

Long-Term Follow-Up of Patients With Chronic Lymphocytic Leukemia (CLL) Receiving Fludarabine Regimens as Initial Therapy

Blood ◽  
1998 ◽  
Vol 92 (4) ◽  
pp. 1165-1171 ◽  
Author(s):  
M.J. Keating ◽  
S. O’Brien ◽  
S. Lerner ◽  
C. Koller ◽  
M. Beran ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Median Survival ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Initial Therapy ◽  
Lymphocytic Leukemia ◽  
Poor Correlation ◽  
American Society ◽  
Febrile Episodes

One hundred seventy-four patients with progressive or advanced chronic lymphocytic leukemia (CLL) have received initial therapy with fludarabine as a single agent or fludarabine combined with prednisone. The overall response rate was 78% and the median survival was 63 months. No difference in response rate or survival was noted in the 71 patients receiving fludarabine as a single agent compared with the 103 patients who received prednisone in addition. The median time to progression of responders was 31 months and the overall median survival was 74 months. Patients over the age of 70 years had shorter survivals. Patients with advanced stage disease (Rai III and IV) had a somewhat shorter survival than earlier stage patients. More than half the patients who relapsed after fludarabine therapy responded to salvage treatment, usually with fludarabine-based regimens. Second remissions were more common in patients who had achieved a complete remission on their initial treatment. The CD4 and CD8 T-lymphocyte subpopulations decreased to levels in the range of 150 to 200/μL after the first 3 courses of treatment. Although recovery towards normal levels was slow, the incidence of infections was low in patients in remission (1 episode of infection for every 3.33 patient years at risk) and decreased with time off treatment. There was no association of infections or febrile episodes with the use of corticosteroids or the CD4 count at the end of treatment and a poor correlation with the increase in CD4 counts during remission. Infectious episodes were less common in patients who had a complete response compared with partial responders. Richter’s transformation occurred in 9 patients and Hodgkin’s disease occurred in 4 patients. Five other patients died from other second malignancies. Fludarabine appears to be an effective initial induction therapy with a reasonable safety profile for patients with CLL. © 1998 by The American Society of Hematology.

scholarly journals Phase 1/2 study of lumiliximab combined with fludarabine, cyclophosphamide, and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 489-495 ◽  
Author(s):  
John C. Byrd ◽  
Thomas J. Kipps ◽  
Ian W. Flinn ◽  
Januaro Castro ◽  
Thomas S. Lin ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Toxicity Profile ◽  
Dose Escalation Study ◽  
Free Survival ◽  
Previously Treated Patients ◽  
Previously Treated

AbstractPreclinical data demonstrate enhanced antitumor effect when lumiliximab, an anti-CD23 monoclonal antibody, is combined with fludarabine or rituximab. Clinical data from a phase 1 trial with lumiliximab demonstrated an acceptable toxicity profile in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). We therefore pursued a phase 1/2 dose-escalation study of lumiliximab added to fludarabine, cyclophosphamide, and rituximab (FCR) in previously treated CLL patients. Thirty-one patients received either 375 mg/m2 (n = 3) or 500 mg/m2 (n = 28) of lumiliximab in combination with FCR for 6 cycles. The toxicity profile was similar to that previously reported for FCR in treatment of relapsed CLL. The overall response rate was 65%, with 52% of patients achieving a complete response (CR), which compares favorably with the CR rate previously reported for the FCR regimen alone in relapsed CLL. The estimated median progression-free survival for all responders was 28.7 months. The addition of lumiliximab to FCR therapy is feasible, achieves a high CR rate, and does not appear to enhance toxicity in previously treated patients with CLL. A randomized trial comparing lumiliximab plus FCR with FCR alone is underway to define the benefit of this combination in relapsed CLL. This trial was registered at clinicaltrials.gov as NCT00103558.

Randomized Comparison of Cladribine Plus Cyclophsophamide with Fludarabine Plus Cyclophosphamide in Progressive Chronic Lymphocytic Leukemia: An Updated Report of Prospective PALG-CLL3 Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2826-2826
Author(s):  
Tadeusz Robak ◽  
Jerzy Z. Blonski ◽  
Joanna Gora-Tybor ◽  
Krzysztof Jamroziak ◽  
Bernadetta Ceglarek ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Purine Analogues ◽  
End Points ◽  
Free Survival ◽  
Treatment Groups ◽  
To Receive

Abstract Purine analogues, Cladribine (2-CdA) and Fludarabine (FA), are highly effective in treatment of chronic lymphocytic leukemia (CLL). This prospective randomized phase 3 trial was designed to compare the efficacy and toxicity of 2-CdA and cyclophsophamide (CC regimen) with FA and cyclophsophamide (FC regimen) in previously untreated progressive CLL. The primary end points of the study were complete response (CR) and overall response (OR) after completion of the therapy. The secondary end points were progression free survival (PFS), overall survival (OS) and treatment related toxicity. Eligible patients were assigned to receive 6 courses of either 2-CdA 0.12 mg/kg/d i.v. with cyclophosphamide 250 mg/m2/d i.v. for 3 consecutive days or FA 25 mg/m2/d i.v. with cyclophosphamide 250 mg/m2/d i.v. for 3 consecutive days administered at 28 day intervals. The treatment response and toxicity were evaluated according to NCI-SWOG guidelines. The study started in January 2004, and here we present updated results from the interim analysis of 227 evaluated patients performed in July 2006. As shown in the table, there were no significant differences in the rates of CR and OR between the treatment groups. Moreover, the treatment related toxicity, including grade ¾ thrombocytopenia, neutroepenia and infections was similar in patients receiving FC or CC regimens. Median time of progression free survival did not differ between both groups (11.0 months in CC arm and 11.2 months in FC arm, p=0.41). There were 5 deaths (3.2%) observed in CC arm and 15 (8.1%) in FC arm. In conclusion, the preliminary results of our study indicate that CC and FC protocols have similar activity and toxicity in previously untreated patients with CLL. Characteristic CC arm FC arm p value Pts enrolled 158 174 Pts evaluated 105 122 OR (%) 88 (83.8) 99 (81.2) 0.60 CR (%) 41 (39.0) 49 (40.2) 0.86 Thrombocytopenia gr 3/4 (%) 12 (10.7) 17 (13.4) 0.53 Neutropenia gr 3/4 (%) 21 (18.8) 30 (23.6) 0.36 Infections gr 3/4 (%) 34 (30.4) 37 (29.1) 0.84

Randomized Comparison of Cladribine Plus Cyclophosphamide with Fludarabine Plus Cyclophosphamde in Untreated Patients with Chronic Lymphocytic Leukemia: Report of the Polish Adult Leukemia Group (PALG-CLL3).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2103-2103 ◽  
Author(s):  
Tadeusz Robak ◽  
Jerzy Z Blonski ◽  
Krzysztof Jamroziak ◽  
Joanna Gora-Tybor ◽  
Beata Stella-Holowiecka ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Randomized Study ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Color Flow ◽  
Significant Difference ◽  
Adult Leukemia

Abstract Purine nucleoside analogues, cladribine(2-CdA) and fludarabine (FA), especially combined with cyclophosphamide (CY) are potent cytotoxic drugs for the treatment of chronic lymphocytic leukemia (CLL). In this randomized study we aimed to establish whether combination of 2-CdA plus CY (CC) with FA plus (FC) provide similar benefit to previously untreated patients with CLL. The trial was started in January 2004 and the recruitment was ended in May 2007. The study primary endpoints were overall response (OR) and complete response (CR). The secondary endpoints included progression free survival (PFS), overall survival (OS), minimal residual disease negativity (MRD/-/) and treatment related toxicity. Eligible patients were randomly assigned to receive 6 courses of either 2-CdA 0.12 mg/kg/d i.v. + CY 250 mg/m2/d i.v. or FA 25 mg/m2/d i.v. + CY 250 mg/m2/d, both combinations for 3 consecutive days. The treatment response and toxicity were evaluated according to NCI-WG guidelines. MRD was evaluated in patients with CR using four-color flow cytometry assay. There were no significant difference in the rates of OR, CR, MRD negativity, grade 3/4 neutropenia, thrombocytopenia and infections. PFS and OS were also similar in both groups. In conclusion, CC and FC regimens are similarly active and toxic in previously untreated CLL, however trend of longer OS in CC group is observed. Characteristic CC arm FC arm P value Pts enrolled 212 211 - Pts evaluated 184 187 - No of courses (median, range) 6 (2–6) 5 (2–6) 0.56 OR (%) 163 (88.6) 159 (85.0) 0.31 CR (%) 86 (46.7) 91 (48.7) 0.43 MRD/–/ (%) 33 (68.8) 44 (72.1) 0.70 PFS (median, years) 2.195 2.361 0.86 Thrombocytopania gr 3/4 (%) 23 (12.6) 22 (11.6) 0.77 Neutropenia gr 3/4 (%) 39 (21.4) 43 (22.8) 0.76 Infection gr 3/4 (%) 53 (29.1) 54 (28.6) 0.91 OS (median, years) 4.066 2.531 0.10 Death (%) 37 (20.2) 53 (27.9) -

scholarly journals Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma

2019 ◽  
Vol 37 (34) ◽  
pp. 3291-3299 ◽  
Author(s):  
Philippe Armand ◽  
Scott Rodig ◽  
Vladimir Melnichenko ◽  
Catherine Thieblemont ◽  
Kamal Bouabdallah ◽  
...  
Keyword(s):  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
End Points ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Duration Of Response

PURPOSE Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692 ) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990 ) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.

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

2012 ◽  
Vol 30 (26) ◽  
pp. 3209-3216 ◽  
Author(s):  
Kirsten Fischer ◽  
Paula Cramer ◽  
Raymonde Busch ◽  
Sebastian Böttcher ◽  
Jasmin Bahlo ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Response Rate ◽  
Complete Response ◽  
Observation Time ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Trisomy 12 ◽  
Severe Infections ◽  
Binet Stage ◽  
Grade 3

Purpose We investigated the safety and efficacy of bendamustine and rituximab (BR) in previously untreated patients with chronic lymphocytic leukemia (CLL). Patients and Methods In all, 117 patients, age 34 to 78 years, 46.2% of patients at Binet stage C, and 25.6% of patients age 70 years or older received BR chemoimmunotherapy for first-line treatment of CLL. Bendamustine was administered at a dose of 90 mg/m2 on days 1 and 2 combined with 375 mg/m2 rituximab on day 0 of the first course and 500 mg/m2 on day 1 during subsequent courses for up to six courses. Results Overall response rate was 88.0% (95% CI, 80.7% to 100.0%) with a complete response rate of 23.1% and a partial response rate of 64.9%. Ninety percent of patients with del(11q), 94.7% with trisomy 12, 37.5% with del(17p), and 89.4% with unmutated IGHV status responded to treatment. After a median observation time of 27.0 months, median event-free survival was 33.9 months, and 90.5% of patients were alive. Grade 3 or 4 severe infections occurred in 7.7% of patients. Grade 3 or 4 adverse events for neutropenia, thrombocytopenia, and anemia were documented in 19.7%, 22.2%, and 19.7% of patients, respectively. Conclusion Chemoimmunotherapy with BR is effective and safe in patients with previously untreated CLL.

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