Bendamustine Versus Chlorambucil as First-Line Treatment in B Cell Chronic Lymphocytic Leukemia: An Updated Analysis from An International Phase III Study.

Abstract Introduction: Bendamustine is a purine analog/alkylator hybrid agent with a unique mechanism of action, which has shown good clinical efficacy and acceptable tolerability in various hematological malignancies, including Hodgkin’s disease, non-Hodgkin’s lymphoma, and multiple myeloma. Patients and Methods: The efficacy and safety of bendamustine and chlorambucil have been compared in a randomized, open-label, multicenter, Phase III trial in patients with previously untreated advanced (Binet stage B/C) B cell chronic lymphocytic leukemia: an updated analysis from this trial is presented here. Patients were randomized to receive bendamustine (100 mg/m2 on days 1 + 2) or chlorambucil (0.8 mg/kg on days 1 and 15) for up to 6 treatment cycles. The median cumulative dose per patient was 1820 mg and 517 mg for bendamustine and chlorambucil, respectively. The primary endpoints were overall remission rate (ORR), which was defined as complete response, nodular partial response or partial response, and progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. The response to treatment was evaluated by a blinded Independent Response Assessment Committee. Results: A total of 319 patients were randomized (162 bendamustine, 157 chlorambucil), of whom all were included in the efficacy analysis and 312 were evaluable for safety. The mean (± SD) number of treatment cycles was 4.8 ± 1.7 in the bendamustine group and 4.6 ± 1.7 in the chlorambucil group; the median duration of follow-up was 29.2 months (29.8 bendamustine, 27.8 chlorambucil). The ORR was significantly higher with bendamustine than with chlorambucil (67% versus 30%, P<0.0001). The median PFS was 21.5 months with bendamustine and 8.3 months with chlorambucil (P<0.0001). No difference in OS was seen between groups. Most doses were given on schedule. The mean overall relative dose intensity was 86% and 96% in the bendamustine and chlorambucil treatment groups, respectively. At least 1 grade 3/4 neutropenia occurred in 43% of bendamustine-treated patients and 21% of those receiving chlorambucil. Grade 3/4 infections were documented in 7% of bendamustine-treated patients and 4% of chlorambucil-treated patients. Conclusion: This study has shown that bendamustine offers significantly greater efficacy than chlorambucil, with manageable toxicity, and should be considered as first-line chemotherapy for patients with advanced B-CLL.

Download Full-text

Rituximab Consolidation and Maintenance Immunotherapy Improve Outcome in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v110.11.2035.2035 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2035-2035 ◽

Cited By ~ 1

Author(s):

Giovanni Del Poeta ◽

Maria Ilaria Del Principe ◽

Luca Maurillo ◽

Francesco Buccisano ◽

Gianfranco Catalano ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Maintenance Therapy ◽

B Cell ◽

Response Duration ◽

Lymphocytic Leukemia ◽

Induction Treatment ◽

Hematologic Toxicity ◽

Grade 3 ◽

Cell Chronic Lymphocytic Leukemia

Abstract Monoclonal antibodies in combination with chemotherapy allowed us to obtain more responses and longer response duration in B-cell chronic lymphocytic leukemia (B-CLL), reducing disease burden to levels detectable only by flow cytometry. Moreover, it has been reported that low-dose rituximab decreases CD20 antigen loss via shaving and promotes enhanced targeting in CLL (Williams, 2006). We performed a phase II study that added rituximab to fludarabine (Flu) as therapy for symptomatic, untreated CLL. Remission status was assessed by a multiparametric flow cytometric method based on the detection of CD19+CD5+CD79b– residual B-CLL lymphocytes. VH mutational status, CD38, ZAP-70 and cytogenetics were obtained in all pts before treatment. We defined as “high risk” pts having at least two of the following markers: unmutated IgVH, CD38>30%, ZAP-70>20%, intermediate/unfavorable cytogenetics (trisomy 12 or del11q or del17p). Eighty-two CLL pts, median age 61 years, received six monthly courses of Flu (25 mg/m2 for 5 days) and four weekly doses of rituximab (375 mg/m2) starting after completion of Flu therapy. According to modified Rai stages, 8 pts had a low stage, 70 an intermediate stage and 4 a high stage. Based on NCI criteria, 66/82 (80%) pts achieved a complete remission (CR), 12/82 (15%) a partial remission (PR) and 4/82 (5%) no response or progression. Hematologic toxicity included mainly neutropenia (grade 3 and/or 4 in 42 pts) and thrombocytopenia (grade 3 and/or 4 in 4 pts). Thirty-five pts in clinical CR or PR, either with CD5+CD19+CD79b– bone marrow (BM) cells >1% (MRD+, n=20 pts) or MRD negative but presenting CD5+CD19+ peripheral blood lymphocytes (PBL) >1000/microl (n=15 pts) within 1 year after completion of the induction treatment, underwent consolidation/maintenance therapy with four monthly cycles of rituximab at 375 mg/m2 followed by twelve monthly doses of rituximab at 150 mg/m2. The median follow-up duration was 46 months. Noteworthy, all B-CLL pts experienced a long progression-free survival (PFS) from the end of induction treatment (68% at 5 years). Nevertheless, CLL pts that underwent consolidation and maintenance therapy (n=35) showed a significant longer response duration (85% at 5 years, Figure). On the other hand, BM and PBL persistently MRD negative (>1 year) pts (n=29) showed a response duration similar to that of the consolidated pts (87% at 5 years). A significant shorter PFS was observed within CD38+ pts (39% vs 78% at 5 years, P=0.002), unmutated pts (45% vs 94% at 2.5 years, P=0.001) and ZAP-70+ pts (36% vs 88% at 6 years; P=0.00002). Notably, within the “high risk” subset (n=30), considering only MRD+ pts in CR or PR (n=20), MRD+ consolidated pts (n=11) showed a significant longer response duration (64% vs 13% at 2 years, P=0.006) in comparison with MRD+ unconsolidated pts (n=9). In conclusion, consolidation/maintenance therapy with rituximab prolongs significantly the response duration in B-CLL, improving also the outcome of the “high risk” subset. Figure Figure

Download Full-text

Acadesine for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL): A Multicentre Phase I/II Study

Blood ◽

10.1182/blood.v116.21.4625.4625 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4625-4625

Author(s):

Eric Van den Neste ◽

Bruno Cazin ◽

Ann Janssens ◽

Eva González-Barca ◽

María José Terol ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Partial Response ◽

Phase I ◽

B Cell ◽

Cell Count ◽

Lymphocytic Leukemia ◽

Pharmacokinetic Data ◽

Dependent Manner ◽

Refractory Disease ◽

Grade 3

Abstract Abstract 4625 CLL - Therapy, excluding Transplantation Acadesine induces cell death in B-cell chronic lymphocytic leukemia (CLL) cells in a dose-dependent manner. Acadesine enters B-cells where it is phosphorylated to ZMP, which induces apoptosis independently of ATM or p53. It is active in vitro against CLL cells from patients who have not responded to prior treatment with fludarabine and/or chlorambucil. A phase I/II open-labeled clinical study was designed to determine the safety and tolerability of acadesine given intravenously as a 4-hour infusion to patients with CLL. Part I is the dose escalation part of the study where patients receive a single dose of acadesine on Day 1 and are followed up to Day 22. In Part II, patients will receive up to 5 doses of acadesine at the maximum tolerated dose (MTD) identified in Part I over a period of up to 20 days. Patient population includes CLL patients with relapsed/refractory disease who have received one or more prior lines of treatment including either a fludarabine or an alkylator-based regimen. A patient is defined as having refractory disease if they fail to achieve less than a partial response (PR) according to the NCI working group guidelines, or relapse within the first 6 months after treatment after achieving at least partial response. Primary endpoints of the study evaluate the safety and tolerability of acadesine. Secondary endpoints evaluate the pharmacokinetics of acadesine and ZMP, and B and T-cell counts in peripheral blood as efficacy biomarkers. Twenty-one patients have been included to date, eighteen in Part I at doses of 50, 83.5, 139.5, 210 or 315 mg/kg, and three in Part II, with two doses at 210 mg/kg at days 1 and 4. Pharmacokinetic data showed acadesine is rapidly converted into ZMP inside blood cells. In part I, at single acadesine dose, the Cmax levels for ZMP in whole blood obtained at 315 mg/kg were similar to the ones obtained at the previous dose (210 mg/kg), suggesting that the saturation plateau was reached, which was confirmed by the PK modeling. In 5 patients treated with acadesine at 210 mg/kg and 315 mg/kg a decrease in absolute B cell count was observed, ranging from 6% to 54% with respect to the B cell count prior to acadesine administration. Reversible asymptomatic hyperuricaemia was observed in four patients in cohorts 1 to 3, probably due the metabolism of acadesine to ZMP and uric acid. Prophylactic allopurinol was used in cohorts 4 and 5 and it has significantly reduced the incidence of hyperuricaemia. Acadesine 315 mg/kg was the dose limiting toxicity (DLT) dose with 2 of 3 patients having DLTs-Tumour Lysis Syndrome (TLS) and clinically significant acute renal failure (CTCAE V3.0 Grade 3-chronic dialysis not indicated). We started Part II of the study, with two consecutive doses at 210 mg/kg (Optimal Biological Dose). Three patients have been included to date. No DLT nor grade 3 or 4 Adverse Events related to acadesine were observed, and in all of treated patients a decrease in absolute B cell count was observed ranging from 6% to 35% with respect to the B cell count prior to acadesine administration. In the following cohort, we will administer 5 consecutive doses of acadesine at 210 mg/kg, at days 1, 4, 8, 11 and 15. In conclusion, a MTD was found at one single acadesine dose. Two consecutive doses have already been tested without safety concerns and 5 consecutive doses are currently planned in part II of this ongoing study. Results for this cohort and additional safety, pharmacokinetics and efficacy data will be presented at the meeting. Disclosures: Saunders: Advancell: Consultancy. de Frias:Advancell: Employment. Campàs:Advancell: Employment.

Download Full-text

Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL)

Blood ◽

10.1182/blood-2002-01-0159 ◽

2002 ◽

Vol 100 (3) ◽

pp. 768-773 ◽

Cited By ~ 371

Author(s):

Jeanette Lundin ◽

Eva Kimby ◽

Magnus Björkholm ◽

Per-Anders Broliden ◽

Fredrik Celsing ◽

...

Keyword(s):

Monoclonal Antibody ◽

Bone Marrow ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Lymphocytic Leukemia ◽

Prolonged Treatment ◽

Line Treatment ◽

First Line ◽

Cell Chronic Lymphocytic Leukemia ◽

First Line Treatment

Abstract This phase II study determined the efficacy and safety of alemtuzumab, a humanized anti-CD52 monoclonal antibody, delivered subcutaneously as first-line therapy, over a prolonged treatment period of 18 weeks in 41 patients with symptomatic B-cell chronic lymphocytic leukemia (B-CLL). Injections were administered subcutaneously 3 times per week, from week 2 to 3 onward. An overall response rate (OR) of 87% (95% CI, 76%-98%; complete remission [CR], 19%; partial remission [PR], 68%) was achieved in 38 evaluable patients (81% of intent-to-treat population). CLL cells were cleared from blood in 95% patients in a median time of 21 days. CR or nodular PR in the bone marrow was achieved in 66% of the patients and most patients achieved this after 18 weeks of treatment. An 87% OR (29% CR) was achieved in the lymph nodes. The median time to treatment failure has not yet been reached (18+ months; range, 8-44+ months). Transient injection site skin reactions were seen in 90% of patients. Rigor, rash, nausea, dyspnea, and hypotension were rare or absent. Transient grade IV neutropenia developed in 21% of the patients. Infections were rare, but 10% patients developed cytomegalovirus (CMV) reactivation. These patients rapidly responded to intravenous ganciclovir. One patient, allergic to cotrimoxazole prophylaxis, developedPneumocystis carinii pneumonia. Alemtuzumab is highly effective as first-line treatment in patients with B-CLL. Prolonged treatment is important for maximal bone marrow response. Subcutaneous administration induced very few “first-dose” flulike symptoms and may reduce health care costs in comparison with the intravenous infusions.

Download Full-text

Rituximab Maintenance Following Chemoimmunotherapy Improves Outcome in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v114.22.2364.2364 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2364-2364

Author(s):

Giovanni Del Poeta ◽

Maria Ilaria Del Principe ◽

Dario Ragusa ◽

Luca Maurillo ◽

Francesco Buccisano ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Maintenance Therapy ◽

B Cell ◽

Response Duration ◽

Lymphocytic Leukemia ◽

Induction Treatment ◽

Hematologic Toxicity ◽

Grade 3 ◽

Cell Chronic Lymphocytic Leukemia

Abstract Abstract 2364 Poster Board II-341 The treatment goal of B-cell chronic lymphocytic leukemia (B-CLL) has already shifted from symptom palliation to the attainment of maximal disease control combining purine analogs with monoclonal antibodies. This immunochemotherapeutic approach resulted both in more complete responses (CR) and longer response duration, often remaining only a minimal residual disease (MRD) detectable by flow cytometry. We treated in first line 120 B-CLL symptomatic patients (pts), median age 62 years, with six monthly courses of intravenous or oral fludarabine at conventional doses and then, after a median time of 31 days, with four weekly doses (375 mg/sqm) of rituximab (rtx). Fourteen pts had a low Rai stage, 103 an intermediate stage and 3 a high stage. We defined as high risk pts having at least two of these markers: unmutated IgVH, CD38>30%, ZAP-70>20%, intermediate unfavorable cytogenetics (trisomy 12 or del11q or del17p). Based on NCI criteria, 92/120 (77%) pts achieved a CR, 24/120 (20%) a partial remission (PR) and 4/120 (3%) no response or progression. Ten pts underwent grade 3 (WHO) infective lung toxicity, 1 patient acute fatal B hepatitis and 2 pts progressed towards Richter's syndrome. Hematologic toxicity included mainly neutropenia (grade 3 and/or 4 in 56 pts) and thrombocytopenia (grade 3 and/or 4 in 8 pts). Fifty-four pts either in CR with B-CLL bone marrow cells >1% (MRD+, n=16 pts) or in CR MRD negative, but with B-CLL peripheral cells going up >1000/microl within 1 year after induction (n=22 pts) or in PR (n=16 pts), underwent consolidation and maintenance therapy with four monthly cycles of rtx at 375 mg/sqm followed by twelve monthly low doses of rtx (150 mg/sqm). The median follow-up duration was 50 months. All treated pts experienced a long progression-free survival from the end of induction treatment (40% at 9 years). On the other hand, global overall survival (OS) was 54% at 10 years. Nevertheless, CLL pts undergoing consolidation and maintenance therapy (n=54) showed a longer response duration vs MRD+ not consolidated pts (n=16; 75% vs 9% at 4 years; P<0.00001, Figure). Noteworthy, persistently MRD negative (>1 year) pts (n=43) showed a very long response duration (79% at 6 years, Figure). Moreover, OS was shorter in MRD+ not consolidated pts (0% vs 79% at 15 years; P=0.0007). Noteworthy, within the high risk subset (n=48), consolidated pts (n=17) showed a longer response duration (56% vs 0% at 2.5 years, P=0.003) vs MRD+ not consolidated pts (n=11). Therefore, rituximab consolidation and maintenance immunotherapy improve response duration in B-CLL, thus potentially increasing OS, also within the high risk subset. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

A Phase III trial of fludarabine, cyclophosphamide, and rituximab vs. pentostatin, cyclophosphamide, and rituximab in B-cell chronic lymphocytic leukemia

Investigational New Drugs ◽

10.1007/s10637-011-9737-y ◽

2011 ◽

Vol 30 (3) ◽

pp. 1232-1240 ◽

Cited By ~ 33

Author(s):

Craig Reynolds ◽

Nicholas Di Bella ◽

Roger M. Lyons ◽

William Hyman ◽

Donald A. Richards ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Phase Iii Trial ◽

Cell Chronic Lymphocytic Leukemia

Download Full-text

FcγRIIIa and FcγRIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2003-07-2548 ◽

2004 ◽

Vol 103 (4) ◽

pp. 1472-1474 ◽

Cited By ~ 147

Author(s):

Sherif S. Farag ◽

Ian W. Flinn ◽

Rama Modali ◽

Teresa A. Lehman ◽

Donn Young ◽

...

Keyword(s):

Amino Acid ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Lymphocytic Leukemia ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Tumor Clearance ◽

Grade 3 ◽

F 33 ◽

Cell Chronic Lymphocytic Leukemia

Abstract In follicular lymphoma (FL), genomic polymorphisms corresponding to the expression of valine (V) or phenylalanine (F) at amino acid 158 of FcγRIIIa alter the binding affinity of immunoglobulin G1 (IgG1) to the receptor and have been associated with varied responses to rituximab. We examined FcγRIIIa polymorphisms of 30 CLL patients with the phenotypes V/V (n = 6), V/F (n = 12), and F/F (n = 12) treated with thrice-weekly rituximab (375 mg/m2) for 4 weeks to correlate polymorphism type with infusion toxicity and response. Infusion toxicity (grade 3 or greater or hypoxia/hypotension requiring transient cessation of therapy) was observed equally among the groups (V/V, 50%; V/F, 33%; F/F, 41.6%; P = .78). The response to rituximab was also similar among the different polymorphism phenotypes (V/V, 33%; V/F, 41.6%; F/F, 50%). These data suggest that FcγRIIIa polymorphisms are not predictive of response in CLL and that, unlike the case with FL, mechanisms of tumor clearance other than antibody-dependent cellular cytotoxicity may be more important.

Download Full-text

Maintenance Alemtuzumab in Refractory B-Cell Chronic Lymphocytic Leukemia Patients: Updated Data.

Blood ◽

10.1182/blood.v106.11.5032.5032 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5032-5032 ◽

Cited By ~ 1

Author(s):

Catherine Thieblemont ◽

Roch Houot ◽

Boubacari Ali Toure ◽

Catherine Traulle ◽

Anne-Sophie Michallet ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Median Duration ◽

Opportunistic Infections ◽

Objective Response ◽

Dose Intensity ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

Standard Regimen ◽

Cell Chronic Lymphocytic Leukemia

Abstract Alemtuzumab has an impressive clinical activity in B-cell chronic lymphocytic leukemia. The standard regimen (30 mg three times weekly for 12 weeks) results in high rate of early responses but frequent early progression. To prolong TTP, we realized a phase II study with an identical initial scheme: 3, 10, 30 mg of Campath-1H on sequential days, followed by 30 mg three times weekly until partial response, and maintenance therapy with 30 mg every one or 2 weeks, then, 30 mg monthly until progression or toxicity. Between January 2001 and August 2005, 16 B-CLL patients have been treated with this regimen and were retrospectively analyzed on an intent-to-treat basis. Eighty-one percent (13/16) of the patients had received 3 or more prior chemotherapy regimens. Response was evaluated at 12 weeks (W12) after the beginning of the treatment by the CLL WG criteria. Survivals were defined from the first day of alemtuzumab. With a median follow-up for alive patients at 26 months, median duration of treatment was 8.5 months (range: 1.5–23.5) corresponding to a median number of 18 injections of alemtuzumab (range 6–36) realized. Nine (56%) patients received more than 6 months of monthly injections. Among them, 3 patients received one injection every 2 or 3 months after these 6 months. Two patients progressed in blood during maintenance. Modulation of the doses was then proposed with more frequent injections during a time period allowing to re-obtain a CR. Maintenance was stopped because of nodal progression in 6 patients, opportunistic infections in 2 patients (1HSV and 1 pulmonary infection), persistent CR in 3 patients, and persistant neutropenia in 1 patient. Objective response at W12 was reached in 13 (81%) of the patients, including 5 (31%) CR and 8 (50%) PR. One patient had a stable disease (disappearance of blood infiltration but stability of lymph nodes involvement) and 2 a progressive disease. Median duration of response was 11.7 months (range: 5–30). Median of TTP and overall survival were 12 months and 38 months, respectively. In this series, patients did not experience more hematological toxicities or opportunistic infections than reported with the standard regimen. Of the 13 patients that progressed at the time of analysis, 7 were re-treated by alemtuzumab (n=4) or alemtuzumab + chemotherapy (n=3). Objective responses were obtained in 6 patients during a median time at 8.7 months. In conclusion, maintenance alemtuzumab with modulation of dose intensity allowed improving time to progression and survival, without adding hematological toxicities and infectious complications. Figure Figure

Download Full-text