scholarly journals Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2085-2093 ◽  
Author(s):  
Xavier C. Badoux ◽  
Michael J. Keating ◽  
Xuemei Wang ◽  
Susan M. O'Brien ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Salvage Therapy ◽  
Progression Free Survival ◽  
Complete Response ◽  
High Risk Group ◽  
Lymphocytic Leukemia ◽  
High Rate ◽  
Free Survival

Abstract Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes.

scholarly journals Relationship between Progression-Free Survival and Overall Survival in Chronic Lymphocytic Leukemia

2012 ◽  
Vol 23 ◽  
pp. ix350
Author(s):  
C. Beauchemin ◽  
J.B. Johnston ◽  
M. Lapierre ◽  
F. Aissa ◽  
J. Lachaine
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Free Survival

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

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

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

scholarly journals FCR achieves long-term durable remissions in patients with IGHV-mutated CLL

Blood ◽  
2017 ◽  
Vol 130 (21) ◽  
pp. 2278-2282 ◽  
Author(s):  
Chatree Chai-Adisaksopha ◽  
Jennifer R. Brown
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Randomized Trials ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Inclusion Criteria ◽  
Free Survival

Abstract In chronic lymphocytic leukemia (CLL) patients with mutated IGHV, 3 recent studies have demonstrated prolonged progression-free survival (PFS) after treatment with fludarabine-cyclophosphamide-rituximab (FCR) chemoimmunotherapy. We performed a systematic review to assess the benefit of FCR for patients with CLL and identified 5 randomized trials that met our inclusion criteria. FCR improved complete remission, PFS and overall survival vs the comparator; median PFS was not reached in the subgroup of CLL patients with mutated IGHV.

Combination Chemoimmunotherapy with Pentostatin, Cyclophosphamide and Rituximab Shows Significant Clinical Activity with Low Accompanying Toxicity in Previously Untreated B-Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 35-35
Author(s):  
Neil Kay ◽  
Susan Geyer ◽  
Timothy Call ◽  
Tait Shanafelt ◽  
Clive Zent ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Free Survival ◽  
Significant Clinical Activity

Abstract BACKGROUND: B-Chronic Lymphocytic Leukemia (CLL) is still uncurable but very powerful new tools are available with the use of chemoimmunotherapy (CIT). Purine nucleoside-based regimens that incorporate rituximab have generated very high levels of overall responses (OR) with significant percentage of those complete responses (CR) in previously untreated CLL. Here we report and update our experience with a phase 2 pentostatin-based CIT regimen for previously untreated CLL as conducted at 2 medical centers. We also studied the association of outcome based on risk stratification parameters and achievement of minimal residual disease. METHODS: Building on prior work of pentostatin in CLL by us (Kay ASH, 2004) and others, we initiated a trial of combined pentostatin (P)(2 mg/m2), cyclophosphamide (C)(600 mg/m2) and rituximab (R)(375 mg/m2) for symptomatic, previously untreated patients (n=65). This PCR regimen is given on a 21-day, 6-cycle schedule. However, the initial cycle of treatment uses thrice weekly rituximab as described by us earlier. In brief, this was rituximab at 100 mg/m2 on day 1, 375 mg/m2 on days 3 and 5 of the first week only. Prophylactic Sulfamethoxazole/Trimethoprim and Acyclovir were given to all patients for 1 year starting on the first cycle of therapy with PCR. All patients were risk stratified using CD38, ZAP-70, immunoglobulin heavy chain variable region gene (IgVH) and FISH panel assessments at entry. RESULTS: These patients were characterized as mostly in high-risk categories. Of 64 evaluable patients, 34 (53%) were high Rai risk (stage 3–4), 71% were non mutated for the IgVH gene, 34% were CD38+ and 34% were ZAP-70+. Thirty patients (52%) had one FISH anomaly, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs, and no major infections. NCI Working Group Criteria Responses occurred in 58 (91%) with 26 (41%) complete responses (CR), 14 (22%) nodular partial responses (nodular PR), and 18 (28%) partial responses (PR) patients. Outcome for all 64 patients demonstrates a median progression-free survival of 32.6 months. Importantly, no high risk factor (i.e., age, FISH, IgVH status, CD38+, ZAP-70+) except for del (17p) defect (n=3) precluded attaining a CR or NPR. In contrast, we found this regimen was equally effective in young vs. elderly (>70 yrs) patients and in del(11)(q22.3) vs. other favorable prognostic FISH factors. Examination of outcome among CR and nodular PR patients for PFS by flow cytometry status (negative vs. positive, i.e., ≤ 1 % CD5+/CD19+ vs. ≥ 1 % CD5+/CD19+) demonstrated improvement in progression free survival for patients who attained flow cytometry negativity (p = 0.009). Conclusion: This novel regimen of pentostatin, cyclophosphamide and rituximab for previously untreated CLL demonstrated significant clinical activity despite poor risk-based prognoses with minimal toxicity in terms of bone marrow suppression and/or infections. The additional feature of this approach is the ability to have durable responses for all age groups and even CLL patients with a del(11)(q22.3).

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.

Alemtuzumab in clinical practice: A British Columbia experience

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8098-8098
Author(s):  
D. Hui ◽  
W. Lam ◽  
C. Toze ◽  
M. Delorme ◽  
M. Noble ◽  
...  
Keyword(s):  
British Columbia ◽  
Overall Survival ◽  
Community Setting ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Community Practice ◽  
Limited Information ◽  
Free Survival ◽  
High Level

8098 Background: Limited information is available on alemtuzumab in the non-clinical trial setting. We evaluated its efficacy and safety in 42 consecutive unselected patients who received alemtuzumab monotherapy in British Columbia between October 2002 and August 2006. Methods: Information on patient demographics, baseline clinical and pathologic characteristics, dose and schedule of treatment, clinical response, survival, and toxicities associated with alemtuzumab were collected retrospectively. Results: Thirty-nine of 42 patients had chronic lymphocytic leukemia, 2 had mycosis fungoides, and 1 had T-cell post-transplant lymphoproliferative disorder. In contrast to previous reports, 42% were treated by community practitioners and 83% received alemtuzumab subcutaneously. The median time from diagnosis to alemtuzumab was 58 months, with a median age of 63 years at alemtuzumab treatment. Patients received a median of 4 treatments prior to starting alemtuzumab. One of 42 patients (2%) achieved a complete response, 20 (48%) achieved a partial response, 13 (31%) had stable disease, and 4 (10%) had progressive disease. The median post-alemtuzumab overall survival was 15.1 months and the median progression-free survival was 5.4 months. Response to alemtuzumab correlated with an increased progression- free survival (11 months versus 3.6 months, p=0.001) and time to next treatment (15.7 months versus 5.4 months, p=0.004). Significant adverse events included grade 3 or 4 neutropenia (75%) or thrombocytopenia (42%), infections (54%) including CMV reactivation (6%), and death (12%). Patients who received alemtuzumab in the community setting had a higher incidence of febrile neutropenia (p=0.05) and infection (p=0.03) compared to academic centres, although no difference in overall survival was noted. Conclusion: Alemtuzumab can be safely administered in a wide variety of clinical settings, including community practice, and is associated with a high level of activity. No significant financial relationships to disclose.

Rituximab - Inmunotherapy Combined with Chemotherapy, CHOP for the Treatment of Patients with Difusse Large B - Cell Lymphoma (DLBCL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4745-4745
Author(s):  
Jorge H. Milone ◽  
Fernando Bezares ◽  
Maria del Carmen Ardaiz ◽  
Dardo Riveros ◽  
Luis Palmer ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
High Risk Group ◽  
Hematologic Toxicity ◽  
Gastric Bleeding ◽  
Bulky Disease ◽  
Free Survival

Abstract Several studies (GELA 98.5, MInT) have demonstrated the benefit of combination rituximab (R) with chemotherapy to improve event free and overall survival in patients with DLBCL. We analyzed retrospectively the safety of combination R-CHOP for 6 cycles (rituximab 375 mg/m2 day 1; cyclophosphamide 750 mg/m2 day 1; doxorrubicin 50 mg./m2 day 1; vincristine 1.4 mg/m2 day 1 and prednisone 100 mg/m2 day 1 to 5) the tolerance and adverse effects. We evaluated the response (R), event free survival (EFS) and the overall survival (OS). Between March to December 2004, 28 patients with DLBCL were evaluated, 17 men and 11 women, with a median age 57 years old (range 28 – 84). They were IPI low 21,4 %, low - intermediate 25%, high - intermediate 35,7 % and high risk 17,9 %. Elevated LDH was present en 14 patients, bulky disease > 7 cm in 50% of cases. During the treatment they presented hematologic toxicity grade III 21,4 % and grade IV 25% of cases; 1 patient had anaphilactic reaction; 2 patients pneumonia; 1 patient sepsis; 4 patients neutropenia and fever; and gastric bleeding 1 patient. Response was achieve in 71,4 %: complete response (CR) in 57,1%, parcial (PR) in 14.3 %, and there was no response in 8 patients (28.6%). With follow up of 10 months (range 2 to 18.5) 15 patients were in CR 53,6%, 8 patients died, 7 of then primary no responders. Analyzed by IPI, 60% of CR in intermediate high and high was obtained. The R-CHOP combination is a feasible and safe treatment in our hospitals, and 71,4 % of response was obtained in all patients and 60% of CR in high risk group.

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

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

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

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

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