scholarly journals Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment [see comments]

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1695-1700 ◽  
Author(s):  
S O'Brien ◽  
H Kantarjian ◽  
M Beran ◽  
T Smith ◽  
C Koller ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Median Time ◽  
Alkylating Agents ◽  
Pneumocystis Carinii ◽  
Lymphocytic Leukemia ◽  
Response To Treatment ◽  
Time To Progression ◽  
Prior Therapy ◽  
Previously Treated Patients ◽  
Previously Treated

Two hundred sixty-four patients with chronic lymphocytic leukemia were treated with fludarabine 30 mg/m2 intravenously for 30 minutes each day for 5 days and with prednisone 30 mg/m2 orally each day for 5 days. Courses were repeated monthly. Of the 264 patients. 125 patients (47%) had Rai stage III-IV disease; 169 patients (64%) were previously treated with a median of 3 prior regimens; and 138 of them (82%) were refractory to therapy with alkylating agents. The overall response (OR) and complete response (CR) rates in the 169 previously-treated patients were 52% and 37%; these were 74% and 63%, respectively, in Rai stage O- II patients and declined to 64% and 46%, respectively, in Rai III-IV disease. Among the previously untreated patients, the OR and CR rates were 79% and 63%, these being 85% and 70%, respectively, in Rai O-II patients, and declining to 64% and 46%, respectively, in Rai III-IV disease. The incidence of minor infections or fever of unknown origin was similar in all patient groups and occurred in 22% of courses. The incidence of sepsis and/or pneumonia was significantly correlated with the extent of prior therapy and with Rai stage, and ranged from 3% of courses in the previously untreated Rai O-II patients, to 13% of courses in the previously treated Rai III-IV patients. Listeria sepsis or Pneumocystis carinii pneumonia was noted in 14 patients. With therapy, CD4 levels were uniformly depressed from a median 1,015/microL pretreatment to a median 159/microL after 3 months of fludarabine therapy. Median time to progression in previously treated patients was 22 months. In previously untreated patients, median time to progression was 30 months for patients who achieved a partial remission and has not been reached in patients who achieved a CR with a median follow-up of 2 years. The median survival was 18 months for previously treated patients and has not been reached for previously untreated patients. Response rates in previously treated and untreated patients, as well as infection rates, were identical to those seen in 110 patients treated with the same dose schedule of fludarabine alone. Logistic regression analysis selected 4 factors to be significantly associated with worse response: Rai III-IV stage disease, prior therapy, older age, and low albumin levels. The regression equation was used to derive a probability of response based on the 4 characteristics. When the model was applied to the same population, patients could be divided into 4 prognostic groups with different outcomes.

scholarly journals Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment [see comments]

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1695-1700 ◽  
Author(s):  
S O'Brien ◽  
H Kantarjian ◽  
M Beran ◽  
T Smith ◽  
C Koller ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Median Time ◽  
Alkylating Agents ◽  
Pneumocystis Carinii ◽  
Lymphocytic Leukemia ◽  
Response To Treatment ◽  
Time To Progression ◽  
Prior Therapy ◽  
Previously Treated Patients ◽  
Previously Treated

Abstract Two hundred sixty-four patients with chronic lymphocytic leukemia were treated with fludarabine 30 mg/m2 intravenously for 30 minutes each day for 5 days and with prednisone 30 mg/m2 orally each day for 5 days. Courses were repeated monthly. Of the 264 patients. 125 patients (47%) had Rai stage III-IV disease; 169 patients (64%) were previously treated with a median of 3 prior regimens; and 138 of them (82%) were refractory to therapy with alkylating agents. The overall response (OR) and complete response (CR) rates in the 169 previously-treated patients were 52% and 37%; these were 74% and 63%, respectively, in Rai stage O- II patients and declined to 64% and 46%, respectively, in Rai III-IV disease. Among the previously untreated patients, the OR and CR rates were 79% and 63%, these being 85% and 70%, respectively, in Rai O-II patients, and declining to 64% and 46%, respectively, in Rai III-IV disease. The incidence of minor infections or fever of unknown origin was similar in all patient groups and occurred in 22% of courses. The incidence of sepsis and/or pneumonia was significantly correlated with the extent of prior therapy and with Rai stage, and ranged from 3% of courses in the previously untreated Rai O-II patients, to 13% of courses in the previously treated Rai III-IV patients. Listeria sepsis or Pneumocystis carinii pneumonia was noted in 14 patients. With therapy, CD4 levels were uniformly depressed from a median 1,015/microL pretreatment to a median 159/microL after 3 months of fludarabine therapy. Median time to progression in previously treated patients was 22 months. In previously untreated patients, median time to progression was 30 months for patients who achieved a partial remission and has not been reached in patients who achieved a CR with a median follow-up of 2 years. The median survival was 18 months for previously treated patients and has not been reached for previously untreated patients. Response rates in previously treated and untreated patients, as well as infection rates, were identical to those seen in 110 patients treated with the same dose schedule of fludarabine alone. Logistic regression analysis selected 4 factors to be significantly associated with worse response: Rai III-IV stage disease, prior therapy, older age, and low albumin levels. The regression equation was used to derive a probability of response based on the 4 characteristics. When the model was applied to the same population, patients could be divided into 4 prognostic groups with different outcomes.

scholarly journals Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 2878-2884 ◽  
Author(s):  
MJ Keating ◽  
S O'Brien ◽  
H Kantarjian ◽  
W Plunkett ◽  
E Estey ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Response ◽  
Alkylating Agents ◽  
Single Agent ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Strongly Correlated ◽  
Prior Therapy ◽  
Previously Treated

Abstract The clinical response and survival of 113 patients with at least 3-year follow-up after treatment with fludarabine as a single agent for chronic lymphocytic leukemia has been evaluated. Seventy-eight patients were previously treated and 35 were untreated. The response to therapy and survival were strongly correlated with the degree of previous therapy, the stage of disease, and whether or not the patients were refractory to alkylating agents. Other characteristics associated with survival were the age of the patient and the serum albumin level at the start of therapy. The median time to progression of responders who had not received prior therapy was 33 months and was 21 months for previously treated patients. Survival after progression of disease was also strongly correlated with the degree of prior therapy. No successful salvage regimen after initial fludarabine therapy was shown for patients refractory to alkylating agents, although fludarabine achieved further remissions in patients who had received fludarabine as their initial treatment or were not refractory to alkylating agents. The morbidity of patients in unmaintained remission on discontinuation of fludarabine was low, with less than one episode of infection per patient-year at risk. The morbidity during this time was correlated with clinical response and whether the patients had received prior therapy. Although fludarabine is a very effective cytoreductive regimen, most patients, including those who achieved true complete remissions, will have recurrent disease. Longer follow-up and comparative trials are required before the effect of fludarabine on survival is shown.

Chemoimmunotherapy With Fludarabine, Cyclophosphamide, and Rituximab for Relapsed and Refractory Chronic Lymphocytic Leukemia

2005 ◽  
Vol 23 (18) ◽  
pp. 4070-4078 ◽  
Author(s):  
William Wierda ◽  
Susan O’Brien ◽  
Sijin Wen ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Partial Remission ◽  
Overall Response Rate ◽  
Patient Characteristics ◽  
Lymphocytic Leukemia ◽  
Time To Progression ◽  
Previously Treated Patients ◽  
Previously Treated

Purpose The efficacy, toxicity, and tolerability of chemoimmunotherapy with the combination of fludarabine, cyclophosphamide, and rituximab (FCR) were evaluated in previously treated patients with chronic lymphocytic leukemia (CLL). The purpose of this study was to improve the complete remission (CR) rate for previously treated patients and evaluate the quality of bone marrow response. Patients and Methods One hundred seventy-seven previously treated patients with CLL were evaluated. Treatment consisted of rituximab 375 mg/m2 day 1 of course 1 and 500 mg/m2 day 1 of courses 2 to 6; fludarabine 25 mg/m2/d days 2 to 4 of course 1 and days 1 to 3 of courses 2 to 6; and cyclophosphamide 250 mg/m2/d days 2 to 4 of course 1 and days 1 to 3 of courses 2 to 6. Courses were repeated every 4 weeks. Results CR was achieved in 25% of 177 patients, and nodular partial remission and partial remission were achieved in 16% and 32% of patients, respectively; the overall response rate was 73%. Twelve (32%) of 37 complete responders tested achieved molecular remission in bone marrow. Univariate and multivariate analyses were used to identify pretreatment patient characteristics associated with CR and overall remission, longer time to progression, and overall survival. Conclusion The FCR regimen was an active and well-tolerated treatment for previously treated patients with CLL. Myelosuppression was the most common toxicity. FCR induced the highest CR rate reported in a clinical trial of previously treated patients with CLL. Furthermore, molecular remissions were achieved in a third of patients achieving CR.

2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia.

1995 ◽  
Vol 13 (3) ◽  
pp. 570-574 ◽  
Author(s):  
A Saven ◽  
R H Lemon ◽  
M Kosty ◽  
E Beutler ◽  
L D Piro
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Opportunistic Infections ◽  
Relative Effectiveness ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Median Response ◽  
Major Activity ◽  
Prior Therapy ◽  
Previously Treated Patients ◽  
Previously Treated

PURPOSE 2-chlorodeoxyadenosine (2-CdA; cladribine) is a purine analog with activity in patients with chronic lymphocytic leukemia (CLL) who fail to respond to alkylator therapy. We conducted a phase II trial of 2-CdA in previously untreated CLL patients. PATIENTS AND METHODS 2-CdA was administered to 20 patients with previously untreated CLL as a 0.1-mg/kg/d 7-day continuous intravenous infusion every 28 to 35 days until maximum response or prohibitive toxicity. RESULTS A median of four courses (range, one to nine) was administered to each patient. Five patients (25%) achieved a complete response and 12 (60%) achieved a partial response, for an overall response rate of 85%. The median response follow-up duration was 8+ months (range, 3 to 27). Myelosuppression was the principal toxicity. Four of 20 patients (20%) experienced grade III or IV thrombocytopenia. Three patients, all of whom received corticosteroid therapy, developed opportunistic infections at a median of 19 months following discontinuation of 2-CdA therapy. CONCLUSION 2-CdA has major activity in patients with previously untreated CLL, and the lower response rates seen in previously treated patients may be due in part to poor marrow reserve from prior therapy. Determination of the relative effectiveness of 2-CdA, fludarabine, and chlorambucil in the treatment of CLL patients will require a randomized trial.

scholarly journals Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 2878-2884 ◽  
Author(s):  
MJ Keating ◽  
S O'Brien ◽  
H Kantarjian ◽  
W Plunkett ◽  
E Estey ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Response ◽  
Alkylating Agents ◽  
Single Agent ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Strongly Correlated ◽  
Prior Therapy ◽  
Previously Treated

The clinical response and survival of 113 patients with at least 3-year follow-up after treatment with fludarabine as a single agent for chronic lymphocytic leukemia has been evaluated. Seventy-eight patients were previously treated and 35 were untreated. The response to therapy and survival were strongly correlated with the degree of previous therapy, the stage of disease, and whether or not the patients were refractory to alkylating agents. Other characteristics associated with survival were the age of the patient and the serum albumin level at the start of therapy. The median time to progression of responders who had not received prior therapy was 33 months and was 21 months for previously treated patients. Survival after progression of disease was also strongly correlated with the degree of prior therapy. No successful salvage regimen after initial fludarabine therapy was shown for patients refractory to alkylating agents, although fludarabine achieved further remissions in patients who had received fludarabine as their initial treatment or were not refractory to alkylating agents. The morbidity of patients in unmaintained remission on discontinuation of fludarabine was low, with less than one episode of infection per patient-year at risk. The morbidity during this time was correlated with clinical response and whether the patients had received prior therapy. Although fludarabine is a very effective cytoreductive regimen, most patients, including those who achieved true complete remissions, will have recurrent disease. Longer follow-up and comparative trials are required before the effect of fludarabine on survival is shown.

scholarly journals Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3016-3024 ◽  
Author(s):  
Xavier C. Badoux ◽  
Michael J. Keating ◽  
Xuemei Wang ◽  
Susan M. O'Brien ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Final Analysis ◽  
Patient Characteristics ◽  
Lymphocytic Leukemia ◽  
Prior Exposure ◽  
Chromosome 17 ◽  
Prior Therapy ◽  
Previously Treated Patients ◽  
First Relapse ◽  
Previously Treated

Abstract Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) is dictated by patient characteristics, prior therapy, and response to prior therapy. We report the final analysis of combined fludarabine, cyclophosphamide, and rituximab (FCR) for previously treated patients with CLL and identify patients who benefit most from this therapy. We explore efficacy of FCR in patients beyond first relapse, patients with prior exposure to fludarabine and alkylating agent combinations, and patients with prior exposure to rituximab. The FCR regimen was administered to 284 previously treated patients with CLL. Patients were assessed for response and progression by 1996 National Cancer Institute–Working Group (NCI-WG) criteria for CLL and followed for survival. The overall response rate was 74%, with 30% complete remission. The estimated median overall survival was 47 months and median progression-free survival for all patients was 21 months. Subgroup analyses indicated that the following patients were most suitable for FCR treatment: patients with up to 3 prior treatments, fludarabine-sensitive patients irrespective of prior rituximab exposure, and patients without chromosome 17 abnormalities. FCR is an active and well-tolerated therapy for patients with relapsed CLL. The addition of rituximab to FC improved quality and durability of response in this patient population.

Pentostatin and Cyclophosphamide: An Effective New Regimen in Previously Treated Patients With Chronic Lymphocytic Leukemia

2003 ◽  
Vol 21 (7) ◽  
pp. 1278-1284 ◽  
Author(s):  
Mark A. Weiss ◽  
Peter G. Maslak ◽  
Joseph G. Jurcic ◽  
David A. Scheinberg ◽  
Timothy B. Aliff ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Response Rate ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Severe Nausea ◽  
Treatment Regimens ◽  
Purine Analogs ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

Purpose: Purine analogs and alkylators are important agents in the treatment of chronic lymphocytic leukemia (CLL). Previously, combinations of fludarabine and chlorambucil were abandoned because of increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin may be least myelosuppressive. We hypothesized that combining pentostatin with cyclophosphamide would have less myelotoxicity than combinations using other purine analogs. Patients and Methods: We studied 23 patients with previously treated CLL. All patients received pentostatin 4 mg/m2. Seventeen patients received cyclophosphamide 600 mg/m2, and six patients received cyclophosphamide 900 mg/m2. Both drugs were administered on day 1 of each cycle, and cycles were repeated every 3 weeks for six treatments. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median number of prior treatment regimens was three (range, one to five) with 13 patients (57%) refractory to prior fludarabine therapy. Results: The cyclophosphamide 900 mg/m2 dose level was associated with moderate to severe nausea, and we chose cyclophosphamide 600 mg/m2 as the dose for further study. There were 17 responses (74%; 95% confidence interval, 63% to 85%), including four complete responses. The response rate was 77% in fludarabine-refractory patients. Myelosuppression was acceptable with grade 3/4 neutropenia and thrombocytopenia, seen in 35% and 30% of patients, respectively. The relative sparing of thrombopoiesis can be seen in that only one patient (5%) with an initial platelet count of more than 20,000 required platelet transfusions while receiving therapy. Conclusion: Pentostatin 4 mg/m2 with cyclophosphamide 600 mg/m2 is safe and effective in previously treated patients with CLL. On the basis of these results, we are currently studying pentostatin, cyclophosphamide, and rituximab (PCR) therapy in patients with CLL.

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.

Incidence and Clinical Significance of SF3B1 Somatic Mutation in Chronic Lymphocytic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2881-2881
Author(s):  
Marianna Rossi ◽  
Ester M Orlandi ◽  
Peter Paschka ◽  
Silvia Zibellini ◽  
Cristiana Pascutto ◽  
...  
Keyword(s):  
Median Time ◽  
Univariate Analysis ◽  
Lymphocytic Leukemia ◽  
Frequent Mutation ◽  
Cd38 Expression ◽  
Previously Treated Patients ◽  
Binet Stage ◽  
Previously Treated ◽  
Active Disease

Abstract Abstract 2881 Our understanding of the genetics of chronic lymphocytic leukemia (CLL) has advanced significantly in the last few years. Recently, somatic mutations in SF3B1, a gene encoding a core component of the RNA splicing machinery, have been detected in tumor samples from variable proportions of CLL patients. Interestingly, mutations of SF3B1 are also found in patients with myelodysplastic syndrome, where they represent founding mutations, are specifically associated with phenotype with ring sideroblasts, and have a favorable prognostic significance. In this study, we analyzed incidence and clinical significance of SF3B1 mutation in 335 consecutive unselected CLL patients followed between 2000 and 2011. We analyzed 359 tumor samples from 335 patients: 191 were collected at diagnosis, 75 during follow up in untreated patients with stable disease (median time from diagnosis to sampling 24 months, range 8–110), 31 at first progression and before first line therapy (median time from diagnosis to sampling 37 months, range 5–110), and 62 in previously treated patients with active disease (median time from diagnosis to sampling 51 months, range 7–171). The overall median follow-up was 57 months (range 10–225). SF3B1 exons 14, 15 and 16 were screened for mutation by using denaturing high-performance liquid chromatography (DHPLC), and positive samples were then analyzed by Sanger sequencing. We detected 30 heterozygous missense mutations in 29 patients, with an overall incidence of 8.7% (29/335). Most of mutations were single base substitutions, and the most frequent mutation was K700E in exon 15, found in 40% of mutated patients, followed by G742D in exon 16 (27% of mutants). While SF3B1 (K700E) is the most frequent mutation also in myelodysplastic syndromes, SF3B1 (G742D) is rarely found in these latter disorders. Mutations frequency was low at diagnosis (6.3%) and in untreated patients with stable disease (5.3%), whereas it increased significantly at progression (9.7%) and in previously treated patients with active disease (16.1%) (P=.027). Of 268 patients evaluated at diagnosis and before progression or treatment, 87% were in Binet stage A and 13% in Binet stage B or C, 40% had unmutated IGHV status, 14% carried del11q or del17p detected by I-FISH, 15% were CD38+ and 25% were ZAP70+. Within this group, SF3B1 mutations were detected in 16/268 (6%) patients, and were associated with advanced Binet stage (B or C) (15% vs 5%, P=.037); there was also a trend for association with unmutated IGHV pattern (P=.053) and CD38 expression (P= .068). Interestingly, of 9 patients carrying IGHV3–21, four were SF3B1 mutated and had a stereotyped HCDR3. In order to evaluate the impact of SF3B1 mutation on overall survival (OS) and time to first treatment (TTFT), we analyzed 234 untreated patients in Binet stage A (161 evaluated at diagnosis and 73 during follow-up). Also in this subset, SF3B1 mutation (11/234 or 5%) was associated with CD38 expression (P=.007) and unmutated IGHV status (P=.05). Median OS was not reached (9 events so far). In univariate analysis, SF3B1 mutation had no impact on OS, whereas unmutated IGHV, CD38 expression and ZAP70 positivity were associated with worse OS (P=.002, P=.002 and P=.003, respectively). Seventy-six patients were treated and median TTFT was 40 months (range 1–154). Univariate analysis showed an adverse impact of SF3B1 mutation on TTFT (median TTFT 26 months in mutated vs 109 months in unmutated patients, P=.0009). Unmutated IGHV, CD38 expression and presence of del17p or del11q had a crude association with shorter TTFT as well (P<.0001, P=.0002 and P=.0009, respectively). However, in a Cox multivariable analysis, SF3B1 mutation status lost significance and only IGHV status maintained an independent adverse impact on TTFT. In 37 CLL patients, serial samples were available for mutation analysis. We identified three SF3B1 mutations that were acquired at follow up, and this occurred in patients who were refractory to or relapsed after at least one line of therapy. In conclusion, the findings of this study indicate that SF3B1 mutations have a low incidence in early stages of CLL, whereas they occur more frequently in advanced stages. At variance with myelodysplastic syndromes, SF3B1 mutations are unlikely to represent founding or driver mutations in CLL patients. More likely, they occur during clonal evolution of the disease, and may therefore be considered as a molecular marker of disease progression. Disclosures: No relevant conflicts of interest to declare.

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