Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients

Blood ◽  
2001 ◽  
Vol 98 (8) ◽  
pp. 2319-2325 ◽  
Author(s):  
Michel Leporrier ◽  
Sylvie Chevret ◽  
Bruno Cazin ◽  
Najda Boudjerra ◽  
Pierre Feugier ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Clinical Remission ◽  
Remission Rate ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Clinical Remission Rate ◽  
Remission Rates ◽  
Advanced Stages ◽  
To Receive

Abstract To comparatively assess first-line treatment with fludarabine and 2 anthracycline-containing regimens, namely CAP (cyclophosphamide, doxorubicin plus prednisone) and ChOP (cyclophosphamide, vincristine, prednisone plus doxorubicin), in advanced stages of chronic lymphocytic leukemia (CLL), previously untreated patients with stage B or C CLL were randomly allocated to receive 6 monthly courses of either ChOP, CAP, or fludarabine (FAMP), stratified based on the Binet stages. End points were overall survival, treatment response, and tolerance. From June 1, 1990 to April 15, 1998, 938 patients (651 stage B and 287 stage C) were randomized in 73 centers. Compared to ChOP and FAMP, CAP induced lower overall remission rates (58.2%; ChOP, 71.5%; FAMP; 71.1%; P < .0001 for each), including lower clinical remission rates (CAP, 15.2%; ChOP, 29.6%; FAMP, 40.1%;P = .003). By contrast, median survival time did not differ significantly according to randomization (67, 70, and 69 months in the ChOP, CAP, and FAMP groups, respectively). Incidences of infections (< 5%) and autoimmune hemolytic anemia (< 2%) during the 6 courses were similar in the randomized groups, whereas fludarabine induced, compared to ChOP and CAP, more frequent protracted thrombocytopenia (P = .003) and less frequent nausea-vomiting (P = .003) and hair loss (P < .0001). For patients with stage B and C CLL first-line fludarabine and ChOP regimens both provided similar overall survival and close response rates, and better results than CAP. However, there was an increase in clinical remission rate and a trend toward a better tolerance of fludarabine over ChOP that may influence the choice between these regimens as front-line treatments in patients with CLL.

Agent Orange Exposure Does Not Predict for Shorter Overall Survival in Patients with Chronic Lymphocytic Leukemia: A National Veteran Affairs Tumor Registry Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5568-5568
Author(s):  
Craig Mescher ◽  
Nicole Randall ◽  
Gobind Tarchand ◽  
Lisa M. Baumann Kreuziger ◽  
Dave Gilbertson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Agent Orange ◽  
Second Line ◽  
First Line ◽  
Tumor Registry ◽  
Risk Of Death ◽  
Veteran Affairs ◽  
To Receive

Abstract BACKGROUND: Agent Orange (AO), a 1:1 mixture of herbicides + TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), was used during the Vietnam War to destroy dense jungle and enemy crops. In 2002 the Department of Veteran Affairs (VA) determined that chronic lymphocytic leukemia (CLL) was associated with AO exposure. Case-control studies suggest an increased risk of death from CLL in areas where herbicide use was highest. There is also an increased incidence of other cancers (prostate, melanoma) in AO-exposed veterans. Limited data exists as to the specific impact of AO exposure on CLL disease presentation and outcome. METHODS: Patients (pts) diagnosed with CLL from 2009-2013 were identified in the National VAMC Tumor Registry. Baseline demographic and laboratory parameters were obtained, including Rai stage, marrow cytogenetics (when available), and lymphocyte doubling time (LDT). AO exposure was identified according to the medical record. The VA Benefits and Compensation officers determine AO exposure based on whether a person served on land and in the brown waters in Vietnam during the appropriate timeframe. Timing and types of CLL therapies were identified to determine if AO exposure influenced CLL treatment. RESULTS: 2052 CLL pts were identified, of which 418 had AO exposure. AO-exposed pts presented at a younger age (63.2 versus [vs] 70.5 years (yrs), p <0.0001), had a higher hemoglobin (14.3 vs 13.8 g/dl, p<0.001) and lower lactate dehydrogenase (LDH) (203 vs 227 IU/L, p = 0.01) compared to those without AO exposure. There were no differences in white cell, platelet, or absolute lymphocyte counts, Rai stage or LDT among the groups. Cytogenetic data was available for 1167 pts. There was no difference in the incidence of 17p-, 11q-, or 13q- between the two groups. Median overall survival (OS) was significantly better in patients with AO exposure, even when adjusted for age and Rai stage (median not reached vs 91.2 months, p <0.0001. OS benefit was primarily seen in pts age 60-69 yrs (p = 0.002), and those with 11q- (p = 0.001). No OS differences were found in pts with 17p- or 13q-. Among all pts, regardless of AO exposure status, OS decreased with higher Rai stage. There was a trend towards AO-exposed pts to be more likely to receive CLL-directed therapies (37% vs 32%, p = 0.07). AO exposed pts were more likely, than unexposed pts, to receive therapies as follows: fludarabine, chlorambucil, rituximab (FCR) first-line (38% vs 21%) and second-line (11.6 vs 5%); bendamustine + rituximab (BR) first-line (25% vs 18%), second-line (35 vs 26%), and third-line (31 vs 23%). Pts with no AO exposure were more likely to receive single agent chlorambucil or cyclophosphamide as first-line therapy (17 vs 10%). CONCLUSION: Pts with AO exposure, compared to unexposed pts, had an OS benefit independent of age and Rai stage, with this benefit seen primarily in younger pts (age 60-69 yrs) and in those with 11q-. AO-exposed pts were also more likely to receive disease-specific therapy. This unexpected OS finding will require further analyses for confounding variables, but could potentially be related to earlier treatment with regimens as FCR or BR. Disclosures Morrison: Celgene: Speakers Bureau; Genentech: Speakers Bureau; Gilead: Speakers Bureau; Pharmacyclics: Speakers Bureau; Celgene: Other: Data Monitoring Committee; Merck: Other: Adjudication Committee.

Fludarabine Monophosphate as First Line Therapy for Chronic Lymphocytic Leukemia (CLL) - 11 Years Clinical Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4970-4970
Author(s):  
J.E. Novoa ◽  
A.L. Rojo ◽  
B. Beñaran ◽  
R. Draper ◽  
H. Calvo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Monoclonal Antibodies ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Response Rate ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Intravenous Formulation

Abstract Background: fludarabine (F) has become the standard first line therapy for chronic lymphocytic leukemia (CLL) in younger patients. Treatment of early stage patients with chlorambucil without risk stratification has not been shown to prolong survival. In recent years effective and potentially curative approaches such as nucleosides analogues, stem cell transplantation or monoclonal antibodies have been developed. The attraction of monoclonal antibodies is based on selective targeting of tumor - relevant surface markers and a distinct mechanism of action (antibody-dependent cellular cytotoxicity). Aims: to assess the efficacy, safety and quality of life of F in previously untreated B-cell CLL patients in a group of medical institutions in Uruguay during 11 years (1995–2006). Methods: 168 patients between the period 1995 – 2006 were evaluated.120 of them received F intravenous formulation (1995–2006) and 48 the oral one (2002–2006). Age: 48 – 85 years old, media 67 years old. Gender: male 90, female 78. Inclusion criteria for B-cell CLL was Binet stages B, C and A progressive (Ap), 18 to 85 years old, non multiorganic failure, performance status 0 – 2 (WHO), written informed consent. First condition was non previous treatment. Staging: Binet A 12/168, B 116/168 & C 40/168. Treatment: as first line therapy all the patients received (minimum): 6 cycles of i.v. Fludarabine (Fludara®, Schering) 25 mg/m2/daily (5 days) e/30 days or Oral Fludarabine, 40 mg/m2/daily (5 days), 6 cycles. Results: on this B-cell CLL cohort the overall response rate (ORR) was 78% (CR+PR), 80% of them have immunophenotypic response. Safety: on the 1100 cycles in 168 patients, the toxicity was: 1 AIHA, 2 pancytopenia, 3 plaquetopenia. Grade 3–4 infection rate was 1,3%. No alopecia was observed in any patient. Kaposi sarcoma (0,7%). Mortality rate: 1,7% (3/168 patients). Other adverse factors to overall survival were, age over 65 (p=0,0001) and hepatic impairment (p=0,0001). Toxicity: (WHO>2): granulocytopenia 28%, thrombocytopenia 8%, infection 2%. Although fludarabine-treated patients experienced more significant myelosuppression, no difference in the treatment group was demonstrated. Causes of death: Richter 12%, sepsis 5%, associated disease 34%, second malignancy 17% and others 30%. Comparing oral with intravenous formulation in overall survival the results were: CLL 34% vs 36% (p= NS). Conclusions: fludarabine monofosfate (Fludara®) looks like an effective and safe treatment for B-cell CLL. The oral and intravenous formulations have a similar response rate in elderly and young patients. The challenge remains to integrate new information to apply novel therapies in a disease-specific and risk-adapted maner. A longer follow up and a larger trial, might be needed to confirm these results.

scholarly journals Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial

Blood ◽  
2012 ◽  
Vol 119 (22) ◽  
pp. 5104-5110 ◽  
Author(s):  
Stephane Lepretre ◽  
Therese Aurran ◽  
Beatrice Mahé ◽  
Bruno Cazin ◽  
Olivier Tournilhac ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Excess Mortality ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Phase 3 ◽  
Free Survival ◽  
Multicenter Phase ◽  
Remission Rates ◽  
Group 3 ◽  
To Receive

A French and Belgian multicenter phase 3 trial was conducted in medically fit patients with untreated chronic lymphocytic leukemia. Of 178 patients enrolled in the study, 165 were randomly assigned to receive 6 courses of oral fludarabine and cyclophosphamide (FC) in combination with rituximab (FCR; 375 mg/m2 in cycle one, 500 mg/m2 in all subsequent cycles) or alemtuzumab (FCCam; 30 mg subcutaneously injected on cycle days 1-3); each cycle was 28 days. Recruitment was halted prematurely because of excess toxicity; 8 patients died in the FCCam group, 3 from lymphoma and 5 from in-fection. Overall response rates were 91% with FCR and 90% with FCCam (P = .79). Complete remission rates were 33.75% with FCR and 19.2% with FCCam (P = .04). Three-year progression-free survival was 82.6% with FCR and 72.5% with FCCam (P = .21). Three-year overall survival was similar between the 2 arms at 90.1% in the FCR arm and 86.4% in the FCCam arm (P = .27). These results indicate that the FCCam regimen for the treatment of advanced chronic lymphocytic leukemia was not more effective than the FCR regimen and was associated with an unfavorable safety profile, representing a significant limitation of its use. This study is registered with www.clinicaltrials.gov as number NCT00564512.

scholarly journals Survival and Treatment of Black Patients with Chronic Lymphocytic Leukemia in the Veterans Health Affairs

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4847-4847
Author(s):  
Martin W. Schoen ◽  
Suhong Luo ◽  
Kenneth R. Carson ◽  
Kristen M. Sanfilippo
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Access To Care ◽  
Median Survival ◽  
Care Delivery ◽  
Lymphocytic Leukemia ◽  
Veterans Health ◽  
Black Race ◽  
Black Patients ◽  
To Receive

Abstract Background: Chronic Lymphocytic Leukemia (CLL) is the most prevalent adult leukemia in western countries and disparities in outcomes based on race have been identified. In national registry data and institutional studies, black patients were found to have worse overall survival and an earlier age at diagnosis with higher rates of adverse cytogenetics. However, racial disparities commonly correlate with access to care, comorbidities, and differences in treatment. In order to limit these potential confounders not available in other data, we studied patients in the Veterans Health Administration (VHA) network to understand differences in treatment and outcomes of black vs. non-black patients with CLL in a single care delivery system. Methods: We used the Veterans Administration Central Cancer Registry to identify patients diagnosed with CLL between September 1999 and October 2015 who were identified by race. Pharmacy records were used identify patients who received fludarabine, cyclophosphamide, rituximab, bendamustine, or chlorambucil as initial treatment of CLL. Comparisons between groups were performed with t-test or chi-square as appropriate. Comorbidity was assessed with Charlson (Romano) index and median survival by the Kaplan-Meier method. Cox proportional hazards regression modeling was used to assess associations between race and while adjusting for age, comorbidity, type of treatment, time to treatment and BMI. The study was approved the Saint Louis VA Medical Center institutional review board. Results: An initial cohort of 7155 patients with CLL was identified, of whom 2597 received chemotherapy within the VHA. Of those receiving chemotherapy, 14.8% were black (345/2597). The median year of treatment was 2006. Black patients were younger (64.0 years vs. 67.1, p<0.001) with similar mean comorbidity scores (2.3 vs. 2.2 p=0.24) compared to non-black patients. The mean time from CLL diagnosis to treatment was shorter for black patients (24.2 months vs. 28.3 p=0.02). Black patients were more likely to receive fludarabine based regimens (43.6% vs. 30.2%, p<0.001) and less likely to receive chlorambucil (25.5% vs. 32.5%, p=0.01). There were no differences based on race in treatment with bendamustine (10.4% vs. 11.4%, p=0.57), cyclophosphamide (8.6% vs. 11.0%, p=0.15) or rituximab alone (11.9% vs 14.9%, p=0.13). Second line treatment was administered to 197 black patients, which was more frequent than non-black (51.2% vs. 43.9%, p=0.01). Mean overall survival from diagnosis was 68.2 months in black patients compared to 72.5 months in non-black (p=0.07) and median overall survival was 76 vs. 83 months (p=0.051) respectively. Mean survival from start of chemotherapy (43.7 months vs. 43.6, p=0.95) in black and non-black patients and median survival was 47 vs. 50 months (p=0.34) respectively. In unadjusted analyses, black race was not associated with differences in survival after chemotherapy (hazard ratio (HR) 1.07, 95% CI:0.93-1.22, p=0.34) nor in overall survival (1.14, 95% CI:0.99-1.30, p=0.051). After adjusting for age, comorbidity index, BMI, duration of observation and treatment characteristics, black race was associated with poorer overall survival (adjusted HR 1.25, 95% CI:1.08-1.44, p=0.002) and survival after chemotherapy (adjusted HR 1.22, 95% CI:1.05-1.41, p=0.008). Conclusions: In this retrospective analysis of patients treated for CLL at the VHA, black patients had worse survival compared to non-black patients in a single health care delivery system, which limits differences in access to care. Black patients were younger and had shorter periods of observation and were more frequently given first-line fludarabine. Future studies should be performed to understand potential differences in CLL disease biology in different racial groups as a potential cause of adverse outcomes in this patient population. Disclosures Carson: Washington University in St. Louis: Employment; Roche: Consultancy; Flatiron Health: Employment. Sanfilippo:BMS/Pfizer: Speakers Bureau.

Practical considerations and questions in the treatment of chronic lymphocytic leukemia

2011 ◽  
Vol 152 (24) ◽  
pp. 958-963
Author(s):  
Béla Telek ◽  
László Rejtő ◽  
Péter Batár ◽  
Gyula Reményi ◽  
Róbert Szász ◽  
...  
Keyword(s):  
Overall Survival ◽  
Treatment Outcome ◽  
Clinical Practice ◽  
Chronic Lymphocytic Leukemia ◽  
Prognostic Markers ◽  
Lymphocytic Leukemia ◽  
Everyday Clinical Practice ◽  
The Past ◽  
Remission Rates ◽  
Molecular Biological Techniques

Understanding the pathogenesis and refine the treatment of chronic lymphocytic leukemia have been tremendously improved in the past decade. Treatment outcome and estimated prognosis have become more accurate due to the advanced molecular biological techniques and the classical prognostic markers. Incorporation of fludarabine and rituximab into the standard protocols fundamentally improved treatment outcome in chronic lymphocytic leukemia. Chemoimmunotherapy has improved not only the remission rates but had a significant impact on overall survival, as well. Eliminating residual leukemia and achieving complete hematological remissions at such high rates establish potential background for cure. Still, a great deal of dispute has been emerged regarding everyday clinical practice. Authors present their institutional experiences and review the literature. Orv. Hetil., 2011, 152, 958–963.

First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia

Blood ◽  
2009 ◽  
Vol 114 (16) ◽  
pp. 3382-3391 ◽  
Author(s):  
Barbara F. Eichhorst ◽  
Raymonde Busch ◽  
Stephan Stilgenbauer ◽  
Martina Stauch ◽  
Manuela A. Bergmann ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Elderly Patients ◽  
Survival Time ◽  
Remission Rate ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy

Abstract Although chronic lymphocytic leukemia (CLL) is a disease of elderly patients, subjects older than 65 years are heavily underrepresented in clinical trials. The German CLL study group (GCLLSG) initiated a multicenter phase III trial for CLL patients older than 65 years comparing first-line therapy with fludarabine with chlorambucil. A total of 193 patients with a median age of 70 years were randomized to receive fludarabine (25 mg/m2 for 5 days intravenously, every 28 days, for 6 courses) or chlorambucil (0.4 mg/kg body weight [BW] with an increase to 0.8 mg/kg, every 15 days, for 12 months). Fludarabine resulted in a significantly higher overall and complete remission rate (72% vs 51%, P = .003; 7% vs 0%, P = .011). Time to treatment failure was significantly shorter in the chlorambucil arm (11 vs 18 months; P = .004), but no difference in progression-free survival time was observed (19 months with fludarabine, 18 months with chlorambucil; P = .7). Moreover, fludarabine did not increase the overall survival time (46 months in the fludarabine vs 64 months in the chlorambucil arm; P = .15). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit compared with chlorambucil. This trial is registered with www.isrctn.org under identifier ISRCTN 36294212.

The Clinical Course of Head and Neck Cancer in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4741-4741
Author(s):  
Aaron D Maybury ◽  
Ephraim P. Hochberg ◽  
Lori J Wirth ◽  
Jeremy S. Abramson ◽  
Kevin S Emerick ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Head And Neck ◽  
Median Overall Survival ◽  
Clinical Course ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Line Therapy ◽  
Treatment Data ◽  
Median Interval

Abstract Abstract 4741 BACKGROUND. Patients with chronic lymphocytic leukemia (CLL) have an increased risk of developing second primary malignancies, including squamous cell cancers (SCC) of the Head and Neck (HNC). While cutaneous SCC have been shown to behave more aggressively in the setting of CLL, little information exists on the clinical course and outcome of SCC of the oral cavity and pharynx. METHODS. The Massachusetts General Hospital Tumor Registry was queried for all patients with ICD-O-3 codes corresponding to both CLL/SLL and HNC from January 1989 to July 2010, returning seventeen patients. The data collected included patient demographics, blood work and cytogenetics (when available) at the time of CLL diagnosis, primary HNC tumor histology and stage, and all pertinent treatment data, including types of treatment and clinical response. Survival was calculated using the Kaplan-Meier method. RESULTS. Seventeen patients had a diagnosis of both CLL and HNC. Of those, three were excluded from the study as treatment data was unavailable. The fourteen remaining included 12 males and 2 females. Eight patients had their CLL diagnosed first, and had a median interval to HNC diagnosis of 80 months (2-210 months; mean 89 months), four had their HNC diagnosed first and had a median interval to CLL of 1 month (1-100 months; mean 26 months), and two patients had concurrent diagnoses. The median age at diagnosis was 58.5 years (CLL) and 64 years (HNC). Nine patients (64%) were former or current smokers, all with at least a 20 pack year smoking history. Seven patients presented with Rai stage 0 CLL, three patients with Rai stage 1, one patient each with Rai stage 2 and 3, and two with unknown presentations. HNC tumor presentations included 3 T1 tumors, 3 T2 tumors, 3 T3 tumors, 2 T4 tumors, and 3 TX tumors. Three patients had HPV assessed in their tumor and all were positive. Out of the fourteen patients, nine (64%) received first-line chemotherapy for their CLL: 4 with chlorambucil, 1 with fludarabine/rituximab (FR), 1 with FR/lenalidomide, 1 with rituximab, and 1 each with cytoxan/vincristine and steroid monotherapy. Eight patients received second line therapy, three received third line therapy and one received 7 lines of therapy. Six patients (43%) received chemotherapy and radiation as their primary treatment for their Head and Neck tumor, three (21%) received surgery and radiation, three (21%) received only radiation, one received surgery, and one received radiation, chemotherapy, and surgery. One patient required hospitalization due to neutropenic fever during their radiation treatment, and one patient had a week of chemotherapy withheld due to leukopenia, but both were able to complete their full course of therapy. Three patients (21%) received chemotherapy for their CLL before any HNC treatment. These three patients were able to tolerate full HNC therapy without infectious complications or unanticipated cytopenias. First-line therapy for HNC had a median progression-free survival of 26.9 months (range 10.7 – 145.2 months; 95% CI, 12 to 42 months) and a median overall survival of 45.1 months (range 1 to 256.1 months; 95% CI, 9 to 81 months). The median overall survival from HNC for treated CLL patients was 22.6 months and for untreated 59.2 months (p= 0.596). Five patients died from their HNC (36%), two patients died from their CLL (14%), two patients died from unrelated causes, and five patients remain in remission. There were no significant differences in HNC presentation or survival between treated and untreated CLL. CONCLUSIONS. Prior or concurrent CLL therapy did not affect HNC treatment or induce any unexpected toxicities. Interestingly, seven out of fourteen patients (including 2 out of 3 HPV positive) were diagnosed with HNC within 6 months of CLL diagnosis, suggesting that the risk of secondary malignancies may be independent of the degree of immunosuppression attributable to progressive CLL or its therapy. This hypothesis should be explored in a larger population. Disclosures: No relevant conflicts of interest to declare.

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