A phase II study of cladribine treatment for fludarabine refractory B cell chronic lymphocytic leukemia: results from CALGB Study 9211.

Cladribine has been reported to have little activity in fludarabine- refractory chronic lymphocytic leukemia (CLL). We sought to determine whether resistance to therapy with cladribine in fludarabine-refractory CLL patients represented primary drug resistance or the inability to tolerate the myelosuppression associated with this therapy. Patients with fludarabine refractory CLL patients without severe thrombocytopenia (platelets >/=50 x 10(9)/l) or granulocytopenia (neutrophils >1.5 x 10(9)/l) were enrolled. All patients received cladribine (0.14 mg/kg) as a 2-h intravenous infusion daily for 5 days, repeated every 4 weeks. Patients received up to six cycles of therapy. Twenty-eight patients enrolled; 13 had intermediate (Rai stage I or II) and 15 high (Rai stage III and IV) risk stages. No patient had a complete remission, but nine (32%; 95% confidence interval, 15-49%) attained a partial remission when assessed using the modified NCI criteria (1996). The median time to relapse for responders was 12 months, while median progression-free survival for the entire group was 9 months (95% confidence interval, 4-14 months). The median overall survival was 2.2 years (95% confidence interval, 0.8-3.1 years). Response was predicted by pre-treatment Rai status with seven of 13 (54%) intermediate risk vs two of 15 (13%) high-risk patients responding (P = 0.04). Toxicity was myelosuppression and infections (grade 3-5: neutropenia 75%, thrombocytopenia 68%, and infections 43%). Cladribine has modest clinical activity and considerable toxicity in a very selected group of patients with fludarabine-refractory CLL lacking pre-treatment neutropenia and thrombocytopenia.     

Sequential Cis-Platinum and Fludarabine with or without Arabinosyl Cytosine in Patients Failing Prior Fludarabine Therapy for Chronic Lymphocytic Leukemia: A Phase II Study

Patients with chronic lymphocytic leukemia (CLL) who fail fludarabine (Fluda) therapy have a poor response to subsequent salvage regimens and a poor prognosis. This study was undertaken to determine the efficacy and toxicity of a cis-platinum, (cis-p)fluda and arabinosyl cytosine (ara-C) combination in patients who were refractory to fluda or had relapsed following prior fluda therapy for CLL. Forty-one patients who had progressive CLL were treated on study. Eleven patients (27%) were sensitive to fluda and thirty (73%) refractory prior to study entry. Therapy consisted of cis-p 100mg/m² continuous intravenous (IV) infusion over 4 days, fluda 30 m/m² IV over 15 minutes on Days 3 and 4 either given alone (PF) or with ara-C 500 mg/m IV over 1 hour on Day 4 (PFA). The median number of PF or PFA courses received was two. No patient achieved a complete response. Eight patients (19%) achieved a partial response (PR), 28 were taken off study with progressive or refractory disease and 5 had induction deaths. The overall median survival was 6 months, 15 months in responding patients, and 4 months in non-responding patients. Rai stage 1-11 patients had a median survival of 7 months and stage 111-IV patients had a median survival of 3 months. Major toxici-ties (myelosuppression, sepsis, renal failure and tumor lysis syndrome) were frequent.

In conclusion, it can be said that the PF and PFA regimens have equivalent modest activity in patients with progressive CLL following prior fluda therapy, predominantly among patients whose disease was sensitive to fluda at last prior exposure. Ara-C did not add to the activity of the cis-plfluda combination in this study group.     

Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805.

PURPOSE: Flavopiridol has in vitro activity in chronic lymphocytic leukemia (CLL) and promotes apoptosis independent of p53 function or prior fludarabine exposure. We sought to determine if flavopiridol has activity in previously treated CLL using two schedules of administration. PATIENTS AND METHODS: Patients with previously treated CLL were enrolled in two sequentially done phase II studies. Patients in the first trial received flavopiridol (50 mg/m(2)/d) as a continuous infusion (CI) for 72 hours every 2 weeks. Patients in the second trial received flavopiridol 50 mg/m(2) as a 1-hour bolus (IVB) daily for 3 days repeated every 3 weeks. Patients received up to 12 (CI cohort) or 8 (IVB cohort) cycles of therapy. RESULTS: Fifteen patients were enrolled in the 72-hour CI phase II trial; 6 (40%) had intermediate-risk (Rai stage I or II) and 9 (60%) had high-risk (Rai stage III and IV) stages. No responses were noted in this group; 27% had stable disease and 73% had progressive disease. Thirty-six patients were enrolled in the second IVB trial, with 13 (36%) having intermediate and 23 (64%) having high-risk disease. Four patients (11%) had partial responses, 19 (53%) had stable disease, and 13 (36%) had progressive disease. The progression-free survival for responders in the IVB trial was 3, 3, 9, and 19 months. The median progression-free survival was 2 months [95% confidence interval (95% CI), 1.8-3.8] for patients in the CI trial and 3 months (95% CI, 2.5-7.4) for the IVB trial. The median overall survival was 27 months (95% CI, 20-42) for the CI trial and 24 months (95% CI, 18-31) for the IVB trial. Toxicity was manageable and included mainly myelosuppression, infections, diarrhea, and fatigue. CONCLUSIONS: Flavopiridol has modest, schedule-dependent clinical activity in relapsed CLL and warrants future investigation utilizing alternative schedules of administration.     

Long-Term Results of CAP Therapy in Chronic Lymphocytic Leukemia

This study was designed to study the efficacy and toxicity of an adriamycin-containing regimen (CAP: cyclophosphamide, adriamycin, and prednisone) in patients with previously untreated chronic lymphocytic leukemia (CLL). CAP was given to clinical complete remission followed by 18 months of cyclophosphamide-prednisone (CP) maintenance. Forty-seven patients with previously untreated CLL were treated. These patients initially presented with advanced stage (Rai III or IV) or had less advanced stage (Rai 0-II) patients and demonstrated evidence of disease progression. Patients received 750 mg/m² of cyclophosphamide intravenously on day 1, 50 mg/m² of adriamycin intravenously on day 1 and 100 mg/day of prednisone on days 1-5. Courses were repeated at 3-week intervals until clinical CR, at which time maintenance with cyclophosphamide and prednisone (CP) was commenced. A maximum cumulative dose of 450 mg/m² of adriamycin (9 courses of CAP) was given. Twenty (43%) of 47 patients obtained a CR and 11 (23%) obtained a partial remission. Bone marrow biopsy criteria were used to define response in addition to clinical and peripheral blood responses. All patients have been followed for 10 years. The median survival was 259 weeks. No patient remains in remission. No impact of response on survival was found. Surprisingly, the response rate and survival were higher and longer for patients with more advanced stages and higher tumor burdens. The median survival times for patients with Rai stage IV and Binet stage C disease were 93 months and 81 months, respectively. Although the regimen was well tolerated, three patients, each with an antecedent cardiac risk factor, developed congestive heart failure. Adriamycin containing regimens can be safely given to elderly patients with CLL and show promise in the treatment of advanced stage disease.     

Analysis of age,estimated creatinine clearance and pretreatment hematologic parameters as predictors of fludarabine toxicity in patients treated for chronic lymphocytic leukemia: a CALGB (9011) coordinated intergroup study

PURPOSE: Fludarabine is a renally excreted agent that is an effective treatment for chronic lymphocytic leukemia (CLL), a disease predominantly of the elderly. We sought to determine whether age, renal function or pretreatment hematologic status predicted toxicity of fludarabine treatment for CLL. METHODS: We evaluated 192 patients with previously untreated B-cell CLL who were entered onto the fludarabine treatment arm (25 mg/m(2) daily for 5 days every 28 days) of CALGB study 9011, an intergroup study with participation from SWOG, CTG/NCI-C and ECOG. Patients were required to have serum creatinine within 1.5 times normal. Hematologic indices and infections were recorded during the first 28-day cycle of treatment. A time-to-toxicity endpoint was evaluated over the entire course of fludarabine treatment. Creatinine clearance (CrCl(est)) was estimated using serum creatinine, age and body mass index. RESULTS: The median age was 64 years (range 37-87 years) and median CrCl(est) was 62 ml/min (range 27-162 ml/min, interquartile range 52-79 ml/min). We found no association between age and incidence of hematologic toxicity or infection during the first cycle of treatment. There was a strong association between CrCl(est) and the time-to-toxicity endpoint. Patients with CrCl(est) below 80 ml/min had increased incidence of toxicity during their treatment course ( P<0.0001). Pretreatment anemia, thrombocytopenia and Rai stage were highly associated with the incidence of neutrophil toxicity and grade III/IV hematologic toxicities during the first cycle of treatment ( P<0.0001). CONCLUSIONS: Patient age was not an independent risk factor for fludarabine-related toxicity, but CrCl(est) was associated with time to toxicity.     

Outcome of First Salvage Therapy in Patients With Chronic Lymphocytic Leukemia Relapsing After First-line Fludarabine,Cyclophosphamide, and Rituximab

Patients receiving salvage therapy for relapsed CLL following first-line FCR have overall response rates of 60% and median survival of 38 months. We describe pre-treatment characteristics predicting for outcome after salvage therapies. Patients receiving chemoimmunotherapy had better response rates and duration compared to antibody therapy alone.Brief AbstractChemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is an effective initial therapy with an estimated 40% relapse rate at 6 years. There is no consensus salvage therapy for relapsed patients. All patients with chronic lymphocytic leukemia (CLL) who relapsed or were refractory following first-line FCR administered between July 1999 and December 2003 were included for analysis. Patients with Richter's transformation were excluded. We analyzed the impact of pre-treatment characteristics (Table 1) and response duration following FCR on responses and survival after salvage therapy. Response outcomes were analyzed using 1996 National Cancer Institute response criteria. Overall survival (OS) and time to treatment failure (TTF) were calculated using the method of Kaplan and Meier. Of 300 patients treated with first-line FCR, 111 patients (37%) have required salvage therapy. Median age at relapse was 61 years, and 36% of patients had Rai stage III or IV disease (Table 1). The salvage regimen included antibody alone, chemoimmunotherapy, or novel therapeutic approaches including lenalidomide. Responses included 17% CR, 12% nodular PR, and 32% PR with an overall response (OR) of 60%. Median OS was 38 months, and median TTF was 9 months. Rai stage III/IV disease, β2M > 4 mg/L, deletion of 17p by fluorescence in situ hybridization and TTF < 12 months following FCR were associated with significantly shorter TTF and OS following first salvage. Patients treated with single-antibody therapy had low response rates (CR/nPR, 9%; OR, 44%) and short TTF (6 months). Combination of alemtuzumab and rituximab improved responses (CR/nPR, 50%; OR, 75%) but did not improve TTF (8 months). Patients treated with FCR or CFAR (cyclophosphamide/fludarabine/alemtuzumab/rituximab) demonstrated good responses (CR/nPR, 50%; OR, 83%) with improved TTF (20 months) but no significant improvement in OS (44 months) compared to patients receiving antibody only (OS, 41 months). Patients who relapse after FCR can be successfully retreated with a similar chemoimmunotherapy regimen (FCR, CFAR) with reasonable response rates and remission duration; however, chemoimmunotherapy does not appear to improve OS over antibody therapy alone in first salvage.     

口服氟达拉滨治疗慢性淋巴细胞白血病小淋巴细胞淋巴瘤的疗效观察

目的:评价口服氟达拉滨治疗慢性淋巴细胞白血病/小淋巴细胞性淋巴瘤（CLL/SLL）的疗效和不良反应。方法:15例CLL/SLL 患者中CLL 10例,SLL 5 例,中位年龄63岁。CLL 患者按照Rai分期分为Ⅱ期5 例,Ⅲ期2 例,Ⅳ期3 例。SLL 患者临床分期为Ⅲ期4 例,Ⅳ期1 例。11例为初治患者,4 例为复治患者。所有患者均口服氟达拉滨片40mg/（m2·d）,持续5 天,每4 周1 疗程,至少连用4 个疗程。12例患者完成4 个疗程,3 例患者4 个疗程后分别又巩固1～2 个疗程。结果:15例患者平均完成4.3 个周期。完全缓解率66.7%（10/15）,部分缓解率26.6%（4/15）,1 例（6.7%）无效,总有效率93.3%（14/15）。 11例初治患者完全缓解9例,部分缓解1 例,1 例由于疾病进展死亡。4 例复治患者1 例完全缓解,3 例部分缓解。不良反应主要为骨髓抑制和感染,5 例（33.3%）出现中性粒细胞下降,1 例Ⅰ级,3 例Ⅱ级,1 例Ⅲ级。感染3 例（20%）。 非血液系统毒性轻微,不良反应均可恢复。结论:口服氟达拉滨治疗CLL/SLL 用药方便,疗效较理想,对既往治疗过的患者亦有较好疗效,不良反应较轻,对于CLL/SLL 患者是值得推荐的治疗方案。      

Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011.

PURPOSE: Patients with chronic lymphocytic leukemia (CLL) may have disease transformation to non-Hodgkin's lymphoma or prolymphocytic leukemia; however, development of therapy-related acute myeloid leukemia (t-AML) is unusual. A series of patients enrolled onto an intergroup CLL trial were examined for this complication. PATIENTS AND METHODS: A total of 544 previously untreated B-cell CLL patients were enrolled onto a randomized intergroup study comparing treatment with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Case report forms from 521 patients were reviewed for t-AML. RESULTS: With a median follow-up of 4.2 years, six patients (1.2%) to date have developed therapy-related myelodysplastic syndrome (t-MDS; n = 3), t-AML (n = 2), or t-MDS evolving to t-AML (n = 1), from 27 to 53 months (median, 34 months) after study entry. This included five (3.5%) of 142 patients treated with fludarabine plus chlorambucil and one (0.5%) of 188 receiving fludarabine; no chlorambucil-treated patients developed t-MDS or t-AML (P =.007). At study entry, the median age among these six patients was 56 years (range, 44 to 72 years); three were male; the CLL Rai stage was I/II (n = 4) or III/IV (n = 2). Response to CLL therapy was complete (n = 4) or partial remission (n = 1) and stable disease (n = 1). Marrow cytogenetics, obtained in three of six cases at diagnosis of t-MDS or t-AML, were complex, with abnormalities in either or both chromosomes 5 and 7. Other abnormalities involved chromosomes X, 1, 8, 12, 17, and 19. Median survival after diagnosis of t-MDS/AML was 3.5 months (range, 0.5 to 10.1 months). CONCLUSION: Our findings raise the possibility that alkylator-purine analog combination therapy may increase the risk of therapy-related myeloid malignancies, which is of particular relevance with regard to ongoing trials using these combination therapies.     

Combination of fludarabine and arabinosylcytosine for treatment of chronic lymphocytic leukemia: clinical efficacy and modulation of arabinosylcytosine pharmacology

Previous studies have demonstrated that treatment with fludarabine 4 h prior to arabinosylcytosine (ara-C) potentiates the accumulation of the active triphosphate of ara-C (ara-CTP) in leukemic lymphocytes. The clinical efficacy of this combination was evaluated in 15 patients with chronic lymphocytic leukemia (CLL) that was advanced in their disease (median Rai stage, IV) and refractory to treatment with fludarabine. Patients received 0.5 g/m² ara-C infused i.v. over 2 h followed at 20 h by a 30-min infusion of 30 mg/m² fludarabine. At 24 h, an identical dose of ara-C was infused. To intensify the therapy and to determine the duration of fludarabine potentiation of ara-CTP accumulation, six additional patients with Rai stage III or IV CLL were treated with an amended 2-week protocol. On week 1, 30 mg/m² fludarabine was infused over 30 min, followed 4 h later by a 2-h infusion of 0.5 g/m² ara-C; on week 2, the fludarabine dose was followed 4 h later by a 4-h infusion of ara-C (1.0 g/m²). In all, 1 partial remission and 7 minor responses in 1 or more disease sites were observed in the 21 patients. The major treatment-related toxic effects were myelosuppression and infection. Comparison of the ara-CTP accumulation area under the concentration-time curve (AUC) in circulating CLL cells of patients on the amended protocol demonstrated a significant (P=0.001) 1.6-fold (range, 1.4-to 2.0-fold) increase after fludarabine administration. Although the initial rates of ara-CTP accumulation were similar for the 2-h and 4-h infusions, ara-CTP accumulation continued for up to 4 h in four of five patients who received the longer infusion. The activity of the fludarabine and ara-C combination is being evaluated in in vitro model systems and in phase II clinical trials in combination with other drugs.This study was supported in part by grants CA32839 and CA57629 from the National Cancer Institute, Department of Health and Human Services, and by Berlex Laboratories, Inc. L.E.R. is the recipient of an ASCO Young Investigator Award     

Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia.

PURPOSE: Fludarabine and cyclophosphamide (FC), which are active in treatment of chronic lymphocytic leukemia (CLL), are synergistic with the monoclonal antibody rituximab in vitro in lymphoma cell lines. A chemoimmunotherapy program consisting of fludarabine, cyclophosphamide, and rituximab (FCR) was developed with the goal of increasing the complete remission (CR) rate in previously untreated CLL patients to >/= 50%. PATIENTS AND METHODS: We conducted a single-arm study of FCR as initial therapy in 224 patients with progressive or advanced CLL. Flow cytometry was used to measure residual disease. Results and safety were compared with a previous regimen using FC. RESULTS: The median age was 58 years; 75 patients (33%) had Rai stage III to IV disease. The CR rate was 70% (95% CI, 63% to 76%), the nodular partial remission rate was 10%, and the partial remission rate was 15%, for an overall response rate of 95% (95% CI, 92% to 98%). Two thirds of patients evaluated with flow cytometry had less than 1% CD5- and CD19-coexpressing cells in bone marrow after therapy. Grade 3 to 4 neutropenia occurred during 52% of courses; major and minor infections were seen in 2.6% and 10% of courses, respectively. One third of the 224 patients had >/= one episode of infection, and 10% had a fever of unknown origin. CONCLUSION: FCR produced a high CR rate in previously untreated CLL. Most patients had no detectable disease on flow cytometry at the end of therapy. Time to treatment failure analysis showed that 69% of patients were projected to be failure free at 4 years (95% CI, 57% to 81%).     

Initial therapy of chronic lymphocytic leukemia

Only chronic lymphocytic leukemia (CLL) patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. Prognostic risk factor profile and comorbidity burden are most relevant for the choice of treatment. For physically fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab remains the current standard therapy. For unfit patients, treatment with an anti-CD20 antibody (obinutuzumab or rituximab or ofatumumab) plus milder chemotherapy (chlorambucil) may be applied. Patients with a del(17p) or TP53 mutation should be treated with the kinase inhibitors ibrutinib or a combination of idelalisib and rituximab. Clinical trials over the next several years will determine, whether kinase inhibitors, other small molecules, immunotherapeutics, or combinations thereof will further improve outcomes for patients with CLL.     

Sequential cis-platinum and fludarabine with or without arabinosyl cytosine in patients failing prior fludarabine therapy for chronic lymphocytic leukemia: a phase II study

Patients with chronic lymphocytic leukemia (CLL) who fail fludarabine (Fluda) therapy have a poor response to subsequent salvage regimens and a poor prognosis. This study was undertaken to determine the efficacy and toxicity of a cis-platinum, (cis-p)fluda and arabinosyl cytosine (ara-C) combination in patients who were refractory to fluda or had relapsed following prior fluda therapy for CLL. Forty-one patients who had progressive CLL were treated on study. Eleven patients (27%) were sensitive to fluda and thirty (73%) refractory prior to study entry. Therapy consisted of cis-p 100 mg/m2 continuous intravenous (i.v.) infusion over 4 days, fluda 30 mg/m2 i.v. over 15 minutes on Days 3 and 4 either given alone (PF) or with ara-C 500 mg/m2 i.v. over 1 hour on Day 4 (PFA). The median number of PF or PFA courses received was two. No patient achieved a complete response. Eight patients (19%) achieved a partial response (PR), 28 were taken off study with progressive or refractory disease and 5 had induction deaths. The overall median survival was 6 months, 15 months in responding patients, and 4 months in non-responding patients. Rai stage I-II patients had a median survival of 7 months and stage III-IV patients had a median survival of 3 months. Major toxicities (myelosuppression, sepsis, renal failure and tumor lysis syndrome) were frequent. In conclusion, it can be said that the PF and PFA regimens have equivalent modest activity in patients with progressive CLL following prior fluda therapy, predominantly among patients whose disease was sensitive to fluda at last prior exposure. Ara-C did not add to the activity of the cis-p/fluda combination in this study group.     

Long-Term Results of Chemoimmunotherapy With Fludarabine,Cyclophosphamide, and Rituximab for Patients With Relapsed and Refractory Chronic Lymphocytic Leukemia

IntroductionThe majority of patients with progressive chronic lymphocytic leukemia (CLL) will relapse after front-line treatment and will require salvage therapy. The addition of rituximab (R) to fludarabine (F) and cyclophosphamide (C) is associated with improved responses and relapse-free survival in untreated patients with CLL (Hallek et al, 2009) and patients with CLL in first relapse (Robak et al, 2008). We present an update of FCR in patients with relapsed or refractory CLL.Patients and MethodsWe administered FCR between November 1999 and 2008 to 284 patients with relapsed CLL. Patients received a combination of fludarabine 25 mg/m² day 1-3, cyclophosphamide 250 mg/m² day 1-3, and rituximab on day 1 at 375mg/m² for cycle 1, and 500 mg/m² for cycles 2 to 6. Patients were assessed for response by 1996 National Cancer Institute (NCI) Working Group response criteria and for time to failure of therapy (TTF) and overall survival (OS). We assessed standard pretreatment characteristics including response to prior therapy.ResultsPatients entered into the study had a median age of 60 years (31-84 years). Median number of prior treatments was 2 (range, 1-10). Responses included 86 patients with CR (31%), 41 nPR (15%), and 84 PR (30%); OR was 75%. Median OS is 46 months (95% CI, 41-54 months), and median TTF is 21 months (95% CI, 19-27 months). On multivariate analysis, the variables independently associated with longer TTF were younger age, higher platelets, lower lactate dehydrogenase (LDH) or serum creatinine, lower number of prior treatment, fludarabine sensitivity, and absence of chromosome 17 abnormalities on karyotype. Six full dose cycles of FCR were administered to 104 patients (36%). The most common hematologic toxicity was grade 3 and 4 neutropenia complicating 22% and 34% of treatment courses. Forty-six patients (16%) experienced one or more episodes of pneumonia or sepsis during or following treatment.ConclusionFCR is an effective regimen in patients with relapsed CLL. FCR should be considered as salvage therapy for patients in third relapse or less, not refractory to fludarabine or without chromosome 17 abnormalities or complex karyotype. Elderly patients (> 70 years) experienced more treatment-related toxicity and should be assessed for comorbidities prior to therapy.     

Impact of therapy With chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia Group B 9011.

PURPOSE: We sought to determine whether therapy with single-agent fludarabine compared with chlorambucil alone or the combination of both agents had an impact on the incidence and spectrum of infections among a series of previously untreated patients with B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Five hundred fifty-four previously untreated CLL patients with intermediate/high-risk Rai-stage disease were enrolled onto an intergroup protocol. Patients were randomized to therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Data pertaining to infection were available on 518 patients. Differences in infections among treatment arms were tested with the Kruskal-Wallis, Wilcoxon, and chi(2) tests. RESULTS: A total of 1,107 infections (241 major infections) occurred in 518 patients over the infection follow-up period (interval from study entry until either reinstitution of initial therapy, therapy with a second agent, or death). Patients treated with fludarabine plus chlorambucil had more infections than those receiving either single agent (P <.0001). Comparing the two single-agent arms, there were more infections on the fludarabine arm (P =.055) per month of follow-up. Fludarabine therapy was associated with more major infections and more herpesvirus infections compared with chlorambucil (P =.008 and P =.004, respectively). Rai stage and best response to therapy were not associated with infection. A low serum immunoglobulin G was associated with number of infections (P =.02). Age was associated with incidence of major infection in the combination arm (P =.004). CONCLUSION: Combination therapy with fludarabine plus chlorambucil resulted in significantly more infections than treatment with either single agent. Patients receiving single-agent fludarabine had more major infections and herpesvirus infections compared with chlorambucil-treated patients.     

Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia.

Thirty-three patients with chronic lymphocytic leukemia (CLL) with advanced Rai stage (III-IV) or progressive Rai stage (0-II) disease were treated with fludarabine as a single agent. Eleven patients (33%) obtained a complete remission (CR), 13 (39%) a clinical CR with residual nodules as the only evidence of disease (nodular partial remission [PR]), and two patients (6%) achieved a PR for a total response rate of 79%. Response was rapid, usually occurring after three to six courses of treatment. The major morbidity was infection. Febrile episodes occurred in 13% of the courses (pneumonia 6%, minor infection 4%, and transient fever of undocumented cause 3%). Fludarabine appears to be the most cytoreductive single agent so far studied in CLL.     

Assessment of 285 cases of chronic lymphocytic leukemia seen at single large tertiary center in Northern India

Abstract Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the West accounting for about 30% of leukemias, but about 2-4% in India. There is no large series reported from India, and hence we decided to undertake this study. We assessed the clinicohematological profiles and treatment outcomes in 285 patients seen over 11 years at our center (median age 59 years, 209 males). Sixty-three patients (22%) were asymptomatic and diagnosed incidentally. The median total leukocyte count at presentation was 50 × 10(9)/L. Rai stage distribution was: stage 0, 10%; stage I, 16%; stage II, 33%; stage III, 20%; and stage IV, 21%. Fifty percent of patients required treatment at presentation. Ninety-six patients received chlorambucil-based (overall response rate [ORR] 69%, complete remission [CR] 3%) and 27 patients received fludarabine-based (ORR 89%, CR 44%) chemotherapy. With a median follow-up of 2.9 years, the median overall survival (OS) and event-free survival (EFS) were 5.1 and 4.6 years, respectively. Fludarabine was more toxic, as half of the patients developed febrile neutropenia and various infections. The majority of patients presented with advanced stage disease. Fludarabine was less commonly used as first-line therapy. Advanced clinical stage (Rai III and IV) was associated with poor OS (hazard ratio [HR] 2.46, 95% confidence interval [CI] 1.19-5.11, p =?0.001) and EFS.     

CD38及ZETA相关蛋白在慢性淋巴细胞白血病中的表达及其临床意义

 【摘要】　目的　探讨CD38及ZETA相关蛋白（ZAP-70）在慢性淋巴细胞白血病（CLL）患者中的表达及其与临床分期的关系,分析其对预后的影响。方法　采用流式细胞术检测42例CLL患者CD38及ZAP-70的表达水平,根据Rai分期将患者分为高危组（Ⅲ、Ⅳ期）（25例）和低中危组（0、Ⅰ、Ⅱ期）（17例）,了解CD38和ZAP-70表达在Rai分期的分布情况,结合患者病情进展、化疗疗效进行分析。结果　CLL患者中CD+38者占47.6 %（20／42）,其中高危组 64.0 %（16／25）,低中危组 23.5 %（4／17）,两组差异有统计学意义（χ2＝6.645,P＝0.014）; ZAP-70+者占40.5 %（17／42）,其中高危组 60.0 %（15／25）,低中危组 11.8 %（2／17）,两组差异有统计学意义（χ2＝9.772,P＝0.003）; ZAP-70+ CD+38和ZAP-70+ CD-38 患者多分布在高危组中,而ZAP-70- CD-38患者多分布在低中危组中,差异均有统计学意义（χ2＝10.076、9.346、6.005,均P＜0.05）。随访48个月（1～136个月）后 ZAP-70+ CD+38及ZAP-70- CD-38患者无进展生存期分别为19.0和58.0个月,差异有统计学意义 （χ2＝11.488,P＝0.003）,而ZAP-70+ CD-38和ZAP-70- CD+38 患者无进展生存时间分别为43.5和51.7个月,差异无统计学意义（χ2＝0.075,P＝0.784）。结论　CD38和ZAP-70在CLL病程后期（Rai分期Ⅲ期和Ⅳ期）表达高于病程早期（Rai分期0期、Ⅰ期和Ⅱ期）,CD38和ZAP-70均阳性CLL患者较单阳性患者病情进展快,生存期明显缩短。     

Separation of chronic lymphocytic-leukemia (cll) cells by a discontinuous density gradient - correlation with clinical stage

Peripheral blood or bone marrow cells of 15 patients with chronic lymphocytic leukemia (CLL) were separated on an albumin density gradient. In 5 of 5 CLL patients, the distribution of malignant B lymphocytes was similar across the gradient when blood and bone marrow were compared, but different from the distribution of cells from healthy volunteers. In 10 patients, B cell colony formation was measured in vitro from peripheral blood cells after gradient fractionation. Although most of the cells in all patients were found in fraction 4, the majority of B-lymphocyte colonies were found in light density fractions (1+2, 3) in patients with more advanced disease (Rai stages 3 or 4), and in heavier fractions (4, bottom) in patients with less advanced disease (Rai stages 0, 1 or 2). The density of CLL cells might provide a new prognostic marker in this disease.     

A phase I/II trial of weekly docetaxel and gefitinib in elderly patients with stage IIIB/IV non-small cell lung cancer

BACKGROUND: Phase III trials in elderly patients with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) reveal treatment with single agent chemotherapy improves survival. The role of double agent therapy in this patient population is an area of investigation. METHODS: A phase I/II trial was performed in elderly patients (age>or=70 years) with stage IIIB/IV disease and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients were treated with gefitinib 250 mg daily. Patients received docetaxel on a treatment schedule of days 1, 8, 15 of an every 28 days schedule. The phase I portion of the trial consisted of dose escalation docetaxel from 30 to 36 mg/m2 using a three patient cohort design. The trial design contained continuous monitoring for excessive toxicity with pre-selected toxicity boundaries. RESULTS: Twenty-six patients were evaluable for efficacy and toxicity analysis. The median age was 75.5 years. The majority of the patients had stage IV disease (85%), ECOG functional status of 0-1 (81%), were male (65%), and current or former smokers (88%). Eleven patients experienced National Cancer Institute Common Toxicity Criteria grades 3-5 non-hematologic toxicity during the first cycle. The toxicity was determined to be unexpected, and the trial was discontinued. Overall response rate (complete+partial responses) was 31%, and the median survival was 6.5 months (95% confidence interval (CI) (3.6-9.0)), and estimated 1-year survival rate was 27% (95% CI (13-55%)). CONCLUSIONS: The combination of weekly docetaxel and gefitinib had activity; however, unexpected toxicity was observed in the elderly patient population.     

Chemoimmunotherapy may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with chronic lymphocytic leukemia

BACKGROUND:

An 11q22 deletion is considered an independent factor predicting poor survival in chronic lymphocytic leukemia (CLL).

METHODS:

We searched the electronic CLL database for consecutive patients who presented to the M. D. Anderson Cancer Center Department of Leukemia from October 2003 to April 2007 with untreated CLL and who had an 11q22 deletion, detected by fluorescence in situ hybridization (FISH) analysis of bone marrow samples. FISH analysis was performed using the following probes: trisomy 12 (12p11.1‐q11), TP53 (17p13.1), ATM (11q22.3), LAMP1 (13q34), and D13S319 loci (13q14.3).

RESULTS:

Sixty‐nine patients with untreated CLL with an 11q22 deletion were identified. The median patient age was 59 years (range, 26–81 years); 80% were men, 53% had Zubrod performance status >0, and 13% had Rai stage III to IV disease. Lymphadenopathy (massive), splenomegaly, anemia, and thrombocytopenia were present in 96% (12%), 19%, 9%, and 4%, respectively. In addition, 62% of patients had deletions in 13q, and 3% had trisomy 12. Forty patients required therapy for progressive disease. The overall response rates for FCR (fludarabine, cyclophosphamide, and rituximab), CFAR (FCR plus alemtuzumab), and rituximab plus granulocyte‐macrophage colony‐stimulating factor were 100%, 100%, and 33%, respectively. The 11q22 deletion was undetectable in 25 of 27 patients monitored after treatment using FISH analysis. The median follow‐up was 17 months. At 1 and 3 years, the survival rates were 97% and 91%, respectively, and the relapse‐free survival rates were 100% and 77%, respectively.

CONCLUSIONS:

CLL with an 11q22 deletion was associated with high rates of response, survival, and relapse‐free survival when treated with chemoimmunotherapy. Cancer 2009. © 2009 American Cancer Society.