***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 × 109/l ) or granulocytopenia ( neutrophils > 1.5 × 109/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 Rituximab ( IDEC-C2B8 ) is a chimeric antibody that binds to the B-cell surface antigen CD20 . Rituximab has significant activity in follicular non-Hodgkin lymphomas . Much less is known about the effects in chronic lymphocytic leukemia ( CLL ) . We have initiated a phase II trial to evaluate the efficacy and safety of rituximab in patients with CD20 + pretreated CLL . To avoid the rituximab-associated toxicity , we restricted the tumor cell load , as measured by the number of circulating lymphocytes and the spleen size , in the first 2 cohorts of patients included in the study . Patients received 4 intravenous infusions of 375 mg/m2 once a week over a period of 1 month . Of the 28 patients evaluable for response , 7 patients showed a partial remission ( National Cancer Institute criteria ) lasting for a median of 20 weeks , with 1 patient still in remission after 71 weeks . Based on lymphocyte counts only , we found at least a 50 % reduction of lymphocyte counts lasting for at least 4 weeks in 13 ( 45 % ) of 29 patients . Fifteen patients from 3 institutions were monitored for the immunophenotype profile of lymphocyte subsets . The number of CD5+CD20 + cells decreased significantly and remained low until day 28 after therapy . T-cell counts were not affected . With the exception of one rituximab-related death , adverse events in the remaining patients were mild . The results suggest that rituximab has clinical activity in pretreated patients with B-CLL .  Toxicity is tolerable . Response duration after withdrawal of rituximab is rather short . Therefore , other modes of application and the combination with other agents need to be tested OBJECTIVES This prospect i ve multicentre study was conducted to assess the efficacy of the monoclonal anti-CD20 antibody rituximab in patients with chronic lymphocytic leukaemia ( CLL ) . Secondary objectives were defined as the tolerability and feasibility of rituximab in patients with CLL . METHODS Twenty-four heavily pretreated patients with CLL were treated with a st and ard dose of 375 mg m-2 of rituximab given once weekly for four doses . RESULTS The overall response rate was 35 % and all the responses were partial as defined by the revised NCI criteria . In 17 ( 85 % ) of 20 patients with initially measurable peripheral lymph nodes the size of lymph nodes decreased by at least 50 % , while an improvement of the bone marrow infiltration was observed only in two ( 11 % ) of 18 evaluable patients . The median duration of the overall response was 12.5 wk . Rituximab was relatively well tolerated . Although side-effects were common ( 75 % ) they were usually mild or moderate . There was only one grade 3 adverse event and no grade 4 events . CONCLUSIONS St and ard-dose rituximab has activity in heavily pretreated patients with CLL , although the response is mainly limited to the lymph nodes and of short duration . Since rituximab has in vitro synergism with chemotherapeutic agents and is well tolerated by CLL patients , it is reasonable to investigate rituximab in combination with other treatments We have developed a new chemoimmunotherapy for patients with relapsed or refractory CD20-positive indolent lymphomas and CLL by combining the chemotherapeutic agents Bendamustine ( B ) and Mitoxantrone ( M ) with the monoclonal antibody Rituximab . Treatment consisted of ( B ) : 90 mg/m2 ( 80 mg/m2 in CLL ) day 1 + 2 , ( M ) : 10 mg/m2 day 1 and ( R ) : 375 mg/m2 day 8,15,22 and 29 . BM was repeated 3 times starting on day 36 , thereafter every 4 weeks . The maximal therapy consisted of 1 × BMR followed by 5 × BM . We have treated 54 patients with BMR . Median age was 68 years ( 36 - 82 ) . Disease distribution was as follows : 21 B-CLL , 1 B-PLL , 8 lymphoplasmacytic , 14 follicular , 2 mantle cell , 2 marginal zone , 6 secondary high grade . Median number of previous treatments was 2 ( 1 - 7 ) . ORR was 96 % with 41 % CR and 55 % PR . Median time to progression is 17 months in CLL and has not been reached in indolent lymphomas with a median observation time of 27 months ( 3 - 60 + ) . The time to next antilymphoma treatment is prolonged significantly by BMR . No therapy associated death or hospitalization occurred within the study period . BMR is a well tolerated very effective outpatient treatment for relapsed and refractory CD20-positive indolent lymphomas and CLL PURPOSE Richter 's syndrome ( RS ) and fludarabine-refractory chronic lymphocytic leukemia ( CLL ) are associated with poor clinical outcomes . We conducted a phase I-II trial of oxaliplatin , fludarabine , cytarabine , and rituximab ( OFAR ) in these diseases . PATIENTS AND METHODS The OFAR regimen consisted of increasing doses of oxaliplatin ( 17.5 , 20 , or 25 mg/m(2)/d ) on days 1 to 4 ( phase I ) , fludarabine 30 mg/m(2 ) on days 2 to 3 , cytarabine 1 g/m(2 ) on days 2 to 3 , rituximab 375 mg/m(2 ) on day 3 of cycle 1 and day 1 of subsequent cycles , and pegfilgrastim 6 mg on day 6 , every 4 weeks for a maximum of six courses . Dose-limiting toxicity ( DLT ) was defined as any nonhematologic , treatment-related toxicity > /= grade 3 . RESULTS Fifty patients were treated ( 20 patients had RS , and 30 had CLL ) . The highest tolerated oxaliplatin dose was 25 mg/m(2 ) , which was the highest dose tested . DLT was not observed . Pharmacodynamic analyses demonstrated enhanced leukemia cell killing by oxaliplatin in the presence of fludarabine and cytarabine . The overall response rates were 50 % in RS and 33 % in fludarabine-refractory CLL . The overall response rate  in 14 patients with age > /= 70 years was 50 % . Responses were achieved in seven ( 35 % ) of 20 patients with 17p deletion , two ( 29 % ) of seven patients with 11q deletion , all four patients with trisomy 12 , and two ( 40 % ) of five patients with 13q deletion . The median response duration was 10 months . Toxicities were mainly hematologic ; prolonged myelosuppression was not observed . CONCLUSION The OFAR regimen is highly active in RS and has activity in fludarabine-refractory patients with CLL . This regimen warrants further investigation in the treatment of these disorders PURPOSE Rituximab has been reported to have little activity in small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia ( CLL ) and to be associated with significant infusion-related toxicity . This study sought to decrease the initial toxicity and optimize the pharmacokinetics with an alternative treatment schedule . PATIENTS AND METHODS Thirty three patients with SLL/CLL received dose 1 of rituximab ( 100 mg ) over 4 hours . In cohort I ( n = 3 ; 250 mg/m(2 ) ) and cohort II ( n = 7 ; 375 mg/m(2 ) ) rituximab was administered on day 3 and thereafter three times weekly for 4 weeks using a st and ard administration schedule . Cohort III ( n = 23 ; 375 mg/m(2 ) ) administered rituximab similar to cohort II for the first two treatments and then over 1 hour thereafter . RESULTS A total of 33 CLL/SLL patients were enrolled ; only one patient discontinued therapy because of infusion-related toxicity . Thirteen patients developed transient hypoxemia , hypotension , or dyspnea that were associated with significant changes in baseline interleukin-6 , interleukin-8 , tumor necrosis factor alpha , and interferon gamma compared with those not experiencing such reactions . Infusion-related toxicity occurred more commonly in older ( median age 73 v 62 years ; P = .02 ) patients with no other pretreatment clinical or laboratory features predicting occurrence of these events . The overall response rate was 45 % ( 3 % CR , 42 % PR ; 95 % CI 28 % to 64 % ) . Median response duration for these 15 patients was 10 months ( 95 % CI , 6.8 - 13.2 ; range , 3 to 17 + ) . CONCLUSION Rituximab administered thrice weekly for 4 weeks demonstrates clinical efficacy and acceptable toxicity . Initial infusion-related events seem to be cytokine mediated and resolve by the third infusion making rapid administration possible . Future combination studies of rituximab with other therapies in CLL seem warranted Safety and efficacy of the fully human anti-CD20 monoclonal antibody , ofatumumab , was analyzed in a multicenter dose-escalating study including 33 patients with relapsed or refractory chronic lymphocytic leukemia . Three cohorts of 3 ( A ) , 3 ( B ) , and 27 ( C ) patients received 4 , once weekly , infusions of ofatumumab at the following doses : ( A ) one 100 mg and three 500 mg ; ( B ) one 300 mg and three 1000 mg ; ( C ) one 500 mg and three 2000 mg . Sixty-seven percent of the patients were Binet stage B , and the median number of previous treatments was 3 . The maximum tolerated dose was not reached . The majority of related adverse events occurred at first infusion , and the number of adverse events decreased at each subsequent infusion . Seventeen ( 51 % ) of 33 patients experienced infections , 88 % of them of grade 1 - 2 . One event of interstitial pneumonia was fatal ; all other cases resolved within one month . The response rate of cohort C was 50 % ( 13/26 ) , one patient having a nodular partial remission and 12 patients partial remission . In conclusion , ofatumumab was found to be well tolerated in patients with chronic lymphocytic leukemia ( CLL ) in doses up to 2000 mg . Preliminary data on safety and objective response are encouraging and support further studies on the role of  ofatumumab in CLL patients . This trial was registered at www . clinical trials.gov as no. NCT00093314 We conducted a multicenter , community-based phase II trial of PCR biochemotherapy ( pentostatin 4 mg/m2 , cyclophosphamide 600 mg/m2 , and rituximab 375 mg/m2 ) every 3 weeks for up to 6 cycles in patients with chronic lymphocytic leukemia ( CLL ) or small lym 
    Output:
    
The identified studies indicate that regimens containing rituximab may be highly efficacious in the fludarabine-refractory CLL setting .