the beginning of immunotherapy with the approval of the anti - cd20-specific monoclonal antibody ( mo - ab ) rituximab by the food and drug administration ( fda ) in 1997 , as part of the first - line treatment of non - hodgkin b - cell lymphoma ( nhl ) , marked an advance in response to treatment and overall survival in the lymphoproliferative disorders . the pivotal clinical trials of follicular non - hodgkin lymphoma ( f - nhl ) that compared anthracycline - based combination chemotherapy with and without rituximab showed clear superiority , with reduced relative risk for treatment failure by 60% and significantly higher overall response rate ( orr ) of 96% versus 90% , and prolonged duration of response . these results were significant ; however , cure can not be guaranteed and still remains a therapeutic goal . the particular radio sensitivity of lymphoid cells made radiation an attractive approach . radioimmunotherapy ( rit ) emerged as an option after mo - ab success , combining the selectivity of the anti - cd-20 immunotherapy with an attached radioisotope , making possible the delivery of radiation exactly within the tumor burden . in 2002 , the fda approved the first radioimmunoconjugate ( ric ) y - ibritumomab ( zevalin ) , and soon thereafter a second ric i - tositumomab ( bexxar ) was approved , both efficient for the treatment of indolent or transformed , relapsed or refractory b - cell lymphoma . y - ibritumomab tiuxetan ( y - it ) is a monoclonal igg1  anti - cd20 antibody attached to tiuxetan , a metal chelator who serves to stabilize the ytrium-90 radioisotope . it is a pure -emitter that produces higher energy and longer path length radiation than i - tositumomab , making it advantageous for bulky , poorly vascularized and heterogeneous antigen expression tumors , and also feasible for outpatient treatment because of its selective beta isotope emissions .   in 2002 , the phase iii randomized study that compared y - it with rituximab immunotherapy in 143 patients with relapsed or refractory low - grade follicular or transformed cd20 + nhl showed significant orr of 80% for the y - it group versus 56% for the rituximab group , and complete response ( cr ) rates of 30% versus 16% , respectively , with a median of duration of response ( dr ) of 14.2 months in y - it group versus 12.1 in control group , and time to progression ( ttp ) of 11.2 versus 10.1 months . the proven result of y - it superiority gave rise to further investigation and new therapeutic horizons extending its use on first - line consolidation therapy . the results of the phase iii randomized study of y - it as front - line consolidation , the first - line indolent trial ( fit ) published in 2008 , showed that y - it consolidation significantly prolonged median progression free survival ( pfs ) after a median of 3.5 years of observation , and converted 77% of partial response ( pr ) after induction into cr , resulting in a cr rate of 87% with low - associated toxicity [ 5 , 6 ] . since september 2005 , therapy with y - ibritumomab tiuxetan ( zevalin ) has been available in the miguel servet university hospital . firstly applied only for relapsed and refractory f - nhl and after the approval included as part of consolidation therapy after first - line induction chemoimmunotherapy in patients with f - nhl . we have treated since then 65 patients , with an everyday clinical practice protocol , with same inclusion criteria and less subjective variations , reasons that make us believe our experience could be of great value . we have created a clinical protocol conducted by a multidisciplinary team formed by clinical hematologists , nuclear medicine physicians , radiopharmacy physicians , and nurses in the miguel servet university hospital at saragossa , spain . it was started in september 2005 and established the use of y - it in patients with an excisional biopsy confirming the diagnosis of cd20 + f - nhl grade 1 , 2 , or 3 according to the revised classification system of the world health organization ( who ) , and who had relapsed or refractory disease after at least a first - line combined chemotherapy , patients had been diagnosed and treated within the same center . in 2007 , the therapeutic inclusion was extended as consolidation after first - line chemotherapy in patients with complete or partial response confirmed by pet / ctscan . before undergoing into rit consideration , all patients were thoroughly examined and had a complete blood count ( cbc ) with leukocyte differential and platelet count , positron emission tomography pet / ctscan , and bone marrow aspiration , and biopsy was carried out . they were also tested for general blood chemistry ( including serum creatinine , liver function tests , uric acid , and lactate dehydrogenase ) . additional inclusion criteria applied to all cases were absolute neutrophil count ( anc )  1,500/l , absolute platelet count ( apc )  100,000/l , and bone marrow total lymphocytes  25% by morphological counting , also serum bilirubin  2.0  mg / dl and serum creatinine  2.0  mg / dl . the therapeutic approach included the intravenous infusion of rituximab on day 1 , at a dose of 250  mg / m , to reduce nonmalignant binding with cd20 + circulating b cells and within the spleen , and the infusion of a second dose of rituximab at 250  mg / m on day 7 , followed by weight - based dose of y - it administered as slow intravenous push over 10 minutes within the next 4 hours of rituximab infusion . the dose of y - it was 0.4  mci y / kg in patients with platelet count > 150 , 000/l , and 0.3  mci y / kg in patients with platelet count between 149,000 and 100,000/l . a cbc was performed weekly in all patients within first 4 weeks after y - it infusion , or until if present , grade 3 or 4 cytopenia recovered , and then every two weeks until the cbc had normalized . the target for transfusion was an apc less than 20,000/l in outpatients and hemoglobin level less than 8  g / dl or symptomatic anemia with poor tolerance . prophylactic antibiotic therapy with levofloxacine was provided in all patients with an anc less than 1,000/l until resolution , and those patients with grade 4 neutropenia received a single dose of pegg - csf for recovery . response assessment was made 12 weeks after treatment ; pet / ctscan was performed in all cases , and response criteria used were the same as the international working group ( iwg ) . subsequent follow - up evaluation also included cbc and physical examination every 3 - 4 months within the first 2 years after y - it therapy , and then every 6 months until relapse or death . a second pet / ctscan was performed at the first year of therapy , and a neck - chest and abdomino - pelvic ctscan was performed at the 5th year of y - it administration . we assessed time to progression ( ttp ) , overall response ( or ) and os in all patients . we also registered side effects , with special emphasis in myelotoxicity and emerging second neoplasms . or was performed following the iwg criteria and classified as complete response ( cr ) , partial response ( pr ) , and no response ( nr ) . ttp and os were calculated from the date of y - it therapy until disease progression or death . a database was created , and the statistical analysis of variables was performed with spss 15.0 program . descriptive statistics , cis and statistical analysis of patient characteristics , response rate , and adverse events were descriptive . analysis of ttp and os were performed on intent to treat basis and were calculated by the kaplan - meier method with cis . between september 2005 and february 2012 a total of 65 patients who met the previously defined eligible criteria were treated with y - it in our hospital . 56 patients completed the follow - up and were considered into the analysis . within demographic characteristics females were slightly more prevalent than males 55.4% ( 36 ) versus 44.6% ( 29 ) . mean age was 61.45 years ( 3085 ) , with overall good performance ecog 0 - 1 in 96.9% of cases . the ann arbor stage distribution was ia 2 ( 3.1% ) ; iia 6 ( 9.2% ) ; iib 2 ( 3.1% ) ; iiia 5 ( 7.7% ) ; iiib 7 ( 10.7% ) ; iva 25 ( 38.5% ) ; ivb 18 ( 27.7% ) . a total of 43 patients had bone marrow involvement at diagnosis . according to prognostic flipi score , the patient distribution was 58.5% ( 38 ) good , 29.2% ( 19 ) intermediate , and 12.3% ( 8) poor . 40% ( 26 ) patients had received more than two different combined chemotherapy schedules . according to status before y - it therapy , the patients were classified as consolidation after first - line therapy 22 ( 33.84% ) , relapsed with more than 12 months after previous therapies 31 ( 47.69% ) , refractory to rituximab schedules 7(10.77% ) , and partial response after first - line therapy 5 ( 7.70% ) . cr in relapsed disease 90% ( 27/30 valuable patients ) , in refractory disease 42.8% ( 3/7 ) , in consolidation with cr after first - line therapy : 92.8% ( 13/14 valuable patients ) , and 100%(5/5 ) of patients that were in pr after first - line induction therapy converted to cr . pr was seen in 8.9% ( 5/56 valuable patients ) and only 3 had no response . 16% ( 9/56 ) were non valuable patients , 8 were still within the first 12 weeks after y - it infusion , and 1 contact loss . according to bone marrow involvement 90.5% of patients obtained a complete response ( 38 of 42 patients ) . mean ttp in patients with relapsed disease was 52.56 months ( cis 95% : 42.3162.81 ) , with refractory disease 12.43 months ( cis 95% : 7.8617 ) , consolidation in cr after first - line induction therapy was 38.81 months ( cis 95% : 32.8744.76 ) , and consolidation in pr after first - line induction therapy was 27,25 months ( cis 95% : 14.7539.75 ) . by the end of the study 28.5% ( 16 ) have relapsed ( figure 2 ) . overall mean ttp was 52.65 months ( sd+ 5.03 , cis 95% : 43.8361.48 ) ( figure 3 ) . the mean estimated os was 63.86 months ( ci 95% : 57.2270.48 ) ( figure 4 ) . median estimated for os and global ttp could not be calculated because of the good response of our patients at a median follow - up time of 57 months ( range 273 ) . grade 3 - 4 thrombocytopenia was the most frequent hematological toxicity presented in 35.7% 20 patients , with a median time of onset around the 4th week after y - it infusion and spontaneous recovery around 8th week . 19% of patients developed grade 3 - 4 neutropenia within 4 weeks after y - it infusion , and spontaneous recovery occurred approximately 2 weeks later . four patients had concomitant neoplasm at the time of treatment ( colon , lung , breast , and prostate ) , and one patient developed prostate neoplasm four years after treatment at the age of 75 . y - it therapy has proven to be efficient achieving complete and durable response rates including pretreated and rituximab refractory f - nhl patients , but there are not manylong term studiesusing this approach in relapsed / refractory follicular non - hodgkin lymphoma patients andconsolidation [ 4 , 5 , 79 ] . the previous reported orr on patients withrelapsed / refractory follicular non - hodgkin lymphoma receiving y - it therapy is as high as 73% , and ttp as long as 3 or more years with even long - term responders reported ( > 5 years ) . the study published by zinzani et al . in a single center with 57 patients evaluated the long - term outcomes of y - it and reported orr of 93% at a median followup of 48 months and cr as high as 70% . the median duration of response is estimated in 14.2 months   and more than 20 months   in two different publications . in our study , the study fit randomized phase iii trial demonstrated a clear prolongation in ttp , higher response rates , and improvement of response in partial responders [ 5 , 11 ] , emerging the need of further investigation to establish a well defined therapeutic approach . the results obtained in our experience can be equalized with those previously reported elsewhere [ 1015 ] . the cr achieved was 85.7% ; overall ttp was around 52.65 months , with a mean estimated os of 63.86 months and a mean follow - up time of 57 months ( range 273 ) , even in patients with bone marrow involvement at diagnosis . it seems that rit with y - it in early stage of treatment induces higher and maintained cr , ttp , and os ( figure 3 ) . the evaluation of response to rit , assessed by fdg - pet , has been reported as a main predictor of pfs , being pet / ctscan result post - rit the only independent predictive factor . y - it was a good - tolerated and low - toxic therapy for the majority of patients , even for those heavily treated . the adverse events and myelotoxicity presented were expected , manageable , and transient , and there were none major side effects or related mortality , making it safe for outpatient administration and even suitable for elderly patients . the addition of y - it into f - nhl treatment improves response and progression free survival of disease , both as part of relapsed or refractory disease , and as consolidation therapy after first - line induction treatment . yet , still there is not unified criteria of the best approach and timing of rit incorporation into treatment , and which chemotherapeutic associations can offer better response at less toxicity . this field needs further investigation in order to adequate rit into schemes and take advantage of what seems a promising therapeutic tool .
background . based on historical data we reviewed our hospital clinical database to analyse our updated information and therapy outcomes of follicular non - hodgkin lymphoma ( f - nhl ) patients treated with 90y - ibritumomab tiuxetan . 
 patients and methods . between 2005 and 2011 , 56 f - nhl patients were included in a clinical protocol conducted by a multidisciplinary team and treated in the same centre . all patients received 0.3 or 0.4  mci / kg iv ( 88% ) of 90y - it ; response evaluation was performed 12 weeks after . 
 results . 
 m / f 44.6%/55.4% , mean age 61.45 years ( 3085 ) ; ecog 0 - 1 96.9% . according to flipi score , 
 distribution were good : 58.5% , intermediate : 29.2% , and poor : 12.3% . 
 previous therapies : > 2 : 40% ( 26 ) . 
 orr was 94.6% ( 53/56 ) . 
 cr : 85.7% ; cr according to previous disease : relapsed disease : 90% ( 27/30 ) , refractory disease : 42.85% ( 3/7 ) , consolidation with cr : 92.85% ( 13/14 ) , and consolidation with pr : 100% ( 5/5 ) . global pr and nr 
 were 8.9% ( 5 ) and 5.3% ( 3 ) , respectively . 
 mean os 63.86 months with a mean follow - up time of 57 months ( 273 ) . 
 mean ttp : 52.65 months ( 95% ci : 43.8361.48 ) . 
 median os and ttp were not achieved . 
 no hospital submissions or deaths were registered . conclusions . 
 this study confirms the safety and high efficacy of 90y - it in f - nhl patients , rit in early stage of disease could improve outcomes .