chronic myeloid leukemia ( cml ) is a myeloproliferative disease that represents 15%25% of all leukemias .
the disease was the result of a reciprocal translocation between chromosome 22 and chromosome 9 , the so - called philadelphia translocation .
this rearrangement joins the c - abl gene on chromosome 9 and bcr on chromosome 22 creating a bcr - abl fusion gene , which codes for a 190230 kda , bcr - abl fusion protein with elevated tyrosine kinase activity .
the upregulated bcr - abl fusion protein includes the tyrosine kinase domain , which likely contributes to dysregulation of the mechanism of cellular signals transduction , normally involved in controlling apoptosis , proliferations , and cell - cell adhesions , and thus promoting leukemogenesis .
the abrogation of bcr - abl function has become a model for development of targeted therapies .
the enzymatic inhibition of bcr - abl using imatinib mesylate ( gleevectm , sti571 ; novartis pharmaceutical corp .
, east hanover , nj ) has been shown to possess potent in vitro and in vivo activities in preclinical studies     [ 3 , 4 ] .
the activity of this inhibitor in patients with previously treated cml was further confirmed in early clinical trials     [ 57 ] .
recently , the landmark international randomized study of interferon versus sti571 ( iris ) study has shown cytogenetic responses in 87% of their patients after 5 years of imatinib as a primary treatment     . over the past few decades , allogeneic bone marrow transplantation ( allo - bmt ) has been used to treat cml and other malignant and nonmalignant diseases .
however , this success is frequently not maintained since leukemic relapse substantially occurs in 30% to 60% of patients who undergo transplantation during the advanced stages of disease ( accelerated phase and blast crisis ) and 5% to 20% of those who undergo transplantation during the chronic phase     .
moreover , the impact of this potential treatment is limited because it depends considerably on the patient 's age and availability of a genetically cross matching donor with the same tissue type to prevent rejection .
the infusion of donor lymphocytes ( dli ) into cml patients who have relapsed following an allo - bmt has been frequently used and proved to effectively treat 70%80% of patients with relapsed chronic leukemia . however , this therapeutic option is less effective in patients with more advanced disease and may also be associated with severe marrow aplasia , high incidence of chronic graft - versus - host disease ( gvhd ) , and transplant - related mortality     [ 1012 ] .
several studies have shown that the administration of imatinib is safe and highly effective in controlling leukemic relapses after allo - bmt     [ 13 , 14 ] .
these compelling facts have made us adopt imatinib therapy as the preferred treatment at our institution . in this study
, we performed a retrospective analysis to determine the efficacy of imatinib administration in treating leukemic relapses after allo - bmt .
from january 2005 to january 2009 , a total of 7 cases with primary relapse of cml after allo - bmt undergoing treatment with imatinib were found after a retrospective search of the cml database at the department of cml ambulatory of the hospital das clinicas , so paulo university .
patients ' medical records were reviewed for the following : sex , age , date of cml diagnosis , time from diagnosis to transplant , time from transplant to relapse , disease stage at relapse , and other variables as shown in table 1 .
the extent of cml was staged ( chronic , accelerated or blast phase ) according to the 2008 revision of the world health organization staging system . in all patients ,
complete blood counts were performed weekly for the first month of follow - up and monthly thereafter .
quantification of bcr - abl transcript numbers was measured every 3 months by real - time pcr and conventional bone marrow cytogenetics were performed every 6 months and then every 12 months .
cytogenetic response was classified as complete ( no ph chromosome - positive cells in metaphase in the bone marrow ) , partial ( 1%34% ph chromosome - positive cells ) , or minor ( 35%90% ph chromosome - positive cells ) .
molecular response was considered major if the bcr - abl level was below 0.1% and complete when it was negative .
toxicities were assessed according to the national cancer institute common toxicity criteria version 3.0 ( national cancer institute , bethesda , md ) .
posttransplant allogeneic hematopoietic chimerism was evaluated by fluorescent - based pcr amplification and capillary gel electrophoresis of microsatellite dna str markers in sequential peripheral blood and bone marrow samples from the recipients using established techniques     .
curves of overall survival and progression free survival were estimated using the kaplan and meier method .
all 7 patients received an allogeneic peripheral blood progenitor cell from hla - identical sibling .
the median time to diagnosis was 7.4 years after transplant . at the time of relapse
, four patients were classified as having a hematologic relapse , two as having a major molecular relapse , and one as having a cytogenetic relapse . the mean time from allobmt to detection of relapse was 4.02 years .
two patients received a dli as a salvage therapy after relapse to enhance donor engraftment without response .
of the seven patients , five had cml in a chronic phase at the time of imatinib initiation , while one patient was diagnosed as having accelerated phase and blast crisis .
imatinib was given at a dose of 400 mg / d ( five patients ) or 600 mg / d ( two patients ) .
this latter patient was in blastic crisis before imatinib administration and died of rapid disease progression 7 months after initiation of therapy , before hematologic recovery .
eventually , all patients could be evaluated for the therapeutic efficacy . at a mean of follow - up of 1.8 years of imatinib therapy ,
all but one patient had achieved complete hematologic , cytogenetic , and major molecular response .
response to imatinib was then evaluated based on relapse classification and found that all but one patient with hematologic relapse achieved major molecular response .
analyses of the safety data in patients who remained alive indicate that the treatment was generally well tolerated and that most of toxicities were mild and transient .
four patients experienced grade 2 hematological toxicities , while one patient developed grade 2 alterations in hepatic enzymes .
the estimated overall and progression - free survivals were 7.1 and 2.1 years , respectively .
a number of therapeutic interventions have met with varying degrees of success in the treatment of cml patients with relapse after allo - bmt .
these options include a second transplant     [ 19 , 20 ] , conventional cytotoxic chemotherapy , and interferon - alpha     . each treatment , however , has limitations .
for example , although the option of second allo - bmt offers a prospect of cure , it is limited to young patients with good performance status and is associated with a very poor outcome     [ 10 , 21 , 22 ] .
evidence from several reports indicated a high remission rate ( 70%80% ) after dli in chronic phase cml .
however , the success of this option has been limited by short duration of response , myelosuppression , significant gvhd , and rare long - term survival [ 1 , 5 , 19 ] .  
it is therefore important to consider the effects of the alternative therapies listed above on outcomes .  
the recent use of imatinib mesylate as new therapeutic approach is eventually become accepted as the preferred treatment of posttransplant relapse setting and offers a number of potential advantages over dli including fewer adverse effects and relatively rapid and durable response . apart from our study ,
several anecdotal and clinical trials have examined the use of imatinib in patients with relapse after bmt .
the largest of these was a prospective phase ii open label multicenter study by hess et al .      who examined the use of imatinib therapy in 44 relapsed patients .
in this 494-day median follow - up study , patients were treated with imatinib at starting dose of 400 mg / d and escalated to 600 mg / d to 800 mg / d if patients did not achieve mmr . of the 37 patients assessable for efficacy analysis , a total of 23 patients ( 62% ) had a cmr during the initial 9 months , which improved to 70% during follow - up .
therapy was generally well tolerated , with a main adverse event of neutropenia / leucopenia .
the review by palandri and coworkers   of the outcomes of 16 patients who received imatinib as first or second line therapy showed that 93% of this group achieved a molecular negativity after 327 months and 75% had negative reverse transcriptase - polymerase chain reaction after 1245 months .   similarly , hayat et al
.   found , in a group of 14 patients who relapsed postallo - bmt from the preimatinib era , that 93% had achieved excellent response to imatinib with a median time of 4 months . in this study , although the sample size is small , imatinib maintained mmr in all 6 evaluable patients for an average time of 21 months of follow - up .
all patients are still on treatment with imatinib and have full - donor chimerism according to the last analysis .
generally , the results presented here compare favorably with the outcomes from previous studies     [ 13 , 19 , 25 ] and lend support to the conclusion that the imatinib therapy is efficiently improving outcome even further in patients with relapse after bmt particularly for chronic phase cml without compromising safety .
although the introduction of imatinib has obviously been a major step forward a high objective response and disease stabilization rate in patients with relapse after bmt , several questions still remain open . among them , how well does imatinib perform over the long - term of therapy ?
is there a tendency for some patients to gradually relapse overtime passage ? can patients eventually stop their therapy without relapsing ? to provide answers to these questions , additional double - blind imatinib - placebo controlled research of long - term follow - up is needed to further evaluate the safety of a long - term , continuous therapy with the imatinib in a large number of patients with relapse after bmt .
 we describe the 
                   response of imatinib as lifesaving treatment of 
                   chronic myeloid leukemia ( cml ) relapse in seven 
                   patients who underwent allogeneic bone marrow 
                   transplantation ( allobmt ) at our institution 
                   over a period of 4 years . 
 retrospective analysis 
                   of their medical records revealed that a mean age at 
                   transplant was 45.2 years . 
 the median time to 
                   diagnosis was 7.4 years after transplant . at 
                   relapse , 
 four , two , and one patients were 
                   classified as having hematologic , major 
                   molecular , and cytogenetic relapse , respectively . 
                   at imatinib initiation , 
 five had cml in a 
                   chronic phase , while one patient was 
                   diagnosed as having accelerated phase and blast 
                   crisis . 
 all these patients could be evaluated 
                   for the therapeutic efficacy . at a mean of 
                   follow - up of 1.9 years of therapy , all 
 evaluable 
                   patients achieved major molecular response 
                   without compromising safety . 
 consistent with 
                   available data , our results indicate that 
                   imatinib is safe and effective treatment option 
                   for patients with relapse after 
                   bmt . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion