over last three decades , the role of hematopoietic stem cell transplant ( hsct ) in chronic myeloid leukemia ( cml ) has seen several phases and continues to be defined . in 1980 's ,
hsct came as a revolutionary concept that offered cure from cml . in 1990 's ,
transplant methodologies were refined , which resulted in increased cure rates and decreased transplant - related mortality .
survival outcomes improved significantly in chronic phase patients with 3 years survival rate of more than 80% .
thirty years later , it is still the only treatment that offers cure in cml .
the ability of allogeneic hsct to cure cml is related to the antileukemic effects of both the conditioning regimen and the graft versus leukemia ( gvl ) effect of the donor lymphocytes . however , with the advent of imatinib in early 2000 's the natural history of cml was changed and so did the way we treated cml . with the excellent response rates and minimal toxicity imatinib soon became the treatment of choice for chronic phase cml , and it was thought that hsct was no longer needed at least in chronic phase . however , as our experience with imatinib increased , issues of resistance / intolerance in chronic phase emerged . at 18 months of treatment , imatinib resistance
also , the treatment of advanced phase disease ( accelerated and blast phases ) with imatinib proved to be inadequate .
second - generation tyrosine kinase inhibitors ( tkis ) including dasatinib and nilotinib were able to achieve < 50% complete cytogenetic response ( ccyr ) in imatinib resistant / intolerant cases .
thus , transplantation still has a definite , though more limited , role in the treatment of cml .
in advanced phase disease , treatment with tkis can achieve initial good response ( second chronic phase ) .
however , such responses are usually short lived and do not appear to be associated with long - term survival . in one study ,
the rate of major cyr and ccyr in accelerated phase patients treated with imatinib at 600 mg / day was only 24% and 17% , respectively . in another analysis of three phase ii studies of cml patients in blast crisis treated with 600 mg / day imatinib , at 36 months only 7% were disease free and only 14% were alive .
however , it would be prudent to start the patient on a tki for two reasons .
first , it tides over the time period required to find human leukocyte antigen ( hla ) matched unrelated donor if hla - matched sibling is not available .
second , cure rates in advanced phase disease are better if transplanted in second chronic phase . among patients in chronic phase treated with imatinib as first line tki therapy , approximately 20% will fail primary therapy , either from intolerance , relapse or progression to advanced phase disease .
it is reasonable to consider hsct at the time of first - line failure . however ,
secondary tki therapy should be started at the time of resistance for two reasons - first , a ccyr on secondary therapy is achieved in approximately 50% patients second , a donor search may take months .
patients who relapse with a t315i mutation should proceed to transplant at the earliest , given the low - response rate to secondary therapy .
similarly , those who have a mutation within the p loop region , which is known to be associated with an increased risk of progression to advance phase disease , transplant is a reasonable option .
thus , current indications for transplant in cml include [ figure 1 ] : 
 advanced phase disease ( accelerated phase and blast crisis)resistance / intolerance to tkisrelapse on tkis . 
 
advanced phase disease ( accelerated phase and blast crisis ) resistance / intolerance to tkis algorithm for consideration of hematopoietic stem cell transplant in chronic myeloid leukemia
several factors influence the outcome of allogeneic hsct in cml , most importantly the phase of the disease , but also , the type of donor used , the nature of the stem cell product , and the age of the patient .
the european group for blood and marrow transplantation ( ebmt ) devised a risk score based on five separate characteristics , which predicted treatment - related mortality and 5 years overall survival following allogeneic hematopoietic cell transplantation .
this system uses hla matching , stage , age , sex of donor / recipient and time from diagnosis to transplant as risk factors .
survival at 5 years varied from 72% for the best score to 22% for the worst score .
the ebmt risk score was later validated using separate data from the international bone marrow transplant registry . however , the value of this prognostic scoring system is largely for prognostication rather than decision - making .
five years disease - free survival varies from 90% in chronic phase to 40 - 50% in accelerated phase to 10 - 20% in blast crisis .
outcome of patients in blast crisis who achieve a second chronic phase with tki therapy is similar to that of patients in accelerated phase .
advances in hla typing and graft versus host disease ( gvhd ) therapy has improved transplant outcomes in cml .
results with a fully matched unrelated donor are quite similar to that achieved with a matched - related donor .
bone marrow harvest has been replaced by peripheral blood mobilization for stem cell collection making the procedure more donor compliant .
two randomized trials involving patients with various hematologic malignancies , including cml , concluded that use of granulocyte colony - stimulating factor mobilized peripheral blood stem cells lead to faster myeloid and platelet recovery , no significant difference in acute or chronic gvhd and an overall survival advantage compared with bone marrow .
however , another study in chronic phase cml showed no significant difference in the outcome between the bone marrow and peripheral blood groups . in earlier studies , younger age has been shown to improve survival after hsct in cml , however , better supportive care , better donor selection and use of reduced intensity conditioning regimens have dampened the effect of age on survival outcome .
some studies had suggested that increased interval from diagnosis to transplant was associated with a worse transplant outcome , higher relapse rate and an increase in nonrelapse mortality .
this was attributed to the development of resistant clones associated with a longer delay to transplantation .
another factor implicated in affecting outcome in earlier studies was the use of prior imatinib , which was shown to be associated with an increase in regimen - related toxicity and mortality , especially from hepatic causes .
however , larger studies have shown that there is no deleterious effect of the pretransplant imatinib on outcome .
furthermore , patients with abl mutations have similar outcomes compared with those with no mutations following transplantation .
on average 5 - 20% of the chronic phase patients and 30 - 60% of advanced phase patients relapse following allo - hsct . increased incidence of relapse is seen with hsct strategies involving t - cell depletion and use of reduced intensity conditioning regimens .
an increasing level of bcr - abl transcript measured by quantitative polymerase chain reaction is predictive of impending disease relapse and needs intervention .
modalities available to prevent and/or treat posttransplant relapse include donor lymphocyte infusion ( dli ) therapy , tki therapy , interferon therapy and infusion of in vitro stimulated cd8 t cells .
dli have been very effective ( 70 - 90% complete remission rate ) for patients who relapse with chronic phase .
the efficacy of dli is the result of gvl effect which is highly pronounced in cml .
however , the drawbacks of dli are ( 1 ) advanced phases of the disease are least responsive to dlis , ( 2 ) effect of dli may last for few months and repeat dli may be required and ( 3 ) it may be complicated by life - threatening gvhd . tki therapy with imatinib
is highly effective in treatment of posttransplant relapse . in a study of 28 cml patients who were treated with imatinib for posttransplant relapse ,
longer follow - up of similar patients had shown that these responses are quite durable .
response rates are higher in patients who relapse in chronic phase compared to those who relapse in advanced phase disease .
furthermore , there is some evidence that imatinb maintenance therapy posttransplant is effective in preventing relapse in high - risk cases .
however , considering the morbidity and mortality associated with hsct and efficacy and favorable toxicity profile of tkis , cml chronic phase patients should be initially treated with tki . for patients with advanced phase disease and those with chronic phase disease who are resistant or intolerant to tki or relapse on tki ,
 indications for hematopoietic stem cell transplant ( hsct ) in chronic myeloid leukemia ( cml ) have changed over time . 
 this change has largely been influenced by the advent of tyrosine kinase inhibitors , increased understanding of the mechanisms underlying disease phase progression as well as drug resistance , refinement of transplant techniques and exploitation of graft versus leukemia effect in this disease . here , we have discussed the status of hsct in cml in the present era with regards to the current indications , factors determining outcome and management strategies for posttransplant relapse . 
INTRODUCTION
CURRENT INDICATIONS OF HEMATOPOIETIC STEM CELL TRANSPLANT IN CHRONIC MYELOID LEUKEMIA
FACTORS DETERMINING OUTCOME FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT IN CHRONIC MYELOID LEUKEMIA
POST-TRANSPLANT RELAPSE
CONCLUSION