hodgkin lymphoma ( hl ) is a potentially curable lymphoma with distinct histology , biologic behaviour , and clinical characteristics .
the reported five - year event - free survival ranges between 80 and 90% with combined modality chemotherapy and radiotherapy .
despite the high cure rate with initial therapy , approximately 5% to 10% of patients have refractory disease , and 10% to 30% patients relapse after an initial complete response .
autologous stem cell transplantation ( asct ) is the standard of care for patients with relapsed hl . about half of all patients undergoing asct
are rescued and definitely cured by such an approach , but the outcome of patients relapsing or refractory to second - line chemotherapy and asct is dismal , with a median survival of less than three years .
one of the most important and widely accepted prognostic factors for patients undergoing asct appears to be chemosensitivity at relapse , with patients responding to second - line chemotherapy and having a much better outcome than patients with refractory disease , whose relapse rate approaches 80% in some published series [ 5 , 6 ] . in the functional imaging with positron emission tomography ( pet ) era ,
pet positive response at the end of induction therapy has been found to be the worst predictor of outcome [ 7 , 8 ] .
there are a few published literatures on the treatment options of patients with rr - hl after autotransplant .
this paper summarizes the current available treatment modalities in these patients with emphasis on novel drugs .
a diagnostic rebiopsy should be considered to confirm relapse or progressive disease if the primary diagnosis was not clear and if the relapse is late ( beyond 35 years of therapy ) or unusual in pattern and in pet positive lesions whenever feasible .
these include radiotherapy , second asct , allogeneic stem cell transplant ( allo - sct ) , monoclonal antibodies , chemotherapeutic drugs , and novel agents [ 9 , 10 ] .
a significant number of patients who relapse after stem cell transplant do so in previously involved sites and may present with disease that could be encompassed in a radiation field .
this strategy appears most beneficial in those who present with ann arbor stage i or ii disease at relapse , without b symptoms , and no extranodal disease .
. reported 5-year freedom - from - treatment failure ( fftf ) of 28% in patients receiving either extended - field or involved - field radiotherapy .
involved - field radiation is an important option when recurrent disease extends beyond previously unirradiated lymph nodes .
radiation in a prior radiation field should be considered if tissue tolerance allows ; however there is little information to support this .
this option seems to be feasible for patients who relapse > 1 year after the initial transplant . a recent report from the center for international blood and marrow transplant research ( cibmtr ) on 40 patients undergoing second transplants included 21 patients with hl : outcomes for patients relapsing within 12 months of the first transplant were very poor , but for those with relapse > 3 years , progression - free survival ( pfs ) and overall survival ( os ) were 25% and 38% , respectively .
allo - sct offers the only chance of cure for suitable patients after failed asct ; however selecting the best conditioning regimen is still controversial .
myeloablative strategies achieve cure in some patients , but at the cost of high transplant - related mortality ( trm ) , whereas reduced - intensity conditioning ( ric ) regimens are associated with high posttransplant relapse rates . a report from the international bone marrow transplant registry of 114 patients with lymphoma undergoing myeloablative allogeneic transplants reported a rate of disease progression at 3 years of 52% and trm of 22% .
this translated to a relatively disappointing 3-year pfs of 25% and os of 33% . with further followup
it was found that 5-year disease - free survival ( dfs ) and os were 5% and 24% , respectively .
based on the assumption of allogeneic graft versus lymphoma ( gvl ) effect , reduced - intensity conditioning was introduced which resulted in a decreased cumulative incidence of nonrelapse mortality ( nrm ) ranging from 11% to 13% . nevertheless , survival outcomes were relatively unchanged , as approximately 50% of all patients undergoing allogeneic sct after ric relapsed [ 14 , 15 ] .
published the results of a retrospective multicenter study on 185 relapsed / refractory hl patients . in this study , outcomes were correlated with donor availability .
the patients from the  donor group  experienced improved 2-year os and pfs as compared with those from the  no donor group  ( os : 66% versus 42% , pfs : 39% versus 14% , p < .001 ) .
investigated the role of in vivo t depletion in 67 relapsed / refractory hl patients , mostof whom had previously undergone asct .
the cumulative trm rate at 2 years was 7% in the alemtuzumab cohort and 29% in the  flumel only  group .
nevertheless , both the 3-year cumulative incidence of relapse ( 54% versus 44% ) and 3-year pfs ( 43% versus 25% ) were higher in patients with the flumel / alemtuzumab regimen .
in addition , there was a trend to longer duration of responses in the alemtuzumab cohort ( median , 33 months versus < 12 months ) . in vivo t - cell depletion
although the feasibility of ric allo - sct has improved , there is still a lack of durable response and the high relapse or progression rates remain unsolved problems .
the need of time is to standardize the indication and the time point of allogeneic sct in therapeutic algorithms of these patients .
for patients relapsing after allogeneic sct , or those not suitable for allogeneic sct , alternative therapeutic approaches include the use of monoclonal antibodies , conventional chemotherapeutic drugs , or novel agents ( table 1 ) .
the monoclonal antibodies that have been studied in relapsed / refractory hl target cd30 , cd20 , and cd25 .
brentuximab vedotin is an antibody - drug conjugate consisting of a chimeric anti - cd30 monoclonal antibody . in a large phase ii single arm multicenter study , 102 heavily pretreated patients who relapsed after asct were treated using the mtd dose of 1.8  mg / kg administered every 3 weeks
the overall response rate was 75% with 34% complete remission and 40% partial remission , and a median pfs and os of 5.6 months and 22.4 months , respectively .
the predominant adverse effects were peripheral sensory neuropathy ( 43% ) , fatigue ( 40% ) , nausea ( 35% ) , neutropenia ( 19% ) , diarrhea ( 18% ) , and pyrexia ( 16% ) .
brentuximab was also found to enable some patients to proceed to allogeneic stem cell transplantation and did not adversely affect stem cell engraftment , graft versus host disease , or survival .
brentuximab was also effective in patients who relapsed after allogeneic stem cell transplantation , demonstrating a 50% overall response rate and a median progression - free survival of 7.8 months .
cd20 antigen is highly expressed by the reactive b cells in the microenvironment of hl . in a pilot study , 22 patients with relapsed classical hl were treated with six weekly doses of rituximab .
five patients ( 23% ) achieved partial or complete remission and eight additional patients had stable disease ( sd ) .
clinical remission was observed in patients regardless of cd20 expression by hrs cells and was limited in patients whose disease was confined to the lymph nodes . in a phase ii study , rituximab was used in combination with gemcitabine in 33 patients of rr - hl , out of which 55% already had a prior asct .
cd25 , an interleukin-2 receptor ( il-2r ) alpha subunit , is expressed in adult t - cell leukaemia , cutaneous t - cell lymphoma , alcl , and hairy cell leukaemia and on reed - sternberg and associated polyclonal t - cells in hl . in a recent phase ii trial , daclizumab conjugated with the radionuclide yttrium-90 ( 90y - daclizumab ) was investigated in 30 relapsed / refractory hl patients .
the main side effects were haematological , with prolonged thrombocytopenia , as well as three patients who developed a myelodysplastic syndrome following treatment .
systemic chemotherapy is often used as a salvage option in patients with rr - hl failing asct .
however the downside with these regimens includes modest response rates and shorter duration of response ranging from 6 to 8 months .
various agents like vinblastine , vinorelbine , gemcitabine [ 2729 ] , and bendamustine have shown some antitumor activity either as a single agent or in combinations .
gemcitabine in combination with vinorelbine has been tested in a limited number of patients with hl after asct , with an encouraging response rate ( 75% , 6 of 8 patients ) .
reported the results of a combination of gemcitabine , vinorelbine , and pegylated liposomal doxorubicin ( gvd ) in patients with recurrent hl , both prior to and for relapse after asct .
the response rate among 39 patients receiving gvd for relapse after asct was 75% ( 17% cr ) , and median event - free survival was 8.5 months .
however , the combination therapy in this setting was associated with significantly more myelosuppression than observed in patients who had not previously undergone asct .
moskowitz et al . reported the activity of single - agent bendamustine in rr - hl that previously failed asct , allogeneic stem cell transplantation ( allo - sct ) , or ineligible for transplant . in this phase ii study
, bendamustine was administered at a dose of 120  mg / m for two consecutive days , every 28 days , for up to maximum of 6 cycles . of evaluable 34 patients
, there were 12 complete responses ( crs ) ( 33% ) and 7 partial responses ( prs ) ( 19% ) for an orr of 56% .
further studies of both single - agent bendamustine and in combination with any other chemotherapy are warranted in rr - hl patients .
the cancer and leukemia group b ( calgb ) conducted phase ii clinical trials ( calgb 50206 ) evaluating bortezomib monotherapy in rr - hl .
histone deacetylases ( hdacs ) are crucial in cell proliferation , apoptosis , angiogenesis , and immune regulation . their alteration has been found to be associated with various malignancies including hl .
vorinostat , is a potent inhibitor of class i and ii hdac . in a phase ii clinical trial evaluating
the safety and efficacy of vorinostat in refractory / relapsed hl , a total of 25 patients were treated with vorinostat at 200  mg given orally twice per day for 14 days every 21-day cycle .
the activity of vorinostat was modest and only one patient achieved a partial remission ( pr ) .
panobinostat , is a potent pan - hdac inhibitor and more potent than vorinostat in lymphoma preclinical models .
a phase ii study of panobinostat in rr - hl showed encouraging clinical activity with orr 27% , 5 patients achieving cr , and 30 patients achieving pr with median pfs of 6.1 months .
currently , the role of panobinostat in maintenance treatment of patients after high - dose chemotherapy is being evaluated in a phase 3 trial .
the phosphatidylinositol 3-kinase ( pi3k ) akt / mtor signalling pathway is one of the most aberrantly activated survival pathways in cancer , making it an important target for drug development .
everolimus , an mtor inhibitor , has demonstrated antiproliferative effect in several solid tumor and hematologic malignancies including hl .
a phase ii trial evaluated the clinical activity and toxicity of everolimus in patients with heavily pretreated rr - hl ( median of 6 prior therapies and 84% had prior hdct - asct ) .
of 19 patients , one patient achieved cr and 8 patients achieved pr resulting in orr of 47% , although median time to response was only 7.2 months .
a phase i clinical trial combining the hdac inhibitor panobinostat with the mtor inhibitor everolimus is currently enrolling patients with non - hodgkin 's lymphoma ( nhl ) and hl .
lenalidomide , an immunomodulatory drug , has emerged as a promising therapeutic option in patients with rr - hl . in a phase ii study ,
38 patients were treated with lenalidomide at a dose of 25  mg / day on days 121 of a 28-day cycle out of which 87% patients had undergone prior stem cell transplantation .
the responses were 1 complete remission ( cr ) , 6 partial remissions ( prs ) , and 5 patients with stable disease ( sd ) for 6 months resulting in an objective overall response rate ( orr ) of 19% and a cytostatic orr of 33% .
the treatment was well tolerated with the most common grade 3/4 aes being neutropenia ( 47% ) , anemia ( 29% ) , and thrombocytopenia ( 18% ) .
showed that inhibition of hsp90 by either geldanamycin derivative 17-aag or rna interference in hl cells led to decrease in cell proliferation and inhibition of stat1 , stat3 , stat5 , and stat6 tyrosine phosphorylation possible secondary to reduced protein expression of janus kinase ( jaks ) .
nearly 3040% of hl patients are known to be ebv positive , making the use of ebv - targeted therapy an attractive option .
ebv specific cytotoxic t lymphocytes ( ctl ) can be generated in vitro and then given to the patients with the intent of targeting specific ebv - infected cancer cells .
lucas et al . demonstrated the clinical efficacy of allogeneic ebv - specific ctls in ebv - positive rr - hl which had previously failed hdc - asct .
significant clinical activity was observed following allogenic ctls infusion despite a lack to detect donor chimerism .
in addition , in a limited number of patients , better clinical responses were observed when fludarabine was administered prior to ctls infusion .
farnesyltransferase is 1 of 3 prenyltransferases used by normal and malignant cells to catalyze covalent attachment of prenyl groups to 300 polypeptides in the human proteome .
farnesyltransferase inhibitors ( ftis ) diminish cell proliferation and induce apoptosis in a variety of preclinical models . in a phase ii study ,
tipifarnib was tried on 93 patients of relapsed non - hodgkin 's lymphoma and rr - hl ( 20% = 19/93 ) .
the overall response rate was 21% in rr - hl with 2 complete responses and 2 partial responses .
the median time to progression and median overall survival was 3.6 months and 14.8 months , respectively , in all patients .
more studies are required to test its efficacy in rr - hl either as a single agent or in combination with other drugs .
patients having localized relapse should be considered for involved- or extended - field radiation , if not previously irradiated .
allogeneic stem cell transplant is the only strategy that allows achieving long - time survival .
reduced - intensity allogeneic transplantation should be considered in suitable patients ( hla - matched donor , young age , and good performance status ) if relapse occurs > 6 months after asct . for patients who are not candidates for allogeneic stem cell transplant , single - agent or combination chemotherapy with gemcitabine or vinorelbine
patients with early relapse ( < 6 months after asct ) and those refractory to chemotherapy may be considered for targeted therapies or participation in clinical trials .
selected patients who relapse > 5 years from asct may be taken up for a second autologous transplant , but the long - term benefits are not known .
the use of novel biological and targeted therapies is a promising approach but where to put them in treatment algorithm is still not clear . as the armamentarium for the treatment of patients with rr - hl continues to expand ,
 despite a high clinical success , relapse in hodgkin lymphoma occurs in 1030% of cases and 510% patients are nonresponsive to initial chemotherapy . 
 the standard management of these patients includes high - dose chemotherapy followed by autologous stem cell transplant . 
 however , 50% of patients ultimately relapse after autotransplant which poses a big challenge . 
 allogeneic stem cell transplantation offers the only chance of cure in these patients . for patients who are 
 not candidates for allogeneic stem cell transplantation , achieving cure with other possible options is highly unlikely , and thus the treatment plan becomes noncurative . 
 various novel agents have shown promising results but the duration of response is short lived . a standard approach to deliver the most effective treatment for these patients is still lacking . 
 this review focuses on the treatment options currently available for relapsed and refractory disease after autotransplant . 
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