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PAPER SPOTLIGHT
Managing GVHD Following HCT : New Uses for Old Treatments ?
Graft-versus-host disease ( GVHD ) remains a major complication following allogeneic hematopoietic cell transplantation ( alloHCT ) and , when severe , is associated with poor long-term overall survival . Two studies recently published in Blood evaluated two new drugs for their effects on GVHD : off-label anti- PD-1 monoclonal antibodies , and the anti-CD30 antibody-drug conjugate brentuximab vedotin ( BV ).
Brentuximab Vedotin in Acute GVHD In a multicenter , phase I study , Yi-Bin Chen , MD , from Massachusetts General Hospital , and co-authors assessed the activity of BV in patients with steroidrefractory GVHD , after murine models suggested that CD30 may mediate acute GVHD ( aGVHD ). 1
The study included 34 patients ( median age = 56 years ; range = 22-73 years ) who had aGVHD that progressed after at least three days of treatment with systemic corticosteroids , that did not improve after at least seven days of daily oral prednisone ≥1 mg / kg or equivalent and warranted treatment with another agent , or that flared during the tapering of corticosteroids . Patients were excluded if they had aGVHD or chronic GVHD ( cGVHD ) overlap syndrome , had significant organ dysfunction , or used more than one systemic agent besides corticosteroids for aGVHD .
The investigators determined the maximum tolerated dose ( MTD ) of BV using a 3 + 3 cohort design , with an initial dose of 0.6 mg / kg weekly , escalating to 0.9 and 1.2 mg / kg weekly . Six patients received BV weekly for three weeks , followed by maintenance dosing every three weeks for four additional doses . After two patients died because of neutropenia , the study protocol was revised , and the next 28 patients were treated with 0.6 mg / kg ( n = 10 ) or 0.8 mg / kg ( n = 18 ) every two weeks for four doses .
The authors established BV 0.8 mg / kg as the MTD , and sepsis was the only dose-limiting toxicity .
At 28 days of treatment , the five patients achieved a complete response ( CR ; defined as resolution of aGVHD , per consensus criteria ) and eight achieved a very good partial response ( VGPR ), for an overall response rate ( ORR ; defined as CR and VGPR ) of 38.2 percent . An additional seven patients achieved CR by day 56 . One patient in CR at day 28 later died , resulting in an overall CR rate of 32.4 percent at day 56 .
Four of the 12 patients who achieved CR by day 56 later required additional therapy for recurrent aGVHD symptoms .
The ORRs at six and 12 months were 41 percent ( 95 % CI 25-57 ) and 38 percent ( 95 % CI 22-54 ), respectively . Of the 18 patients whose GVHD responded to treatment by day 56 , 12 were alive at 12 months of follow-up ; six died from infection ( n = 3 ), disease relapse ( n = 2 ), or GVHD ( n = 1 ). Of the 16 non-responders , only one patient was alive at 12 months of followup and 11 of those deaths were related to GVHD . The remaining causes of death were infection ( n = 3 ) or disease relapse ( n = 1 ).
In the 29 patients with peripheral blood mononuclear cells collected at baseline , CD30 expression was not associated with clinical response . “ The lack of correlation of CD30 expression in central memory CD8 + T cells in this trial may be [ because ] this population of patients [ was ] already steroidrefractory when samples were collected ,” the authors noted .
The study is limited by its small and heterogenous patient population . Though the authors observed “ significant activity ” for BV in patients with steroidrefractory aGVHD , “ future investigation should focus on identifying a biologically defined population most likely to respond to BV .”
Anti-PD-1 Monoclonal Antibodies In a multicenter , retrospective study , Bradley M . Haverkos , MD , MPH , MS , from the Division of Hematology at the University of Colorado , and co-authors assessed whether anti-PD-1 monoclonal antibodies had activity in the setting of lymphoma that relapsed following alloHCT ; the study evaluated the risk of GVHD after PD-1 blockade in that patient population . 2
“ There have been a few [ patients with ] severe and even fatal transplant-related complications , including GVHD , when anti-PD-1 monoclonal antibodies were given for disease control prior to alloHCT , which has led to a package insert warning ,” the authors explained .
For this study , the researchers contacted transplant programs with high volumes of patients with post-transplant lymphoma to identify 31 evaluable patients ( median age at time of transplant = 37 years ; range = 20-68 years ) who were receiving nivolumab or pembrolizumab . Most patients ( 87 %) received salvage therapy ( median = 2 therapies ; range = 0-6 therapies ) before initiating anti- PD-1 therapy , and many patients ( n = 19 ; 61 %) experienced GVHD prior to anti-PD-1 treatment .
Patients received a median of two doses of anti-PD-1 therapy ( range = 1-31 doses ). After a median follow-up of 428 days ( range = 133-833 days ) after the first dose of anti-PD-1 therapy , the ORR ( defined as CR and partial response [ PR ]) was 77 percent in 30 evaluable patients , including 15 who achieved CR and eight who achieved PR . Three patients had stable disease and four had progressive disease .
“ While disease response rates were high , the frequency of GVHD after anti-PD-1 was also high ,” the authors wrote . More than half of the patients ( 55 %; n = 17 ) developed treatment-emergent GVHD after initiating anti-PD-1 therapy :
• 6 with aGVHD , following a median of 1 dose ( range = 1-2 doses )
• 7 with cGVHD , following a median of 2 doses ( range = 1-25 doses )
• 4 with aGVHD / cGVHD overlap , following a median of 2 doses ( range = 1-2 doses )
Responses to treatment for GVHD were also poor , the authors added , with 14 of 17 patients requiring two or more systemic therapies , including steroids , calcineurin inhibitors , extracorporeal photopheresis , topical or local therapy , rituximab , and sirolimus . Of the 10 deaths during follow-up , eight ( 26 %) were deemed related to new-onset GVHD following anti-PD-1 therapy .
The majority of treatmentemergent GVHD occurred in patients with a history of GVHD ( n = 12 ; 71 %), but the only factor that was associated with development of GVHD after anti-PD-1 therapy was alloHCT with matched sibling donor ( p = 0.02 ).
“ PD-1 blockade [ in these patients ] appears to be highly efficacious but frequently complicated by rapid onset of severe and treatment-refractory GVHD ,” the authors concluded . “ Providers should be cognizant of this potentially fatal and morbid complication . … Administration of anti-PD-1 after alloHCT should be done with extreme caution and preferably carried out within the context of a clinical trial .”
The study is limited by its small patient population and retrospective design . Responses were also assessed by individual investigators at each participating center , rather than by central monitoring .
Drs . Chen and Perales report financial relationships with Seattle Genetics , Inc ., which provided BV and funding for the clinical trial . Drs . Haverkos and Abbott report financial relationships with Merck .
REFERENCES
1 . Chen YB , Perales MA , Li S , et al . Phase I multicenter trial of brentuximab vedotin for steroid refractory acute graft-vs . -host disease ( GVHD ). Blood . 2017 May 4 . [ Epub ahead of print ]
2 . Haverkos BM , Abbott D , Hamadani M , et al . PD-1 blockade for relapsed lymphoma post allogeneic hematopoietic cell transplant : high response rate but frequent GVHD . Blood . 2017 May 3 . [ Epub ahead of print ]
18 ASH Clinical News August 2017