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Adding Rituximab to Corticosteroids and Cyclosporine A in Patients With cGVHD Improves ORR
Standard firstline treatment for chronic graft-versus-host disease ( cGVHD ) includes corticosteroids and cyclosporine A , but disease control often requires long-term immunosuppressive treatment , which impairs patients ’ immune function and increases the risk of opportunistic infection .
In a multicenter , prospective , phase II study , Florent Malard , MD , PhD , from the Centre de Recherche en Transplantation et Immunologie at the Université de Nantes in France , evaluated whether adding the anti-CD20 monoclonal antibody rituximab to standard frontline therapy could improve overall response rates ( ORRs ) and enable patients to more quickly and effectively taper corticosteroid use . Their results were published in Blood .
“ Based on our findings , targeting B cells [ with rituximab ] appears to be an effective therapeutic strategy for firstline treatment of cGVHD .”
— FLORENT MALARD , MD , PhD
The study included 24 adult patients ( median age = 47 years ; range = 23-63 years ) who were newly diagnosed with cGVHD following first allogeneic hematopoietic cell transplantation ( alloHCT ) for a hematologic malignancy . Patients were excluded if they had acute GVHD ; had cGVHD not requiring systemic immunosuppressive therapy ; received prednisone at doses of ≥1 mg / kg / day ; had cGVHD following donor lymphocyte infusion ; or had uncontrolled systemic infection associated with an increased risk of death within one month .
Six patients ( 25 %) had myeloid malignancies and 18 ( 75 %) had lymphoid malignancies . Ten donors ( 42 %) received alloHCT from human leukocyte antigenmatched siblings , nine ( 37 %) from matched unrelated donors , and five ( 21 %) from mismatched unrelated donors . Cells were derived from bone marrow in five alloHCTs ( 21 %).
Four patients had previously received rituximab to treat their underlying malignancy . Per study protocol , once patients were diagnosed with cGVHD requiring systemic therapy , they received rituximab 375 mg / m 2 weekly for four consecutive weeks , as well as cyclosporine A and corticosteroids 1 mg / kg / day . Patients who achieved a complete remission ( CR ; defined as complete disappearance of any sign of cGVHD ) after the first cycle of rituximab did not continue treatment ; those who achieved a partial response ( PR ; defined as improvement in ≥1 organ or site without progression in any other organ or site ) were eligible to receive another cycle of rituximab eight weeks after the first rituximab infusion .
The median time from alloHCT to cGVHD diagnosis was 5.9 months ( range = 2.4-32.7 months ), and patients were followed for a median of 6.7 months ( range = 4.2-33.6 months ) after alloHCT . Most patients had severe ( n = 15 ; 62 %) or moderate cGVHD ( n = 7 ; 29 %), and two ( 8 %) had mild cGVHD .
By one year after first rituximab administration , 20 patients had responded to treatment , for an ORR ( primary endpoint ) of 83 percent , including seven CRs ( 29 %) and 13 PRs ( 54 %). Treatment failure ( defined as a lack of CR or PR at week 6 , requirement of another therapy before week 6 , or death before week 6 ) was reported in two patients ( 8 %). The cumulative incidence of non-relapse mortality was 14 percent ( n = 3 ).
Eight patients received only one course of rituximab because of CR ( n = 5 ), resistance ( n = 2 ), or study withdrawal related to cGVHD progression under treatment ( n = 1 ). Two-thirds of patients received a second course of rituximab , and four ( 25 %) experienced an improvement from PR to CR .
At last follow-up , three patients remained in CR , whereas two lost CR but remained in PR . Another patient who did not initially respond to rituximab and did not receive a second rituximab course achieved a PR at three months without additional treatment and remained in PR at last follow-up .
Eleven non-hematologic serious adverse events ( AEs ) were reported : sepsis ( n = 3 ), lung infection ( n = 2 ), sinus infection ( n = 1 ), progressive multifocal leukoencephalopathy ( PML ; n = 1 ), hyperglycemia ( n = 1 ), acute renal failure ( n = 1 ), thrombotic microangiopathy ( n = 1 ), and transient global amnesia ( n = 1 ). All non-hematologic serious AEs resolved , except in the patient with PML , who died . Two other patients died during follow-up because of underlying disease relapse and infection . Hematologic AEs included grade 3 / 4 lymphopenia ( n = 12 ; 50 %) and grade 3 / 4 neutropenia ( n = 5 ; 21 %).
Of the 23 patients who were evaluable at three months after first rituximab infusion , 19 ( 83 %) could safely decrease corticosteroid use by 30 percent or more , including two patients ( 9 %) who discontinued corticosteroids entirely . At one year , four patients ( 21 %) had reduced corticosteroid use by 30 percent or more and 14 ( 74 %) were off corticosteroids entirely .
“ Based on our findings , targeting B cells [ with rituximab ] appears to be an effective therapeutic strategy for firstline treatment of cGVHD ,” the authors wrote . As the researchers expected , PD-L1 hi -naïve B cells , which are involved in cGVHD pathophysiology , were significantly decreased at cGVHD diagnosis but were increased after B-cell depletion with rituximab ( 2.4 % vs . 6.7 %; p = 0.01 ). “ The increase in naïve B cells goes along with an increase in PD-L1 hi B cells in patients without cGVHD ,” the authors reported .
“[ These ] results suggest that [ the ] addition of rituximab may be effective [ and provide ] a framework for a possible new mechanism of action of rituximab in the setting of cGVHD , mediated through PD-L1 hi B cells and T follicular helper cells ,” the authors concluded . However , “ this hypothesis remains to be confirmed in a randomized , prospective , phase III clinical trial .” The study is limited by its small patient population and lack of a comparator arm .
Corresponding authors report financial relationships with Roche , manufacturer of one of the drugs included in this trial .
REFERENCE
Malard F , Labopin M , Yakoub-Agha I , et al . Rituximabbased first line treatment for chronic GVHD after allogeneic SCT : results of a phase 2 study . Blood . 2017 September 1 . [ Epub ahead of print ]
32 ASH Clinical News November 2017