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Characterizing Long-Term Outcomes of Eltrombopag in Patients With Severe Aplastic Anemia
In an analysis of a phase II trial published in Blood , researchers found that the addition of eltrombopag to standard immunosuppression led to similar rates of relapse and clonal evolution as immunosuppression alone in patients with severe aplastic anemia ( AA ). However , relapse and clonal evolution occurred earlier among eltrombopag-treated patients , with no increase in the rate of high-risk evolution to myeloid malignancy .
Lead author Bhavisha Patel , MD , a staff clinician and hematologist with the National Institutes of Health ’ s National Heart , Lung , and Blood Institute , told ASH Clinical News that these findings “ will help us guide future interventions to decrease these long-term complications in this patient population .”
Treatment for severe AA , including bone marrow transplant and immunosuppression , typically depends on patient age , comorbidities , and donor availability . While immunosuppression may be a useful option in older , unfit patients , Dr . Patel and colleagues explained that relapse or clonal evolution to myeloid malignancy may occur in half of patients who achieve an initial treatment response . The cumulative incidence of relapse in this patient population also has not generally improved with additional immunosuppression therapy or more potent treatment options .
In this phase II study , researchers evaluated the long-term outcomes of 178 patients with severe AA who had not been definitively treated with antithymocyte globulin ( ATG )– based immunosuppression therapy . Patients either declined transplantation , lacked a suitable matched related donor , or were ineligible due to medical comorbidities . All patients received a combination therapy consisting of immunosuppression , horse ATG ( hATG ), cyclosporine , and eltrombopag .
The study included three cohorts of different eltrombopag treatment regimens : cohort 1 , eltrombopag from day 15 to 6 months ( n = 30 ); cohort 2 , eltrombopag from day 1 to 3 months ( n = 31 ); and cohort 3 , eltrombopag from day 1 to 6 months ( n = 117 ).
Patients in each cohort received hATG from day 1 for four days , as well as therapeutic cyclosporine from day 1 to six months . Dr . Patel added that another 86 patients had been recruited under an extension arm since the initial publication of the findings .
For comparison , the researchers included a historic group that consisted of 102 patients with severe AA who were treated with only immunosuppression . Also included in the historic group were patients from study control arms who received only hATG and cyclosporine .
At six months , the overall response rate was 81 %, which was significantly higher than that of the historical group ( 67 %). According to the investigators , the cumulative relapse rate was 39 % in patients who responded to treatment . Thrombocytopenia was the most prominent feature of relapse , followed by neutropenia .
They also observed that relapse occurred at distinct timepoints : shortly after six months ( when cyclosporine maintenance dose was lowered and eltrombopag was discontinued ) and again after two years ( when maintenance course was completed ). Two-thirds of relapses occurred before two years , with a median time to relapse of 280 days ( range = 194-2,703 ).
At four years , the rate of clonal evolution was 15 % in all patients who received treatment , which was similar to the rates observed in the historical group . High-risk evolution to a myeloid malignancy was observed in 5.7 % of the eltrombopag-treated patients , compared with 10.3 % of the historical group who received only immunosuppression . However , median time to high-risk clonal evolution was much earlier in the eltrombopag-treated group ( 186 vs . 777 days ).
Most patients who relapsed underwent retreatment with therapeutic doses of cyclosporine with or without eltrombopag . Approximately two-thirds of patients responded to retreatment with this regimen .
Four-year overall survival rates were 92.5 % and 85 % in the eltrombopag- and immunosuppressiontreated groups , respectively . Most patient deaths were due to infections with concurrent neutropenia . The authors added that incidence of clonal evolution or chromosome 7 abnormality was associated with worse overall survival .
“ As expected , not having a response to treatment conferred a poorer prognosis , but to our surprise , survival was not different between patients with complete and partial response ,” Dr . Patel and coauthors wrote .
While the findings confirm the “ excellent ” survival outcomes with eltrombopag in patients with severe AA , “ the pattern of high-risk clonal evolution also emphasizes the importance of earlier , more frequent marrow evaluations with this treatment regimen ,” the authors concluded .
Dr . Patel also explained that “ the major limitation of the study is the historical comparator arm , which may have biased our analysis .” She added that the findings should be confirmed shortly in the randomized control RACE trial , which is currently ongoing in Europe .
The authors report no relevant conflicts of interest .
Reference Patel BA , Groarke EM , Lotter J , et al . Long-term outcomes in severe aplastic anemia patients treated with immunosuppression and eltrombopag : a phase 2 study [ published online ahead of print , 2021 Sep 15 ]. Blood . 2021 Sep 15 . doi : 10.1182 / blood . 2021012130 .
Evaluating Pembrolizumab in Relapsed / Refractory B-Cell Lymphomas
Pembrolizumab showed clinical benefit in patients with relapsed / refractory B-cell lymphomas following CD19-directed CAR T-cell therapy according to research findings published in Blood .
Patients who responded to pembrolizumab had less exhausted CAR T and non-CAR T cells compared with non-responders . The researchers , led by Elise Chong , MD , of the University of Pennsylvania , suggest this “ is likely more easily improved by PD-1 blockade , which may explain a lower threshold for activation of the cells after PD-1 blockade and subsequent higher proliferation .”
This phase I / IIa study enrolled patients with relapsed / refractory B-cell lymphomas who had received a single dose of CAR T-cells . Patients were treated with intravenous pembrolizumab 200 mg every three weeks for up to a year or until disease progression , therapylimiting toxicity , or elective discontinuation . Response was assessed every 12 weeks for up to two years following the initial pembrolizumab dose .
The study included 12 patients who previously received CAR T cells across two clinical trials . Eleven patients had diffuse large B-cell lymphoma and one had follicular lymphoma . All patients had measurable disease following CAR T cells and 83 % had biopsydocumented lymphoma following CAR T cells . Nine patients ( 75 %) had disease that was considered refractory to therapy , while the remaining 25 % ( n = 3 ) had relapsed disease following responses to CAR T cells .
Overall , the median progression-free survival ( PFS ) following CAR T cells was 2.8 months , and the median duration between infusion to initial dose of pembrolizumab was 3.3 months . Among patients whose disease relapsed , the median PFS and time to first pembrolizumab dose was 26.2 months and 27.1 months , respectively .
The most common grade 3-4 adverse event was neutropenia ( 25 %). Approximately one-quarter of the patients experienced grade 1 / 2 fever following the first pembrolizumab infusion . Only one patient had possibly related hyperbilirubinemia , and this patient was found to have unrelated cytomegalovirus infection and discontinued therapy .
The best post-pembrolizumab overall response rate ( ORR ) was 25 %, which included one complete response ( CR ) and two partial responses ( PRs ). At three months , the ORR was 25 %. No difference was observed in ORR or PFS according to prior CAR T-cell response or pre-treatment variables such as age , Eastern Cooperative Oncology Group performance score , number of prior therapies , or absolute lymphocyte count .
Following treatment with pembrolizumab , four patients who had a clinical benefit experienced increased percentage of CAR T cells by mass cytometry . Three of these patients experienced increases in CAR19 transgene levels . According to deep immune profiling , there was increased CAR T-cell activation and proliferation as well as less T-cell exhaustion in patients who were considered clinical responders .
The investigators concluded that , while the study population was small , the findings “ suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and non-responders that influence the clinical efficacy of PD-1 blockade administered in this setting .” ●
The authors report no relevant conflicts of interest .
Reference Chong EA , Alanio C , Svoboda J , et al . Pembrolizumab for B-cell lymphomas relapsing after or refractory to CD19-directed CAR T-cell therapy [ published online ahead of print , 2021 Sep 9 ]. Blood . doi : 10.1182 / blood . 2021012634 .
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