On Location
Conference Coverage
UPDATES IN MALIGNANT HEMATOLOGY
CLINICAL NEWS
SH Clinical News was on site at this year ’ s American Society of Clinical Oncology ( ASCO ) Annual Meeting in Chicago to bring you the latest advances in malignant hematology presented at the meeting . Here , we provide highlights from the meeting , including natural killer cells in myeloma , ivosidenib in acute myeloid leukemia , and a chemotherapy-free combination in follicular lymphoma .
Visit ashclinicalnews . org / on-location and ashclinicalnews . org / multimedia for more of our news and exclusive videos . Also , look for more coverage of the practice-changing research shared at the meeting in our special issue in mid-July .
Attendees at the 2018 ASCO Annual Meeting
High Rates of Response , Survival With Ibrutinib Plus Rituximab in Waldenström Macroglobulinemia
Treatment with a combination of ibrutinib and rituximab improved progression-free survival ( PFS ) over rituximab alone in patients with Waldenström macroglobulinemia ( WM ), according to results from a phase III randomized trial presented at the 2018 ASCO Annual Meeting . This survival benefit was observed regardless of disease stage or genotype .
“ This is a combination with a remarkable activity as far as PFS , it is well-tolerated , and it [ may become ] a new standard of care for patients with this disease ,” presenter Meletios A . Dimopoulos , MD , of the National and Kapodistrian University of Athens School of Medicine in Greece , said of the results , which were published simultaneously in The New England Journal of Medicine .
The prospective , randomized trial included 150 patients with symptomatic WM that was rituximabsensitive ( i . e ., not refractory to last prior rituximabbased therapy or had not received rituximab within 12 months of study entry ).
Participants were randomized to receive intravenous rituximab 375 mg / m 2 once-weekly on weeks one through 4 and 17 through 20 with either ibrutinib 420 mg once-daily ( arm A ; n = 75 ) or placebo ( arm B ; n = 75 ).
Patient characteristics were similar among both arms : Median age was 70 years ( range = 36-89 years ) in arm A and 68 years ( range = 39-85 years ) in arm B , and one-third of patients were older than 75 years . Approximately one-third had a high International Prognostic Scoring System score , and 45 percent in each arm had previously untreated disease .
Ninety-three percent of patients in arm A completed treatment , while 71 percent in arm B completed treatment . Treatment discontinuation was related to progressive disease in seven patients ( 9 %) and 33 patients ( 44 %) in arms A and B , respectively , and to adverse events ( AEs ) in four patients ( 5 %) and three patients ( 4 %), respectively .
At a median follow-up of 26.5 months ( range not provided ), the median PFS was not reached in the ibrutinib plus rituximab cohort , compared with 20.3 months in the rituximab plus placebo cohort ( ranges not reported ; hazard ratio [ HR ] = 0.20 ; 95 % CI 0.11- 0.38 ; p < 0.0001 ). The 30-month PFS rates were 82 percent and 28 percent , respectively .
“ Improved progression-free survival was seen across all prespecified subgroups , including age , prior history of treatment , baseline levels of immunoglobulin M ( IgM ), and – most importantly – different genotype ,” Dr . Dimopoulos said . “ We know that ibrutinib has less activity [ with respect to ] response and progression-free survival in patients who experience mutations with MYD88 and CXCR4 , but that was not the case [ in this analysis ].” Hazard ratios for PFS in selected subgroups were :
• treatment-naïve disease ( HR = 0.34 ; 95 % CI 0.12-0.95 )
• relapsed disease ( HR = 0.17 ; 95 % CI 0.08-0.36 )
• MYD88 L265P / CXCR4 WT mutation ( HR = 0.17 ; 95 % CI 0.06-0.49 )
• MYD88 L265P / CXCR4 WHIM mutation ( HR = 0.24 ; 95 % CI 0.09-0.66 )
• MYD88 WT / CXCR4 WT mutation ( HR = 0.21 ; 95 % CI 0.04-1.1 )
The 30-month overall survival rate was similar in both treatment arms ( 94 % vs . 92 %; p value not reported ); this analysis included the 30 patients in the placebo arm who were allowed to cross over to single-agent ibrutinib .
Four patients died in the ibrutinib group , and six patients died in the placebo group . However , the overall , long-term survival data are immature .
Regarding the overall response rate ( defined as a major response or better ), Dr . Dimopoulos noted that there was “ still significant activity of singleagent rituximab in these patients ( 47 %), however the combination of ibrutinib and rituximab increases
the response rate to 92 percent ( p < 0.0001 ). The major response rate ( defined as a partial response or better ) was also higher in the combination group ( 72 % vs . 32 %; p < 0.0001 ).
The activity was rapid , he added , particularly in patients with high levels of IgM at baseline ( ≥50 g / L ): At week 9 , mean IgM reduced 39 percent from baseline in arm A , and none of the patients required plasmapheresis .
The investigators observed more “ significant and sustained ” improvements in hemoglobin levels with ibrutinib plus rituximab , both in the entire patient population and in patients with baseline hemoglobin ≤11 g / dL : 73 percent versus 41 percent ( p < 0.0001 ) and 95 percent versus 56 percent ( p < 0.0001 ), respectively . “ This is an important endpoint that affects patients ’ quality of life ,” Dr . Dimopoulos added , particularly because “ anemia was one of the most common reasons for initiating therapy .”
Rates of AEs were similar in each group : all patients experienced at least one AE , and 45 and 46 patients ( 60 % and 61 %) in arms A and B , respectively , experienced a grade ≥3 AE . The most common AEs included infusion-related reactions ( 32 [ 43 %] and 44 [ 59 %]), diarrhea ( 21 [ 28 %] and 11 [ 15 %]), and anemia ( 14 [ 19 %] and 4 [ 5 %]), respectively .
Dr . Dimopoulos stressed that the safety profile was manageable in the ibrutinib-rituximab group , even though median treatment duration was longer in the combination group ( median = 25.8 months ; range = 1.0-37.2 months ) than in the placebo group ( median = 15.5 months ; range = 0.4-34.3 months ). The study is limited by its short duration of follow-up , and the preplanned analysis may have introduced potential bias .
The authors report financial relationships with Janssen and Roche .
REFERENCE
Dimopoulos MA , Tedeschi A , Trotman J , et al . Randomized phase 3 trial of ibrutinib / rituximab vs placebo / rituximab in Waldenström ’ s macroglobulinemia . Abstract # 8003 . Presented at the 2018 American Society of Clinical Oncology Annual Meeting , June 1 , 2018 ; Chicago , IL .
ASHClinicalNews . org ASH Clinical News
41