On Location ASH Annual Meeting
Will Replacing Bleomycin With Brentuximab Vedotin Revolutionize Frontline Hodgkin Lymphoma Treatment ?
For patients with advanced-stage Hodgkin lymphoma ( HL ), eliminating bleomycin ( and its associated risks of pulmonary toxicity ) from the standard ABVD ( doxorubicin , bleomycin , vinblastine , dacarbazine ) regimen and replacing it with brentuximab vedotin and AVD ( A + AVD ) could prolong modified progressionfree survival ( mPFS ). Though the risks of pulmonary toxicity were lower with A + AVD , the regimen appeared to be associated with increased risks of peripheral neuropathy and neutropenia , according to research presented as a plenary abstract at the 2017 ASH Annual Meeting .
“ The anti-CD30 antibody drug conjugate brentuximab vedotin is the most active agent for the treatment of HL in decades , so we wanted to know , ‘ Where is the best place to put a new targeted agent that we ’ ve been using in relapsed and subsequent settings for some time ?’” lead author Joseph M . Connors , MD , from the British Columbia Cancer Agency Centre for Lymphoid Cancer
Joseph M . Connors , MD in Vancouver ,
Canada , told ASH Clinical News . “ If this new regimen is widely adopted , it will change firstline treatment of advanced HL .” Dr . Connors presented results from the phase III ECHELON-1 trial , which were simultaneously published in the New England Journal of Medicine .
From November 19 , 2012 , through January 13 , 2016 , ECHELON-1 investigators randomized 1,344 patients with previously untreated , stage III or IV classic HL to receive up to six cycles of either ABVD ( n = 670 ) or A + AVD ( n = 664 ). The median age was 36 years ( range = 18-83 years ), 64 percent of patients in each group had stage IV disease , and 58 percent in each group had B symptoms .
Response was evaluated via computed tomography scans obtained at screening , at the end of cycle two , after administration of the last dose of frontline therapy , and every three months during follow-up . Patients with a positive scan after cycle two ( defined as a Deauville score of 5 ) could switch to alternative therapy at the treating physician ’ s discretion .
Treatment success was determined by independentlyreviewed mPFS ( defined as the time to progression , death , or non-complete response and use of subsequent anticancer therapy ). By selecting mPFS as the study ’ s primary endpoint , “ we asked ‘ What is the point that defines success , and after which we can avoid the need for subsequent therapy ?’” While some cases of treatment failure are straightforward , Dr . Connors explained , “ there are scenarios in which patients have loss of response to therapy , but the disease has not progressed and the patient has not died .”
After a median of 24.9 months follow-up ( range not provided ), rates of two-year mPFS were significantly higher in the A + AVD group : 82.1 percent ( 95 % CI 78.7-85.0 ) versus
77.2 percent ( 95 % CI 73.7-80.4 ; p values not reported ). This corresponded to a 23 percent lower risk for progression , death , or modified progression in the A + AVD group than the ABVD group ( hazard ratio [ HR ] = 0.77 ; 95 % CI 0.60-0.98 ; p = 0.03 ).
The need for subsequent therapy appeared to be nearly doubled in the ABVD group ( 8 % [ n = 9 ] and 15 % [ n = 22 ], respectively ), Dr . Connors noted .
Though A + AVD was only modestly superior to ABVD in mPFS , “ it means that one-quarter of the patients who would have relapsed or had a lack of success of their primary treatment can avoid that by taking newer experimental treatment ,” Dr . Connors said .
The most common adverse events ( AEs ) in each arm were neutropenia , constipation , vomiting , fatigue , and peripheral neuropathy . As expected , pulmonary toxicity was more frequent and more severe with ABVD than A + AVD ( 3 % vs . < 1 %), but neutropenia and peripheral neuropathy were more common in the A + AVD arm . Eighty-eight ( 13 %) and 105 ( 16 %) patients , respectively , discontinued treatment because of AEs .
There were 22 on-treatment deaths ; seven of nine deaths ( 78 %) in the A + AVD group were associated with neutropenia , and 11 of 13 ( 85 %) in the ABVD group were associated with pulmonary toxicity .
“ Of the deaths that occurred during treatment , the entire excess number of deaths in the ABVD arm were due to pulmonary toxicity ,” Dr . Connors reported . “ When the bleomycin is out , there isn ’ t the risk of unexpected pulmonary toxicity – which is already low , even in the ABVD arm , because our clinicians are smart and know how to manage bleomycin – but wasn ’ t completely eliminated .” With the addition of prophylactic granulocyte colony-stimulating factor in the A + AVD arm toward the end of the study ( based on a higher incidence of febrile neutropenia in this group ), febrile neutropenia incidence decreased from 21 percent ( n = 119 / 579 ) to 11 percent ( n = 9 / 83 ). Grade ≥3 infections also dropped from 18 percent ( n = 107 / 579 ) to 11 percent ( n = 9 / 83 ).
Peripheral neuropathy was also more frequent in the A + AVD arm , but the authors wrote , “ two-thirds of patients experiencing peripheral neuropathy in the A + AVD arm had resolution or improvement in pain at last follow-up .”
“ In the past , the only [ alternative regimens ] that have demonstrated superiority over ABVD have come with an unacceptably high price of toxicity ,” he concluded . “[ These data ] allow us to move forward with some confidence that , without asking our patients to put up with increased burden of long-term toxicity , we can do something that improves the likelihood that they can be cured the first time around .”
The study ’ s findings will need to be confirmed with longer-term follow-up , and the use of physician discretion may have introduced bias . Questions about the salvageability of frontline A + AVD also remain unanswered .
As several attendees noted during the plenary scientific session , the costs associated with adding brentuximab vedotin to AVD , particularly without an equally substantial increase in survival , are a concern . In addition , only 9 percent of patients in each group were 65 years or older , and these patients saw no significant benefit in efficacy , which limits the applicability of these findings to the older HL population .
“ Ultimately , our most severe test will be the impact on overall survival ( OS ),” Dr . Connors concluded . A preplanned OS analysis is ongoing , but results were not sufficiently matured before the presentation . He hinted , though , that the results were “ encouraging in favor of the experimental arm .”
On January 2 , 2018 , the U . S . Food and Drug Administration granted priority review to the supplemental biologics license application for brentuximab vedotin in the frontline setting , supported by data from ECHELON-1 .
The authors report financial relationships with Janssen , Genentech , Merck , Roche , Seattle Genetics , Amgen , and Bristol-Myers Squibb .
REFERENCE
Connors JM , Jurczak W , Straus DJ , et al . Brentuximab vedotin plus doxorubicin , vinblastine , dacarbazine ( A + AVD ) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma ( HL ): the phase 3 Echelon-1 study . Abstract # 6 . Presented at the 2017 American Society of Hematology Annual Meeting , December 10 , 2017 ; Atlanta , GA .
Voxelotor : A New Option for Young Patients With Sickle Cell Disease ?
Treatment with the hemoglobin S polymerization inhibitor voxelotor led to “ a remarkable increase in hemoglobin levels ” in young patients with sickle cell disease ( SCD ), according to preliminary results from a phase IIa study presented by Carolyn C . Hoppe , MD , of the Children ’ s Hospital of Oakland Research Institute in California , at the 2017 ASH Annual Meeting . Patients also experienced improvement in clinical measures of hemolysis and total symptom burden , supporting voxelotor as a potential disease-modifying therapy for people with SCD .
“ What sets this drug apart is that it was designed specifically for sickle cell disease .”
— CAROLYN C . HOPPE , MD
In this ongoing , open-label , phase IIa trial , Dr . Hoppe and colleagues assessed the safety , pharmacokinetics , and efficacy of voxelotor ( previously GBT440 ) in adolescents with SCD . Voxelotor is an oral , once-daily therapy that modulates hemoglobin affinity for oxygen , inhibiting hemoglobin polymerization .
“ What sets this drug apart is that it was designed specifically for SCD ,” Dr . Hoppe said during a press briefing discussing the study ’ s results . “ This is one of the first drugs that intentionally targets the fundamental mechanism of SCD [ to prevent ] cells from sickling early on , eliminating all the downstream consequences of sickling .”
The study enrolled patients 12 to 17 years of age with SCD . Patients who had a vaso-occlusive crisis ( VOC ), required chronic red blood cell transfusion therapy , or
28 ASH Clinical News January 2018 Annual Meeting Edition