CLINICAL NEWS
On Location ASH Annual Meeting
Reducing Pain Crises With Novel Selectin Inhibitor in Patients With Sickle Cell Disease
Results from the SUSTAIN trial found that the monoclonal antibody crizanlizumab , which targets anti-P-selectin , reduces the frequency of pain crises by nearly half , compared with placebo , in adolescents and adults with sickle cell disease ( SCD ). These results suggest that crizanlizumab may offer another treatment option for patients with SCD who cannot tolerate or are reluctant to take hydroxyurea ( the only FDA-approved treatment for SCD complications ) or those for whom hydroxyurea is ineffective .
The SUSTAIN trial enrolled 198 SCD patients ( age range = 16-65 years ) who had experienced at least two and as many as 10 pain crises during the previous year . Patients were randomly assigned to one of three treatment arms : crizanlizumab 5 mg / kg ( n = 67 ), crizanlizumab 2.5 mg / kg ( n = 66 ), or placebo ( n = 65 ), administered intravenously once monthly . Patients in all arms received an initial loading dose , a dose 14 days later , and then a dose every four weeks through week 50 , for a total of 14 doses .
“ Pain crises are a significant morbidity for patients with SCD , and these episodes are unpredictable , varying from very mild to extremely severe ,” lead study author Kenneth I . Ataga , MD , MBBS , of the University of North Carolina at Chapel Hill , told ASH Clinical News . “ We don ’ t have very many options for SCD , other than hydroxyurea , so seeing this type of effect with a new drug is impressive .”
After one year , compared with placebo , the median annual rate of pain crises was reduced by 47 percent with crizanlizumab 5 mg / kg ( 1.6 vs . 3.0 ; p = 0.010 ) and reduced by 33 percent with crizanlizumab 2.5 mg / kg ( 2.0 vs . 3.0 ; p = 0.180 ). In addition , the median times between first and second pain crises were prolonged in patients treated with crizanlizumab 5 mg / kg , compared with placebo : 4.1
Improving Quality of Life Through Gene Therapy for Patients With Hemophilia B
Preliminary data from an ongoing phase I / II trial suggest that patients with hemophilia B produced factor IX ( FIX ) at sufficient levels after receiving a single infusion of an investigational adeno-associated , virus-mediated gene therapy agent . The therapy , called SPK-9001 , uses an inactive virus to deliver FIX into a patient ’ s cells a small section of DNA that , when stabilized in the patient ’ s own liver cells , allows the body to produce its own FIX .
Lead author Lindsey A . George , MD , from the Department of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia , reported that this trial demonstrated the highest and most consistent levels of FIX production of any gene therapy tested to date .
The SPK-9001 trial enrolled nine adult patients with severe hemophilia B ( defined as a baseline FIX expression of < 2 %); as of the data cutoff point on November 30 , 2016 , seven patients ( age range = 18-52 years ; all male ) had received infusions of SPK-9001 at a dose of 5x10 11 vg / kg . Before infusion , four patients were receiving prophylaxis for bleeding and three patients were being treated on-demand for bleeding ; only one patient had a bleeding episode .
These patients reached median FIX expression of > 28 percent ( range = 12-46 %) by 12 weeks postinfusion , resulting in a mean FIX expression of 32.3 percent . These levels approached those seen in healthy adults and “[ after a followup of 52 weeks ] permitted termination of prophylaxis , prevention of
versus 1.4 months ( p = 0.001 ) and 10.3 versus 5.1 months ( p = 0.022 ), respectively .
“ Although some side effects were reported , overall the drug seemed to be well tolerated ,” said Dr . Ataga . “ I believe it will make a significant difference in patients ’ lives .”
Compared with placebo , crizanlizumab 5 mg / kg also reduced the annual rate of uncomplicated pain crises ( defined as pain crises other than acute chest syndrome , priapism , and hepatic or splenic sequestration ) by 62 percent ( median = 1.1 vs . 2.9 ; p = 0.015 ) and the annual rate of days hospitalized by 42 percent ( median = 4.0 vs . 6.9 ; p = 0.450 ). Compared with patients in the placebo group , patients in an active-dose group experienced more arthralgia , pruritus , vomiting , chest pain , diarrhea , road traffic accident , fatigue , myalgia , musculoskeletal chest pain , abdominal pain , influenza , and oropharyngeal pain ( all adverse events occurred in ≥5 % of patients ).
Five deaths occurred during the study : two at the 5.0 mg / kg dose , one at the 5.0 mg / kg dose , one at the 2.5 mg / kg dose , and two in the placebo group . None of these deaths were considered related to the study drug .
Long-term , follow-up studies will be needed to establish whether the drug affects survival and if it is effective in younger patients . “ This study was restricted to patients between 16 and 65 years old , so we are interested in preforming this study in young children because they have pain crises as well ,” said Dr . Ataga .
REFERENCE
Ataga KI , Kutlar A , Kanter J , et al . SUSTAIN : a multicenter , randomized , placebo-controlled , double-blind , 12-month study to assess safety and efficacy of SelG1 with or without hydroxyurea therapy in sickle cell disease patients with sickle cell-related pain crises . Abstract # 1 . Presented at the 2016 ASH Annual Meeting , December 4 , 2016 ; San Diego , California .
bleeding , and nearly complete cessation of factor use ,” the researchers reported . Six of the seven patients reported increased physical activity and improved quality of life , determined by the Haemophilia Quality of Life Questionnaire for Adults .
Two participants experienced an autoimmune response to SPK-9001 and were put on corticosteroids . Despite this and a decline in FIX activity level , these two participants have not had any bleeds or required replacement FIX , according to Dr . George . Another participant was infused with FIX concentrate for a suspected ankle bleed two days after vector infusion . The study is ongoing , and the researchers will continue to track patient outcomes for at least five years .
The study is limited by the small population and the heterogeneity among participants .
REFERENCE
George LA , Sullivan SK , Giermasz A , et al . SPK-9001 : Adenoassociated virus mediated gene transfer for hemophilia B achieves sustained mean factor IX activity levels of > 30 % without immunosuppression . Abstract # 3 . Presented at the 2016 ASH Annual Meeting , December 4 , 2016 ; San Diego , California .
Attempting to Reduce the Chemotherapy Burden of Children With Acute Lymphocytic Leukemia
Reduced-intensity treatment was inferior to standard-intensity treatment in duration of diseasefree survival ( DFS ) in pediatric patients with acute lymphocytic leukemia ( ALL ) who have standardrisk disease and are at a low risk for relapse , according to an analysis of the AIEOP-BFM-ALL 2000 trial . However , reduced-intensity treatment was associated with “ dangerous ” rates of relapse , according to lead author Martin Schrappe , MD , PhD , from the Department of General Pediatrics at the Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein in Kiel , Germany , who presented the results .
“ These patients are at a very low risk for relapse , if any , so we wanted to see if it was possible to move away from the more toxic parts of therapy in the later stages of treatment , because relapses in lowrisk leukemia occur late ,” Dr . Schrappe told ASH Clinical News . “ We found that it is dangerous to reduce treatment . It doesn ’ t cause ‘ big ’ trouble , but it causes significant trouble .”
In this trial , 1,164 pediatric patients with ALL ( age range = 1-17 years ) were randomized to standard protocol II ( P-II ; n = 579 ) or reducedintensity protocol III ( P-III ; n = 584 ) to determine if it was possible to safely reduce treatment burden while maintaining efficacy and minimizing the risk of relapse . Patients included in the study had standard-risk disease and were minimal-residual disease ( MRD ) -negative at both days 33 and 78 after the start of induction therapy .
Both protocols consisted of dexamethasone , vincristine , doxorubicin , and cyclophosphamide ; compared with P-II , P-III had a shorter cycle duration ( 29 vs . 49 days ), a 30-percent lower dose of dexamethasone , and 50-percent lower doses of vincristine , doxorubicin , and cyclophosphamide .
After a median follow-up of 8.6 years , four-year DFS was 91.8 percent and 95.8 percent among patients who received reduced-intensity and standard-of-care treatment , respectively ( p = 0.04 ). However , the four-year cumulative incidence of relapse doubled among patients in the reducedintensity P-III group , compared with the standard P-II group : 6.3 percent and 3.2 percent , respectively ( p = 0.09 ).
“ Negative MRD does not mean that [ a patient ] is cured . If a patient has reached a plateau of cure ( above 90 %) be careful , because one cannot play around with this disease ,” Dr . Schrappe concluded . “ However , I can imagine that in the future , we will be able to identify subsets of patients through genetic screening who can be treated successfully with a different type of therapy .” ●
REFERENCE
Schrappe M , Zimmermann M , Moricke A , et al . Reduced intensity delayed intensification in standard-risk patients defined by minimal residual disease in childhood acute lymphoblastic leukemia : results of an international randomized trial in 1164 patients ( Trial AIEOP-BFM ALL 2000 ). Abstract # 4 . Presented at the 2016 ASH Annual Meeting , December 4 , 2016 ; San Diego , California .
28 ASH Clinical News January 2017