CLINICAL NEWS
Selinexor Induces Response in Patients With Various Subtypes of Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia
The heterogeneity of the various subtypes of non-Hodgkin lymphomas ( NHLs ) necessitates the development of specific therapies that address fundamental mechanisms that are dysregulated in these cancers . One such viable therapeutic target is tumor suppressor proteins , nearly all of which are exported from the nucleus to the cytoplasm by Exportin 1 ( XPO1 ).
A phase I study published in Blood evaluated the safety and efficacy of selinexor , an orally bioavailable , first-in-class XPO1 inhibitor , in patients with relapsed / refractory NHL or chronic lymphocytic leukemia ( CLL ). Investigators found that selinexor was associated with an “ encouraging ” objective response rate across various NHL subtypes , but also with a high rate of withdrawal due to adverse events ( AEs ).
“ We are finally starting to see the development of a new generation of therapies in aggressive NHL ,” lead author John Kuruvilla , MD , from the Division of Medical Oncology and Hematology at the Princess Margaret Cancer Centre and the University of Toronto in Canada , told ASH Clinical News . “ There is more work to be done , but we have an active new agent that will hopefully be integrated into the standard of care for patients with NHL .”
The multicenter , dose-escalation study was conducted at 12 sites in the United States , Canada , and Denmark , and it enrolled 79 heavily pretreated adult patients ( median age = 64 years ; range = 30-82 years ; median number of prior therapies = 4 ; range = 1-12 therapies ) between July 2012 and December 2014 . Patients were included if they had relapsed or refractory disease and adequate hematologic and cardiovascular function . “ This early-phase study had inclusion criteria that allowed clinicians to recruit sick patients with poor blood counts who typically would be excluded from clinical trials ,” Dr . Kuruvilla explained .
Patients who had received any form of anti-cancer therapy within 2 weeks prior to treatment cycle 1 or had active graft-versus-host disease after allogeneic hematopoietic cell transplantation were excluded .
During the dose-escalation phase , 47 patients ( 40 with NHL and 7 with CLL ) received selinexor at 13 dose levels , ranging from 3 to 80 mg / m 2 doses in 3- or 4-week cycles . As the maximum tolerated dose was not reached , and based on preclinical toxicology studies , investigators used 35 mg / m 2 or 60 mg / m 2 doses to assess the safety , tolerability , and efficacy of selinexor in the dose-expansion phase , which included 32 patients ( 28 with diffuse large B-cell lymphoma [ DLBCL ], 3 with Richter ’ s transformation , and 1 with follicular lymphoma grade 3b ).
The median treatment duration was 49 days ( range = 4-1,071 days ), with 18 percent of patients continuing treatment for more than 6 months and 8 percent continuing for more than 1 year . In the doseexpansion cohorts , the median durations of therapy were 66 days for the 35 mg / m 2 dose ( range = 23-602 days ) and 32 days for the 60 mg / m 2 dose ( range = 11-314 days ; p values not provided ).
For the 70 patients who were evaluable for response , treatment with selinexor led to an objective response rate ( ORR ) of 31 percent ( n = 22 ), including four complete responses ( CRs ; 6 %) and 18 partial responses ( PRs ; 26 %).
The most common non-hematologic AEs were nausea ( 66 %), fatigue ( 61 %), anorexia ( 57 %), vomiting ( 37 %), and diarrhea ( 34 %), and the most common grade 3 / 4 hematologic AEs were thrombocytopenia ( 47 %), neutropenia ( 32 %), and anemia ( 27 %). Fifty serious AEs were reported , 11 of which were deemed treatment-related and occurred at selinexor doses of 30-70 mg / m 2 .
“ Grade 3 or 4 AEs were largely hematologic in nature ,” the authors wrote , adding , “ Given the permissive inclusion criteria of the study , many patients presented at baseline with significant cytopenias , and therefore , high incidences of grade 3 or 4 hematologic toxicities are expected in this patient population .”
Twelve patients required dose reductions from a median of 35 mg / m 2 ( range = 30-70 mg / m 2 ) to 23 mg / m 2 ( range = 20-60 mg / m 2 ). Twenty-eight patients withdrew from the study , 15 because of incidence or severity of AEs . The 35 mg / m 2 dose was further identified as the recommended phase II dose .
Of the 79 enrolled patients , nine were not evaluable for response because of withdrawal from the study ( n = 6 ), death unrelated to selinexor ( n = 2 ), or inadequate baseline imaging ( n = 1 ). Nearly one-third of patients ( 30 %; n = 21 ) had stable disease , which was sustained for more than 4 months in five patients , for a disease control rate ( DCR ) of 61 percent .
In the 41 evaluable patients with DLBCL ( the most common NHL subtype in the study population ), the ORR was 32 percent , including four CRs and nine PRs , and the DCR was 51 percent .
“ Compared with other targeted therapies studied across a spectrum of relapsed / refractory NHL , selinexor showed comparable or favorable response rates with durable clinical benefit [ median duration of response > 7 months ],” the authors concluded . “ Selinexor for the treatment of patients with DLBCL warrants further development , as this is the most common NHL in the Western world and is a high unmet medical need population given the inferior overall survival of patients who fail primary rituximab-based therapy .”
The study is limited by its small patient population and non-comparative design . “ Selinexor will undergo further testing to determine the optimal dose as a single agent , to better understand toxicities at this dose and optimized schedule , and to identify biomarkers of response and resistance ,” Dr . Kuruvilla added .
REFERENCE
Kuruvilla J , Savona M , Baz R , et al . Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin ’ s lymphoma . Blood . 2017 May 3 . [ Epub ahead of print ]
Enoxaparin Increases Risk of Intracranial Hemorrhage in Patients With Glioma
Venous thromboembolism occurs in approximately one-third of patients with glioma , but the decision to treat patients with anticoagulation is complicated by the risk for spontaneous intracranial hemorrhage ( ICH ). The incidence of ICH in patients with glioma receiving anticoagulation is not known , making it difficult to determine the risk – benefit profile of anticoagulation in this setting .
In a matched , retrospective cohort study published in Blood , Charlene Mantia , MD , from the Department of Medicine at Beth Israel Deaconess Medical Center at Harvard Medical School , and co-authors assessed the safety of anticoagulation in patients with high-grade glioma , finding that those receiving enoxaparin were three times more likely to develop a major ICH , compared with those who did not receive anticoagulation ( 14.7 % vs . 2.5 %; hazard ratio [ HR ] = 3.37 ; 95 % CI 1.02-11.14 ; p = 0.036 ).
“ We were surprised that enoxaparin in patients with glioma was associated with a significantly increased risk of major ICH ,” co-author Jeffrey I . Zwicker , MD , told ASH Clinical News . “ We believe caution is warranted when considering therapeutic anticoagulation in this setting .”
The researchers collected data from electronic medical records at Beth Israel Deaconess Medical Center between 2000 and 2016 . Patients were included if they had a World Health Organization grade III or IV glioma , had at least two radiographic brain images on file , and had received care at the facility for at least 2 months . Their outcomes were compared with a control cohort ( matched for age at diagnosis , year of diagnosis , and sex ) of patients with glioma who did not receive anticoagulation .
A total of 133 patients with primary brain tumors ( the most common of which were glioblastoma [ 84 %], anaplastic oligodendroglioma [ 10 %], and anaplastic astrocytoma [ 5 %]) were enrolled ; 50 received enoxaparin and 83 comprised the control cohort .
Most patients ( 76 %) received enoxaparin 1 mg / kg ; two patients
ASHClinicalNews . org ASH Clinical News
17