CLINICAL NEWS
Evaluating the Hedgehog Inhibitor Glasdegib in Patients With Heavily Pretreated Myelofibrosis
In a phase Ib / II trial of patients with myelofibrosis whose disease did not respond to JAK inhibitors , treatment with the hedgehog inhibitor glasdegib did not significantly improve symptom burden or reduce spleen volume , according to study results presented by Aaron T . Gerds , MD , of the Cleveland Clinic Taussig Cancer Institute in Cleveland , Ohio , at the 2017 ASCO Annual Meeting .
However , the authors shared anecdotal evidence of patient-reported symptom improvement , suggesting that certain patient-reported outcomes may be more sensitive indicators of treatment benefit than the standard endpoints of spleen volume reduction ( SVR ) and total symptom score ( TSS ).
“ Maybe we should rethink how we assess [ treatment response ] in heavily pretreated patients and possibly change the goal ,” Dr . Gerds told ASH Clinical News . “ Perhaps a 50 percent reduction in symptom burden is not meaningful for some patients – maybe all they need is a 20 percent reduction to be more functional and have better quality of life .”
Dr . Gerds presented interim results of the study at the 2017 ASCO Annual Meeting . At the time of the presentation , 21 patients ( mean age = 69.3 years ; range = 58-83 years ) with primary / secondary myelofibrosis who had previously been treated with at least one JAK inhibitor ( including ruxolitinib ) were enrolled . Fifteen percent of patients had received two previous JAK inhibitors , and 52 percent were refractory to previous JAK inhibitor therapy .
Spleen volume and symptom burden ( measured by TSS ) were assessed at baseline ; primary efficacy endpoints were the proportion of patients with ≥35 percent SVR and ≥50 percent reduction in TSS from baseline to week 24 . Patients received glasdegib 100 mg orally in 28-day cycles , and the median duration of treatment was 85 days ( range = 22-343 days ).
No patients achieved the primary endpoint of SVR ; five patients did experience a mild decrease in spleen volume , but the greatest reduction was only 21.4 percent . No progressive disease was reported before day 71 of treatment .
At baseline , patients reported mostly mild symptoms , with four reporting severe symptoms ( primarily severe fatigue ). At week 24 , only one patient met the efficacy endpoint for reduction in symptom burden . Notably , that patient had severe baseline symptoms . The authors also reported that three and four patients , respectively , achieved TSS reductions of 30 percent and 20 percent .
“ Early on , the symptoms stayed the same , and they actually improved as the study went on ,” Dr . Gerds noted , with patients reporting substantial improvements on certain TSS components , including spleen-related symptoms ( 52 % reduction ), inactivity ( 58 % reduction ), and fatigue ( 36 % reduction ). “ But very few patients met the endpoint for symptom burden reduction .”
The most common adverse events ( AEs ; occurring in ≥20 % of patients ) were :
• dysgeusia ( n = 13 )
• muscle spasm ( n = 12 )
• alopecia ( n = 8 )
• decreased appetite ( n = 7 )
• fatigue ( n = 7 )
• lipase increase ( n = 5 )
• weight decrease ( n = 5 )
Except for one case of fatigue , no AEs were considered serious .
Overall , the results associated with glasdegib do not compare favorably with those of the JAK inhibitor ruxolitinib , the only myelofibrosis treatment approved by the U . S . Food and Drug Administration . Despite negative results , the study highlights new directions for myelofibrosis clinical research .
“ Ruxolitinib can improve symptoms by shrinking the spleen and reducing cytokine levels , but , to the best of our knowledge , it doesn ’ t change the disease biology , it doesn ’ t reduce the fibrosis , and it doesn ’ t reduce the mutant allele burden to a significant degree ,” said Dr . Gerds . “ Preclinical models of glasdegib emphasize where we ’ re going with myelofibrosis treatment . … We ’ re looking for different ways to uproot the disease from the bone marrow .”
The study is limited by its single-arm design and small population . Also , Dr . Gerds noted that , given that symptom improvement was noted only anecdotally , “ we might not have been doing the quality-of-life surveys as often as we should have ” to evaluate glasdegib ’ s impact on patient-reported outcomes .
Dr . Gerds reports research funding from Pfizer .
REFERENCE
Gerds AT , Tauchi T , Ritchie EK , et al . Phase I / II trial of glasdegib in patients with primary or secondary myelofibrosis . Abstract # 7061 . Presented at the 2017 ASCO Annual Meeting , June 5 , 2017 ; Chicago , Illinois .
Updated Results From ZUMA-1 Show “ Promising ” Response Rates With CAR T-Cell Therapy in Relapsed / Refractory NHL
Treatment with the chimeric antigen receptor ( CAR ) T-cell therapy axicabtagene ciloleucel led to a high objective response rate ( ORR ) in patients with relapsed / refractory non-Hodgkin lymphoma ( NHL ), according to updated results of the phase I / II ZUMA-1 trial presented at the 2017 ASCO Annual Meeting . Frederick Locke , MD , from the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center and Research Institute in Tampa , Florida , shared the new data , which expand on interim data initially reported at the 2016 ASH Annual Meeting .
“ One infusion of axicabtagene ciloleucel led to responses in more than 80 percent of patients and complete responses ( CRs ) in more than 50 percent of patients ,” Dr . Locke told ASH Clinical News . “ This compares favorably to the historical control data from the SCHOLAR-1 meta-analysis , which showed that , with standard of care in the same group of patients , less than one out of four patients [ had ] a response , and less than one out of 10 [ had ] a CR .”
The ZUMA-1 trial enrolled 111 patients ( median age = 58 years ; range = 23-76 years ) with previously treated diffuse large B-cell lymphoma ( DLBCL ), primary mediastinal large B-cell lymphoma , or transformed follicular lymphoma from 22 institutions . Participants were required to have an Eastern Cooperative Oncology Group score of 0-1 and refractory disease .
Sixty-nine percent of patients received at least three prior lines of therapy . Most ( 79 %) were refractory to chemotherapy and had not received autologous hematopoietic cell transplantation ( AHCT ). The remaining 21 percent had received AHCT but relapsed within 12 months .
“ These truly were patients without any standard-of-care options ,” said Dr . Locke . “ More than 50 percent not only didn ’ t respond to their last line of chemotherapy , but they didn ’ t respond to their last two consecutive lines of chemotherapy .”
CAR T cells were manufactured successfully in 99 percent of patients , with an average turnaround time from apheresis
“ One infusion ... led to responses in more than 80 percent of patients .”
— FREDERICK LOCKE , MD
to the clinical site of 17 days . As of the data cutoff date ( January 27 , 2017 ), 101 patients ( 91 %) had received axicabtagene ciloleucel 2 × 10 6 cells / kg , following conditioning with low-dose cytarabine and fludarabine . Ten patients did not receive treatment for the following reasons : serious adverse events ( AEs ; n = 7 ), no measurable disease ( n = 2 ), or product unavailability ( n = 1 ).
After a median follow-up of 8.7 months ( range not provided ), the ORR ( primary endpoint ) was 82 percent , including a CR rate of 54 percent .
As of data cutoff , 44 percent of patients maintained their response , including 39 percent of those who achieved CR , the authors noted . The median duration of response was 8.1 months ( range not provided ) and was not reached for patients who achieved CR . The median overall survival ( OS ) also was not reached during study follow-up , and the 6-month OS rate was 80 percent .
Response rates were consistent across disease subgroups , the authors added . Patients with germinal center B-cell ( GCB ) DLBCL and activated B-cell ( ABC ) DLBCL had similar ORR and CR rates to the general study population :
• GCB ( n = 69 ): 88 % and 57 %
• ABC ( n = 69 ): 76 % and 59 %
Also , levels of CD19 expression did not appear to influence response rates to this
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