CLINICAL NEWS had cardiac abnormalities were excluded from the trial . The study is being conducted in two parts : In part A , children and adolescents are receiving a single dose of voxelotor 600 mg ; in part B , patients are receiving multiple doses of voxelotor ( 900 mg and 1500 mg ) administered over 24 weeks .
Dr . Hoppe reported results from 24 patients ( median age = 14 years ; range = 12-17 years ) who received voxelotor 900 mg daily for 24 weeks . As of November 6 , 2017 ( data cutoff ), 12 patients had been treated with voxelotor 900 mg for at least 16 weeks .
“ The vast majority of patients ( n = 21 ; 88 %) were receiving daily hydroxyurea , the standard of care for SCD ,” Dr . Hoppe reported , “ and the patients were typical of what we see in in our clinic at this age .” Almost half of patients ( n = 11 ; 46 %) had no VOC in the year prior to study .
The median hemoglobin ( Hgb ) level at baseline was 8.7 g / dL ( range = 6.3-10.9 g / dL ). By 16 weeks of treatment , six of 11 evaluable patients ( 55 %) experienced a > 1 g / dL increase in Hgb ( the study ’ s primary endpoint ). Data were not available for one patient , who was excluded from the efficacy analysis .
Patients also saw improvement in symptom burden , which was measured by total severity score ( TSS ) via self-completed patient diaries . “ At week 16 , 10 of 12 patients showed a reduction in TSS from baseline , including five patients who had a decrease in TSS to zero ,” Dr . Hoppe said . Greater improvements in hemoglobin levels appeared to correspond with better adherence and exposure to voxelotor , she added , commenting on results from the pharmacokinetic analysis .
Data on safety and tolerability among all 24 patients treated with voxelotor were “ reassuring ,” Dr . Hoppe noted , and adverse events ( AEs ) “ were similar to what we have seen in adults treated with this drug .” Treatment-related AEs ( occurring in ≥2 patients ) included :
• nausea ( n = 3 ; 12.5 %)
• headache ( n = 2 ; 8.3 %)
• rash ( n = 2 ; 8.3 %)
There also were no serious AEs associated with voxelotor , and there were no drug discontinuations related to serious AEs .
The reliance on self-reported patient diaries to monitor changes in symptom burden is a limitation of the study ’ s findings . The study also included a small number of patients , but Dr . Hoppe noted that the results were encouraging enough to support the evaluation of the higher voxelotor dose ( 1,500 mg ). Some patients are moving into the phase III , randomized , double-blind HOPE ( Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization ) trial , which will evaluate voxelotor in up to 400 young patients with SCD who have had at least one episode of VOC in the prior year .
Carolyn C . Hoppe , MD
The authors report financial relationships with Global Blood Therapeutics , the manufacturer of voxelotor .
REFERENCE
Hoppe CC , Inati AC , Brown C , et al . Initial results from a cohort in a phase 2a study ( GBT440-007 ) evaluating adolescents with sickle cell disease treated with multiple doses of GBT440 , a HbS polymerization inhibitor . Abstract # 689 . Presented at the 2017 American Society of Hematology Annual Meeting , December 11 , 2017 ; Atlanta , GA .
Myeloma : The Next Frontier for CAR T-Cell Therapy
Chimeric antigen receptor ( CAR ) T-cell therapies have shown great success in acute lymphocytic leukemia and non-Hodgkin lymphoma , and the results of a study presented at the 2017 ASH Annual Meeting suggest that myeloma is the next frontier for these revolutionary therapies .
“[ CAR T-cell therapy ] is an approach that has been exploding over the last 10 years , and in myeloma in particular , we have seen exciting results with this anti – B-cell maturation antigen CAR ,” James N . Kochenderfer , MD , from the National Cancer Institute at the National Institutes of Health Clinical Center in Bethesda , Maryland , told ASH Clinical News .
He presented updated results from a multicenter , phase I study of the anti-BCMA CAR T-cell therapy bb2121 in patients with relapsed and / or refractory multiple myeloma ( MM ). The trial enrolled patients who had received three or more prior regimens , including a proteasome inhibitor and an immunomodulatory agent , or whose disease was refractory to bortezomib and thalidomide and / or lenalidomide . Participants also were required to have at least 50 percent BCMA expression on malignant cells . “[ bb2121 ] is a second-generation CAR construct targeting BCMA to redirect T cells to myeloma cells ,” Dr . Kochenderfer explained . “ BCMA is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells , plasma cells , and some mature B cells .”
The study followed a standard 3 + 3 design with planned dose levels ranging from 50 × 10 6 to 1,200 × 10 6 cells / kg . Prior to CAR T-cell infusion , patients underwent lymphodepletion with fludarabine 30 mg / m 2 and cyclophosphamide 300 mg / m 2 daily for three days .
As of October 2 , 2017 ( data cutoff ), 21 patients were enrolled ( median age = 58 years ; range = 37-74 years ) at a median of four years ( range = 1-16 years ) since MM diagnosis . This was a heavily pretreated group , Dr . Kochenderfer noted . Patients had a median of seven prior lines of therapy ( range = 3-14 therapies ), and all had prior autologous hematopoietic cell transplantation . Fifteen of 21 patients ( 71 %) had exposure to five prior therapies ( bortezomib , lenalidomide , carfilzomib , pomalidomide , daratumumab ) and six of 21 ( 29 %) were refractory to them . Two-thirds had high-risk cytogenetics .
Eighteen patients were evaluable for initial clinical response at one month , all of whom had been treated with doses ranging from 150 × 10 6 to 800 × 10 6 cells / kg . ( Lower doses were found to be clinically inactive , Dr . Kochenderfer noted .)
After a median follow-up of 35 weeks ( range = 6.6- 69 weeks ) after bb2121 infusion , 17 patients ( 94 %) had responded , including 10 complete responses ( CRs ), six very good partial responses , and one partial response . Among the people who responded , after a median follow-up of 40 weeks ( range = 6.6-69.1 weeks ), the median time to first response was 1.02 months ( range = 0.5- 3.0 months ), the authors reported . The median duration of response and median progression-free survival ( PFS ) had not been reached . Rates of PFS at six months and nine months were 81 percent and 71 percent , respectively .
Safety analyses of all infused patients showed that no dose-limiting toxicities ( DLTs ) and no treatment-emergent grade ≥1 neurotoxicities occurred , comparable to findings from other CAR T-cell clinical trials .
“ In my experience , this protocol seems to be trending toward having less severe toxicity [ than other
regimens and other CAR T-cell therapies ]. We have to wait for the final analysis , but so far , it ’ s clearly a favorable toxicity profile ,” Dr . Kochenderfer said . Any-grade cytokine release syndrome ( CRS ) was reported in 15 of 21 patients ( 71 %); two patients had grade 3 CRS that resolved within 24 hours , and four patients received tocilizumab ( one with steroids ) to manage CRS . Five deaths occurred , including three patients whose disease progressed at the clinically inactive dose of 50 × 10 6 cells / kg . The other two patients were treated at active doses and were in CR at the time of death ( from cardiac arrest or development of myelodysplastic syndrome following bb2121 discontinuation ).
The findings of this study initially support the potential of CAR T therapy with bb2121 as a new treatment paradigm in relapsed / refractory MM , Dr . Kochenderfer added . Though the results are limited by the small number of patients enrolled and the lack of a comparator arm , he was optimistic about the role of CAR T-cell therapy in this patient population . “ CAR T-cell therapy is completely different from other available treatments for MM ,” he said . “ We have patients who have a sustained response and have been able to go for [ more than ] a year with no additional myeloma therapy and tolerable adverse effects .”
The authors report financial relationships with Bluebird Bio and Celgene , both of which provided funding for the study .
REFERENCE
Kochenderfer JN , Berdeja JG , Lin Y , et al . Durable clinical responses in heavily pretreated patients with relapsed / refractory multiple myeloma : Updated results from a multicenter study of bb2121 anti-bcma CAR T cell therapy . Abstract # 740 . Presented at the 2017 American Society of Hematology Annual Meeting , December 11 , 2017 ; Atlanta , GA .
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