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 .
ASHClinicalNews . org ASH Clinical News
29
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 re-
ceiving 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 pa-
tients (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 treat-
ment, 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, in-
cluding 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 “reas-
suring,” Dr. Hoppe noted, and ad-
verse 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 as-
sociated 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 par-
ticular, 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 Insti-
tutes 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
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