CLINICAL NEWS
Most of the bleeds were
mucosal (55.2%; n=106), followed
by joint bleeds (30.7%; n=59),
episodes in other sites (19.3%;
n=37), and gastrointestinal bleeds
(3.1%; n=6). All bleeds were
treated successfully, with an overall treatment rate of 100 percent
(95% CI 87.3-100.0). In addition,
hemostatic efficacy in all bleeding
episodes was rated as “excellent”
(96.9%) or “good” (3.1%). See
TABLE 1 for a summary of bleeding
episodes.
The median dose of rvWF
and rFVIII administered per bleed
was 46.5 IU/kg and 33.6 IU/kg, respectively, and the majority of the
bleeding events were adequately
treated by one infusion (81.8%).
In the pharmacokinetic analysis, the profile of rvWF was not
influenced by rFVIII, with FVIII
concentrate levels increasing rapidly after rvWF alone. rvWF also
provided a longer half-life than
plasma-derived vWF products.
Hemostatic levels were quickly achieved (within 6 hours) and
were sustained through 72 hours
post-infusion. The sustained
stabilization of endogenous FVIII
“has the potential to obviate the
need for rFVIII after the first infusion when additional infusions
are required,” the authors noted.
A total of 125 adverse events
(AEs) were observed during the
study, with eight AEs (6.4%) considered to have a causal relationship to rvWF, including tachycardia, infusion site paresthesia,
chest discomfort, generalized
pruritus, hot flush, dysgeusia,
heart rate increase, and electrocardiogram T wave inversions.
Six of the eight AEs were not
considered serious.
The low number of patients
with severe, non-type 3 vWD is a
potential limitation of the study,
the authors added, with only
two patients with type 1 and six
patients with type 2 vWD.
“The study showed that this
product is safe and effective for
treating bleeding in patients
with severe forms of von Willebrand disease,” Dr. Gill said.
“Although the number of severe
bleeding episodes treated in the
study were limited, the patients
responded to treatment, giving us
positive results and an indication
to move forward with surgical and
other studies.” ●
REFERENCE
Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy,
safety and pharmacokinetics of a recombinant von
Willebrand factor in severe von Willebrand disease. Blood.
2015 August 3. [Epub ahead of print]
ASHClinicalNews.org
Examining Toxicity Profiles for Multiple Myeloma
Regimens
Though treatment combinations
such as melphalan, prednisone,
and thalidomide (MPT-T) and
melphalan, prednisone, and
bortezomib (MPV) have improved
survival in patients with multiple
myeloma (MM) compared with
their predecessors, the potential
toxicities of bortezomib and thalidomide may limit the long-term
tolerance and thus the success of
these regimens – particularly in
older patients with MM. There is a
need, then, for a therapy combination that offers a similarly high response rate, but minimizes toxicity.
In a phase III trial recently
published in Blood, Keith Stewart,
MBChB, Mayo Clinic, Arizona,
and colleagues compared the
safety profile and efficacy of melphalan, prednisone, thalidomide
(MPT-T) with melphalan, prednisone, lenalidomide (mPR-R) in
patients with untreated MM.
“Lenalidomide is an active
agent in MM with high response
rates and a modest toxicity profile
when used in combination with
dexamethasone,” the authors
explained. The mPR-R combination could further improve
progression-free (PFS) and overall
survival (OS) in older MM patients without increasing toxicity,
Dr. Stewart and authors hypothesized.
Patients were eligible for study
inclusion if they had a confirmed
diagnosis of MM, as well as evidence of end-organ damage at the
time of diagnosis and had not been
previously treated for MM (except
for treatment with prednisone or
dexamethasone for <4 weeks total
dosing, alone or in combination
with thalidomide or lenalidomide
for <2 weeks total dosing).
A total of 306 patients (median
age=75.7 years) were enrolled and
randomized to receive either:
the authors noted. Both therapies
were continued for twelve 28-day
cycles followed by thalidomide 100
mg or lenalidomide 10 mg daily
until progression or unacceptable
toxicity.
Mean duration of overall treatment (induction and maintenance
therapy) was 15.6 months and 14.9
months, respectively. Of all treated
patients, 139 (46.6%) went on to
maintenance therapy, with similar
proportions between the two
study arms. Patients entering the
maintenance phase of the study
received, on average, 13.5 months
of thalidomide and 13.3 months of
lenalidomide.
After 12 months of treatment,
56 percent of patients in the MPTT cohort and 60 percent of patients
in the mPR-R cohort had stopped
treatment.
At the time of analysis, 222
PFS events had been observed.
The study’s primary outcome,
defined as a PFS hazard ratio
(HR) of MPT-T/mPR-R of 0.82 or
lower, was not met: In the MPT-T
group, patients had a median PFS
of 21 months, compared with
18.7 months for the mPR-R group
(HR=0.84; 95% CI 0.64-1.09;
p=0.186). Overall survival and
per-protocol partial response rates
were also higher in the MPT-T
group (TABLE 2).
• melphalan 9 mg/m2 and
prednisone 100 mg each on
days 1-4 with thalidomide
100 mg administered daily
(MPT-T arm; n=154)
On the safety side, “neither regimen was particularly
well-tolerated,” Dr. Stewart and
authors wrote, “with at least 58
percent of mPR-R-treated patients
and 73 percent of MPT-T-treated
patients experiencing grade 3
toxicity, half the patients discontinuing treatment before finishing
12 months of planned induction
therapy, and toxicity being the
primary reason (42%) for stopping treatment.”
Toxicity rates were significantly lower in the mPR-R group
• melphalan 5 mg/m2 and
prednisone 100 mg each on
days 1-4 with lenalidomide
10 mg on days 1-21 (mPR-R
arm; n=152)
The lower doses of melphalan in both arms were selected
to reduce the myelosuppression
that has been seen in other trials,
than in the MPT-T group, though
(TABLE 2). Grade ≥3 or higher
treatment-related toxicities occurring in at least 5 percent of
patients included:
• hemoglobin <8 g/dL (n=16 in
the MPT-T arm; n=11 in the
mPR-R arm)
• leukocytes <2.0 x 109/L (n=29
MPT-T; n=17 mPR-R)
• lymphopenia <0.5 x 109/L
(n=21 MPT-T; n=10 mPR-R)
• neutrophils <1.0 x 109/L
(n=41 MPT-T; n=33 mPR-R)
• platelets <50.0 x 10