CLINICAL NEWS
Written in Blood
Continued from page 28
95 percent and 100 percent, respectively.
This included complete response (CR) or
CR with incomplete marrow recovery rates
of 37 percent and 78 percent, respectively
( TABLE 1 ). Responses were similar among
patients in the different cytogenetic sub-
groups, the authors reported.
Three months following the last dose of
obinutuzumab, the rates of undetectable
MRD (sensitivity of <10 -4 ) were 64 percent
and 91 percent in the relapsed/refractory
and firstline cohorts, respectively. The re-
searchers noted high concordance between
MRD-negative levels in peripheral blood
and bone marrow samples.
Several other therapeutic combina-
tions are being tested, all of which include
venetoclax plus a Bruton tyrosine kinase
inhibitor (e.g., ibrutinib or acalabrutinib
with or without obinutuzumab). “Of the
agents currently being evaluated, the best
two- or three-drug combination remains
unknown,” commented Dr. Flinn. “We
know that the combination of veneto-
clax and an anti-CD20 antibody such as
obinutuzumab appears synergistic, but
the addition of obinutuzumab to ibruti-
nib does not produce the same depth of
(PR),” said Dr. Flinn. “This finding is prob-
ably due to response criteria classifying
patients with small residual lymph nodes
seen on CT scans as PR, when, in reality,
[these measurable lymph nodes] may be
of no consequence.”
The authors report relationships with
Genentech and AbbVie, which provided
support for this study.
remission that is seen with obinutuzumab
plus venetoclax.”
Ultimately, he added, these findings
need to be confirmed in larger, randomized
clinical trials. Limitations of this early-
phase study include the small number of
enrolled patients, the lack of a randomized
design, and the single-arm design.
“While the number of patients is
small, this combination appeared to work
well in both high- and low-risk groups,
and MRD-negativity rates were equal
in patients who achieved CR compared
with those who achieved partial response
REFERENCES
Flinn IW, Gribben JG, Dyer MJS, et al. Phase 1b study of venetoclax-
obinutuzumab in previously untreated and relapsed/refractory chronic
lymphocytic leukemia. Blood. 2019 March 12. [Epub ahead of print]
Evaluating Thalidomide-Cyclophosphamide-Prednisone for Idiopathic
Multicentric Castleman Disease
An oral combination of thalidomide,
cyclophosphamide, and prednisone
(TCP) induced durable tumor and
symptomatic response rates in nearly
half of patients with newly diagnosed
idiopathic multicentric Castleman
disease (iMCD), according to a small
phase II study published in Blood. The
researchers also found that the TCP
regimen was relatively safe, with no
patients experiencing grade ≥3 adverse
events (AEs).
“Although the anti-IL6 therapy
siltuximab has been recommended as
firstline therapy for all patients with
iMCD – according to the first-ever
expert consensus [for iMCD treat-
ment] – this drug is not effective for
more than half of patients and is not
available everywhere,” said co-author
Jian Li, MD, from the Peking Union
Medical College Hospital in Beijing.
Its high price and the requirement for
repeated intravenous administration
also limit its use as firstline therapy in
lower-income countries.
In this single-center trial, Chinese
researchers evaluated the safety and
efficacy of TCP as an alternative treat-
ment for patients with newly diag-
nosed iMCD who do not respond to
or do not have access to siltuximab.
A total of 25 patients (median age
= 40 years; range not reported) were
enrolled between June 2015 and June
TABLE 2.
2018. All participants had histopatho-
logic lymph node features consistent
with iMCD.
TCP was administered for two
years or until treatment failure in the
following treatment schedule:
• thalidomide 100 mg/day at
bedtime for years 1-2
• cyclophosphamide 300 mg/m 2
weekly on days 1, 8, 15, and 22 of
a 4-week cycle for year 1
• prednisone 1 mg/kg on days 1-2,
8-9, 15-16, and 22-23 of a 4-week
cycle for year 1
The primary endpoint was the incidence
of durable tumor and symptomatic
response sustained for at least 24 weeks.
Responses were defined as:
• complete response (CR), or
complete disappearance of
measurable and evaluable disease
as well as a resolution of iMCD-
associated baseline symptoms
• partial response, or ≥50%
reduction in the sum of
the product of diameters of
measurable lesions, with at least
stable disease in the absence of
treatment failure (defined as
sustained increase in disease-
related symptoms, initiating a
new iMCD treatment, or death)
After administration of TCP, 12
patients (48%) met the primary end-
point for response, seven of whom
had achieved CR. Three patients
(12%) had stable disease, and the
remaining 10 patients (40%) experi-
enced treatment failure. The authors
observed that responders were more
likely to have fever (p=0.008) and less
likely to have pulmonary involvement
(p=0.039) at baseline, compared with
nonresponders.
Treatment with TCP also was
associated with significant improve-
ments in symptom score, IL-6 level,
hemoglobin, erythrocyte sedimenta-
tion rate, albumin, and immunoglobin
G from baseline (all p<0.05; TABLE 2 ).
During follow-up, one patient
died from pulmonary infection and
one patient had a grade 3 AE; another
patient died from disease progression.
The most common grade 1-2 AEs
included: constipation (40%), pruritus
(20%), rash (16%), peripheral sensory
neuropathy (16%), and nausea (16%).
During the median follow-up of
14 months (range = 6-36 months),
estimated progression-free and overall
survival rates were 60 percent and 88
percent, respectively. However, the
actual survival data were not reported,
which limits the applicability of these
findings.
“As a single-arm study without a
control group, it is difficult to perform
a rigorous comparison between the
TCP regimen and other treatment
options, and further study is needed,”
Dr. Li explained. “However, accord-
ing to our clinical experience with
CHOP (cyclophosphamide, doxo-
rubicin, vincristine, prednisone) or
CHOP-like regimens – which were
the most widely used therapies for
Chinese patients when siltuximab was
unavailable – oral TCP represented an
economical and convenient treatment
option with good safety profiles and
acceptable response rates.”
Dr. Li noted that investigators
are continuing to collect data on the
long-term efficacy and safety of this
regimen. “Moreover, a well-designed
multicenter trial that employs the new
consensus response criteria is needed,”
he added. “Hopefully, a controlled
study with siltuximab will be carried
out in the future.” ●
The authors report relationships
with Janssen Pharmaceuticals.
REFERENCE
Zhang L, Zhao AL, Duan MH, et al. Phase 2 study using oral
thalidomide-cyclophosphamide-prednisone for idiopathic
Multicentric Castleman disease. Blood. 2019 February 13. [Epub
ahead of print]
Improvements in iMCD Characteristics From Baseline
Characteristics
Symptom score
IL-6 (pg/mL)
Hemoglobin (g/L)
C-reactive protein (mg/L)
Baseline,
Median (Range)
Week 24,
Median (Range) p Value
Last Follow-up,
Median (Range) p Value
16 (7-38) 1 (0-6) 28.6 (7.4-865) 10.0 (2-23.5) 0.003 0.5 (0-6) 0.002
0.012 3.7 (2-25.1) 0.002
98 (76-133) 125.5 (93-150) 0.093 132 (93-177) 0.013
41.6 (0.2-185.6) 12.4 (0.8-54.8) 0.028 3.2 (0.7-53.0) 0.005
ESR (mm/h) 90 (6-115) 31 (5-125) 0.042 16 (1-125) 0.013
Albumin (g/L), median (range) 32 (26-43) 37 (36.7-56) 0.018 39.5 (36-56) 0.007
21.7 (14.4-43.8) 12.4 (7.3-20.3) 0.012 14.5 (7.9-24.6) 0.002
IgG (g/L), median (range)
ESR = erythrocyte sedimentation rate; IgG = immunoglobin G
30
ASH Clinical News
May 2019