Written in Blood
Sirolimus Monotherapy Found to Be Safe, Effective in Treating Children
with Relapsed/Refractory Autoimmune Cytopenias
Children with multi-lineage autoimmune cytopenias often have chronic
disease that is refractory to the few available treatments and require
chronic immunosuppression.
Autoimmune lymphoproliferat ive syndrome (ALPS) is one rare
disorder that can lead to the development of multi-lineage cytopenias,
along with chronic nonmalignant lymphadenopathy, splenomegaly, and
lymphoma. Treatment of ALPS varies, and there is no overall consensus
on management of the disease. According to a recent study published in
Blood, monotherapy with the mTOR inhibitor sirolimus is a safe and effective option for patients with relapsed/refractory autoimmune cytopenias, suggesting that it can be used as a first-line, steroid-sparing option
earlier in treatment – particularly in patients with ALPS.
The current study expands on a previous small trial conducted by
Karen L. Bride, MD, PhD, from the division of oncology at the Children’s Hospital of Philadelphia in Pennsylvania, and colleagues, that
found that treatment with sirolimus led to complete responses (CR) in
children with ALPS. To further characterize the safety and efficacy of
sirolimus in this patient population, Dr. Bride and colleagues conducted
a multicenter, prospective, open-label clinical trial in 30 patients (12
months to 40 years old) with a diagnosis of autoimmune cytopenias
(either autoimmune neutropenia, autoimmune thrombocytopenia, or
autoimmune hemolytic anemia) requiring medication.
Following a maximum initial dose of sirolimus (4 mg/m2 per day),
the drug was administered at a dose of 2 mg/m2 to 2.5 mg/m2 per day
in either liquid or tablet form. The intended treatment length was six
months, though patients with a good response were allowed to continue
treatment with follow-up to monitor toxicities.
Of the 30 patients, 12 were diagnosed with ALPS: eight had Evans
syndrome (ES), two had common variable immunodeficiency (CVID),
and two had systemic lupus erythematosus (SLE). The median patient
age was five years (range, 5-19 years), and the median age at the start of
sirolimus treatment was 11 years (range = 1.8-21 years).
All of the 12 ALPS patients were previously treated with corticosteroids; although nine of these patients did respond to steroids, they were
unable to be weaned off of the medication. The remaining three patients
had either no or poor response to steroids.
After the start of sirolimus, drug trough levels were monitored twice
weekly until they reached a steady state. To assess response, Dr. Bride
and researchers evaluated blood counts every two weeks until the goal
trough sirolimus levels (4.6-20.0 ng/mL) were attained, then spaced them
out to every three months. Efficacy was also measured by immune cell
assays and immune function, including:
• T-cell subsets (CD4+, CD8+, and double negative T cells)
• Quantitative immunoglobulin G
• Mitogen assays (phytohemagglutinin A, concanavalin A, and poke
weed mitogen)
Of the patients with ALPS, 11 experienced a hematologic CR within
three months of starting sirolimus; the remaining patient achieved a partial response during the first year and reached CR by 18 months. Notably,
all ALPS patients were able to wean off of steroids, and all but one were
able to wean off of all other immunosuppressants within one week to one
month (the remaining patient was weaned off by three months). Of the
patients with multilineage autoimmune cytopenias, three patients with
ES, two patients with CVID, and one patient with SLE reached CR by
three months after starting sirolimus treatment.
Over a median follow-up of two years (range, 0-8 years), the authors
observed durable responses in the ALPS patients, with patients remaining on treatment for a median of 3.5 years (range = 1.5-8 years). The
drug was also well tolerated; grade 1 or 2 mucositis was the most common adverse event, occurring in 10 of 30 patients.
“Our data re-emphasize the safety and efficacy of steroid-sparing
oral immune suppressants,” David Teachey, MD, corresponding author
on the study, told ASH Clinical News, noting that corticosteroids are as-
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ASH Clinical News
sociated with long-term morbidity. “Sirolimus is safe to treat patients for
years and effective in many patients with refractory multi-lineage autoimmune cytopenias, including patients with ALPS, lupus, and common
variable immune deficiency.”
“In addition, our data suggest single-agent sirolimus, while effective,
does not affect B- or T-cell function in most patients. Accordingly, the
risk of infection is very low,” Dr. Teachey added.
The current study is small – only a 30-patient cohort – so these
results will need to be confirmed in larger populations. Additionally, one
patient with ES who had reached CR for more than one year experienced
a life-threatening relapse two months later; further studies are necessary
to determine whether discontinuation of sirolimus is possible. ●
REFERENCE
Bride KL, Vincent T, Smith-Whitley K, et al. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a
prospective multi-institutional trial. Blood. 2015 October 26. [Epub ahead of print]
Combination of Carfilzomib,
Pomalidomide, and
Dexamethasone Well Tolerated in
Patients with Relapsed/Refractory
Multiple Myeloma
Combination therapies for patients with relapsed and/or refractory forms of multiple myeloma
(MM) continue to expand with a
number of recent drug approvals,
including the proteasome inhibitor carfilzomib.
In a recent phase I, open-label,
multicenter, dose-escalation trial,
“This combination is very
well tolerated
without any
neuropathy
or significant
toxicity, and
is also highly
active in patients with
high-risk
MM.”
—JATIN J. SHAH, MD
Jatin J. Shah, MD, and colleagues
examined the safety of a threedrug combination of carfilzomib
and pomalidomide together with
dexamethasone (CPD) in patients
with relapsed and/or refractory
MM, and found that the combination was well tolerated in this
population.
“When patients become
refractory to lenalidomide and
bortezomib, unfortunately, the
survival is rather short,” Dr. Shah
told ASH Clinical News. “This
combination is very well tolerated without any neuropathy or
significant toxicity, and is also
highly active in the most difficultto-treat disease, such as patients
with high-risk [MM].”
Dr. Shah and co lleagues enrolled 32 adult patients in the trial.
Patients were included if they had
a confirmed diagnosis of MM that
was relapsed after prior therapy
or that was refractory to the most
recently received therapy.
Patients also must have received prior lenalidomide therapy
and have been refractory to a
regimen containing a full 25 mg or
maximum tolerated dose (MTD)
of lenalidomide. Additional study
inclusion criteria included: Eastern
Cooperative Oncology Group
score of 0 to 2, adequate hepatic
function, and adequate bone marrow function.
November 2015