CLINICAL NEWS
machine-learning algorithm that used
genomic and clinical data to estimate
a patient’s prognosis. The system was
“trained” in a cohort of 1,471 patients,
then validated in a separate data set of 831
patients from the Moffitt Cancer Center.
The clinical characteristics in the train-
ing and validation cohorts were similar
and were representative of a typical MDS
cohort, the authors noted.
After running the demographic,
clinical, and genomic data of the train-
ing cohort through the algorithm, the
researchers identified the clinical variables
with the greatest prognostic importance,
including (from most to least important):
• cytogenetic risk categories by IPSS-R
• platelets
• hemoglobin • absolute neutrophil count
• bone marrow blasts percentage • presence of one of 11 mutations (e.g.,
TP53, RUNX1, STAG2, ASXL1, etc.)
• 2008 World Health Organization
diagnosis
• White blood cell count
• age
• mutation number
REVLIMID [lenalidomide] capsules, for oral use
antithrombotic prophylaxis, the overall frequency of thrombotic events
was 17.4% in patients in the combined Rd Continuous and Rd18 Arms,
and was 11.6% in the MPT Arm. The median time to first thrombosis
event was 4.3 months in the combined Rd Continuous and Rd18 Arms.
Thromboprophylaxis is recommended. The regimen of thromboprophylaxis
should be based on an assessment of the patient’s underlying risks.
Instruct patients to report immediately any signs and symptoms
suggestive of thrombotic events. ESAs and estrogens may further
increase the risk of thrombosis and their use should be based on a
benefit-risk decision in patients receiving REVLIMID [see Drug
Interactions (7.2)].
5.5 Increased Mortality in Patients with CLL
In a prospective randomized (1:1) clinical trial in the first line treatment
of patients with chronic lymphocytic leukemia, single agent REVLIMID
therapy increased the risk of death as compared to single agent
chlorambucil. In an interim analysis, there were 34 deaths among
210 patients on the REVLIMID treatment arm compared to 18 deaths
among 211 patients in the chlorambucil treatment arm, and hazard ratio
for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a
92% increase in the risk of death. The trial was halted for safety in
July 2013.
Serious adverse cardiovascular reactions, including atrial fibrillation,
myocardial infarction, and cardiac failure occurred more frequently in
the REVLIMID treatment arm. REVLIMID is not indicated and not
recommended for use in CLL outside of controlled clinical trials.
5.6 Second Primary Malignancies
In clinical trials in patients with MM receiving REVLIMID, an increase
of hematologic plus solid tumor second primary malignancies (SPM)
notably AML and MDS have been observed. An increase in hematologic
SPM including AML and MDS occurred in 5.3% of patients with NDMM
receiving REVLIMID in combination with oral melphalan compared with
1.3% of patients receiving melphalan without REVLIMID. The frequency
of AML and MDS cases in patients with NDMM treated with REVLIMID in
combination with dexamethasone without melphalan was 0.4%.
In patients receiving REVLIMID maintenance therapy following high dose
intravenous melphalan and auto-HSCT, hematologic SPM occurred in
7.5% of patients compared to 3.3% in patients receiving placebo. The
incidence of hematologic plus solid tumor (excluding squamous cell
carcinoma and basal cell carcinoma) SPM was 14.9%, compared to 8.8%
in patients receiving placebo with a median follow-up of 91.5 months.
Non-melanoma skin cancer SPM, including squamous cell carcinoma
and basal cell carcinoma, occurred in 3.9% of patients receiving
REVLIMID maintenance, compared to 2.6% in the placebo arm.
In patients with relapsed or refractory MM treated with REVLIMID/
dexamethasone, the incidence of hematologic plus solid tumor (excluding
squamous cell carcinoma and basal cell carcinoma) SPM was 2.3%
versus 0.6% in the dexamethasone alone arm. Non-melanoma skin cancer
SPM, including squamous cell carcinoma and basal cell carcinoma,
occurred in 3.1% of patients receiving REVLIMID/dexamethasone,
compared to 0.6% in the dexamethasone alone arm.
Patients who received REVLIMID-containing therapy until disease
progression did not show a higher incidence of invasive SPM than
patients treated in the fixed duration REVLIMID-containing arms. Monitor
patients for the development of second primary malignancies. Take into
account both the potential benefit of REVLIMID and the risk of second
primary malignancies when considering treatment with REVLIMID.
5.7 Increased Mortality in Patients with MM When Pembrolizumab Is
Added to a Thalidomide Analogue and Dexamethasone
In two randomized clinical trials in patients with MM, the addition of
pembrolizumab to a thalidomide analogue plus dexamethasone, a use
for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in
increased mortality. Treatment of patients with MM with a PD-1 or PD-L1
blocking antibody in combination with a thalidomide analogue plus
dexamethasone is not recommended outside of controlled clinical trials.
5.8 Hepatotoxicity
Hepatic failure, including fatal cases, has occurred in patients treated with
lenalidomide in combination with dexamethasone. In clinical trials, 15%
of patients experienced hepatotoxicity (with hepatocellular, cholestatic
and mixed characteristics); 2% of patients with multiple myeloma and 1%
of patients with myelodysplasia had serious hepatotoxicity events. The
mechanism of drug-induced hepatotoxicity is unknown. Pre-existing
viral liver disease, elevated baseline liver enzymes, and concomitant
medications may be risk factors. Monitor liver enzymes periodically. Stop
REVLIMID upon elevation of liver enzymes. After return to baseline values,
treatment at a lower dose may be considered.
5.9 Severe Cutaneous Reactions Including Hypersensitivity Reactions
Angioedema and severe cutaneous reactions including Stevens-Johnson
syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction
Cosmos Communications
eosinophilia and systemic symptoms (DRESS) have been reported. Dress
may present with a cutaneous reaction (such as rash or exfoliative
dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic
complications such as hepatitis, nephritis, pneumonitis, myocarditis,
and/or pericarditis. These events can be fatal. Patients with a prior
history of Grade 4 rash associated with thalidomide treatment should not
receive REVLIMID. REVLIMID interruption or discontinuation should be
considered for Grade 2-3 skin rash. REVLIMID must be discontinued for
angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN, or
DRESS is suspected and should not be resumed following discontinuation
for these reactions.
5.10 Tumor Lysis Syndrome
Fatal instances of tumor lysis syndrome have been reported during
treatment with lenalidomide. The patients at risk of tumor lysis syndrome
are those with high tumor burden prior to treatment. These patients
should be monitored closely and appropriate precautions taken.
5.11 Tumor Flare Reaction
Tumor flare reaction has occurred during investigational use of
lenalidomide for CLL and lymphoma, and is characterized by tender
lymph node swelling, low grade fever, pain and rash. REVLIMID is not
indicated and not recommended for use in CLL outside of controlled
clinical trials.
Monitoring and evaluation for tumor flare reaction (TFR) is recommended
in patients with MCL. Tumor flare reaction may mimic progression of
disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR;
all reports were Grade 1 or 2 in severity. All of the events occurred in
cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide
may be continued in patients with Grade 1 and 2 TFR without interruption
or modification, at the physician’s discretion. Patients with Grade 1
and 2 TFR may also be treated with corticosteroids, non-steroidal anti-
inflammatory drugs (NSAIDs) and/or narcotic analgesics for management
of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended
to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1.
Patients with Grade 3 or 4 TFR may be treated for management of
symptoms per the guidance for treatment of Grade 1 and 2 TFR.
5.12 Impaired Stem Cell Mobilization
A decrease in the number of CD34+ cells collected after treatment
(> 4 cycles) with REVLIMID has been reported. In patients who are ASCT
candidates, referral to a transplant center should occur early in treatment
to optimize the timing of the stem cell collection. In patients who
received more than 4 cycles of a REVLIMID-containing treatment or for
whom inadequate numbers of CD 34+ cells have been collected with
G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF
with a CXCR4 inhibitor may be considered.
5.13 Thyroid Disorders
Both hypothyroidism and hyperthyroidism have been reported [see
Adverse Reactions (6.2)]. Measure thyroid function before start of
REVLIMID treatment and during therapy.
5.14 Early Mortality in Patients with MCL
In another MCL study, there was an increase in early deaths (within
20 weeks), 12.9% in the REVLIMID arm versus 7.1% in the control arm.
On exploratory multivariate analysis, risk factors for early deaths include
high tumor burden, MIPI score at diagnosis, and high WBC at baseline
(≥10 x 10 9 /L).
6 ADVERSE REACTIONS
The following adverse reactions are described in detail in other sections
of the prescribing information:
• Embryo-Fetal Toxicity [see Boxed Warning, Warnings and
Precautions (5.1, 5.2)]
• Hematologic Toxicity [see Boxed Warning, Warnings and
Precautions (5.3)]
• Venous and Arterial Thromboembolism [see Boxed Warning,
Warnings and Precautions (5.4)]
• Increased Mortality in Patients with CLL [see Warnings and
Precautions (5.5)]
• Second Primary Malignancies [see Warnings and Precautions (5.6)]
• Increased Mortality in Patients with MM When Pembrolizumab Is
Added to a Thalidomide Analogue and Dexamethasone [see
Warnings and Precautions (5.7)]
• Hepatotoxicity [see Warnings and Precautions (5.8)]
• Severe Cutaneous Reactions Including Hypersensitivity Reactions
[see Warnings and Precautions (5.9)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.10)]
• Tumor Flare Reactions [see Warnings and Precautions (5.11)]
• Impaired Stem Cell Mobilization [see Warnings and Precautions
(5.12)]
• Thyroid Disorders [see Warnings and Precautions (5.13)]
• Early Mortality in Patients with MCL [see Warnings and Precautions
(5.14)].
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They then built a physician-friendly and
patient-friendly web application that
allows the user to generate survival prob-
abilities.
In head-to-head comparisons between
the new model and IPSS and IPSS-R