38
Written in Blood
muscle mass in this patient population.
“Several exercise interventions for
currently treated patients and for
survivors are also in the planning
stages,” she added.2
References
1. Ness KK, DeLany JP, Kaste SC, et al. Energy balance and fitness in
adult survivors of childhood acute lymphoblastic leukemia. Blood.
2015 March 26. [Epub ahead of print]
2. Esbenshade AJ, Friedman DL, Smith WA, et al. Feasibility and
initial effectiveness of home exercise during maintenance therapy
for childhood acute lymphoblastic leukemia. Pediatr Phys Ther.
2014:26:301-7.
HCT Remains Best Bet for High-Risk Primary Myelofibrosis
Physicians treating patients with
primary myelofibrosis have one curative
treatment option: hematopoietic cell
transplantation (HCT). The procedure,
can be associated with significant
morbidity and mortality, though,
so accurate patient selection and
counseling are vital. Which patients
are better suited for transplant, and
who would benefit more from non-
transplant approaches?
In a recent Blood article, a team of
European researchers, led by Nicolaus
Kröger, MD, of the University Hospital
Hamburg in Germany, analyzed 438
patients with clonal myeloproliferative
neoplasms stratified according to risk, as
determined by the Dynamic International
Prognostic Scoring System (DIPSS).1
Using the DIPSS, patients with
primary myelofibrosis fall into four risk
categories: low, intermediate 1 (int-1),
intermediate 2 (int-2), and high.
“In general, selecting a patient
according to DIPSS is helpful in
deciding which therapy will offer the
best chance of survival,” Dr. Kröger
told ASH Clinical News. However, he
cautioned, “more research is necessary
to reach a more ‘individualized’
T:7”
5.6 Second Primary Malignancies
In clinical trials in patients with multiple myeloma receiving REVLIMID an
increase of invasive second primary malignancies notably AML and MDS
have been observed. The increase of cases of AML and MDS occurred
predominantly in NDMM patients receiving REVLIMID in combination with
oral melphalan (frequency of 5.3%) or immediately following high dose
intravenous melphalan and ASCT (frequency of up to 5.2%). The
frequency of AML and MDS cases in the REVLIMID / dexamethasone
arms was observed to be 0.4%. Cases of B-cell malignancies (including
Hodgkin’s Lymphomas) were observed in clinical trials where patients
received lenalidomide in the post-ASCT setting.
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 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.
5.8 Allergic Reactions
Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have
been reported. 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 or TEN is suspected
and should not be resumed following discontinuation for these reactions.
5.9 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.
5.10 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 antiinflammatory 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.
5.11 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.
All Adverse Reactionsa
Grade 3/4 Adverse
Reactionsb
Rd
Rd
System organ class Continuous Rd18
MPT Continuous Rd18
MPT
Preferred term
(N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541)
General disorders and administration site conditions
Fatigue%
173 (32.5) 177 (32.8) 154 (28.5) 39 (7.3)
46 (8.5)
31 (5.7)
Asthenia
150 (28.2) 123 (22.8) 124 (22.9) 41 (7.7)
33 (6.1)
32 (5.9)
Pyrexiac
114 (21.4) 102 (18.9) 76 (14.0) 13 (2.4)
7 (1.3)
7 (1.3)
< 1%
< 1%
18 (3.3)
8 (1.5)
Non-cardiac
chest pain f
29 (5.5)
31 (5.7)
18 (3.3)
<1%
Gastrointestinal disorders
Diarrhea
242 (45.5) 208 (38.5) 89 (16.5) 21 (3.9)
Abdominal pain%f 109 (20.5) 78 (14.4) 60 (11.1)
Dyspepsia f
57 (10.7)
28 (5.2)
36 (6.7)
7 (1.3)
9 (1.7)
< 1%
<1%
< 1%
0 (0.0)
(continued)
T:10”
REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment
should be evaluated in patients with lactose intolerance.
6 ADVERSE REACTIONS
The following adverse reactions are described in detail in other sections of
the prescribing information:
• Embryo-Fetal Toxicity [see Boxed Warnings, Warnings and
Precautions (5.1, 5.2)]
• Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings
and Precautions (5.3)]
• Venous and arterial thromboembolism [see Boxed Warnings,
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)]
• Hepatotoxicity [see Warnings and Precautions (5.7)]
• Allergic Reactions [see Warnings and Precautions (5.8)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.9)]
• Tumor Flare Reactions [see Warnings and Precautions (5.10)]
• Impaired Stem Cell Mobilization [see Warnings and Precautions (5.11)]
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug and may
not reflect the rates observed in practice.
6.1 Clinical Trials Experience
Specific Populations
Newly Diagnosed Multiple Myeloma:
Data were evaluated from 1613 patients in a large phase 3 study who
received at least one dose of REVLIMID with low dose dexamethasone
(Rd) given for 2 different durations of time (i.e., until progressive disease
[Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72
weeks, Arm Rd18; N=540] or who received melphalan, prednisone and
thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles
(72 weeks). The median treatment duration in the Rd Continuous arm was
80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7).
In general, the most frequently reported adverse reactions were
comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea,
anemia, constipation, peripheral edema, neutropenia, fatigue, back pain,
nausea, asthenia, and insomnia. The most frequently reported Grade 3 or
4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia,
asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia,
dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of
infections occurred in Arm Rd Continuous (75%) compared to Arm MPT
(56%). There were more grade 3 and 4 and serious adverse reacti ons of
infection in Arm Rd Continuous than either Arm MPT or Rd18.
In the Rd Continuous arm, the most common adverse reactions leading to
dose interruption of REVLIMID were infection events (28.8%); overall, the
median time to the first dose interruption of REVLIMID was 7 weeks. The
most common adverse reactions leading to dose reduction of REVLIMID
in the Rd Continuous arm were hematologic events (10.7%); overall, the
median time to the first dose reduction of REVLIMID was 16 weeks. In
the Rd Continuous arm, the most common adverse reactions leading to
discontinuation of REVLIMID were infection events (3.4%).
In both Rd arms, the frequencies of onset of adverse reactions were
generally highest in the first 6 months of treatment and then the frequencies
decreased over time or remained stable throughout treatment, except for
cataracts. The frequency of onset of cataracts increased over time with
0.7% during the first 6 months and up to 9.6% by the 2nd year of
treatment with Rd Continuous.
Table 4 summarizes the adverse reactions reported for the Rd Continuous,
Rd18, and MPT treatment arms.
Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions
in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms*