ASH News Daily - Saturday, December 10, 2011 - (Page A-12)
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ASH NEWS DAILY
JAK2: The Beginning of a Mosaic
MPN
By heather landau, Md
derived disorders characterized
by proliferation of one or more
myeloid cell lines. The Education
Program session, “Current Issues
in Myeloproliferative Neoplasms,”
which will take place this afternoon
at 4:00 p.m. and again tomorrow
at 9:30 a.m., in Room 20CD of the
San Diego Convention Center, will
focus on the three “classic” BCR-
M
yeloproliferative neoplasms
(MPNs) are a diverse
group of stem-cell-
ABL-negative MPNs including
polycythemia vera (PV), essential
thrombocytosis (ET), and primary
myelofibrosis (PMF).
Although the most prominent
mutation found in MPNs is the G to
T change on exon 14 of the JAK2 kinase
(JAK2V617F), this is not the entire
story and, in fact, may represent
a single piece in a complex puzzle.
In the first part of the session, Dr.
Nicholas C. P. Cross, University of
Southampton, will review our current
knowledge regarding the genetics
of MPNs and highlight areas
of recent progress and controversy.
Direct or indirect deregulation of
JAK2 signaling by acquired mutations
has emerged as a central principle
of the pathogenesis of MPNs.
In addition to JAK2V617F, mutations
at exon 12 of JAK2 result in
constitutive activation of the JAK2
without receptor activation. Other
less frequent genetic mutations and
epigenetic changes contributing to
the pathogenesis of this disorder
will also be described. The genetic
and epigenetic nature of MPNs is
clearly multifaceted and complex,
Saturday, December 10, 2011
partially explaining the modest activity
of JAK2 inhibitors.
The second speaker, Dr. Francisco
Brief Summary
INDICATIONS:
VELCADE®
(bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.
VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma
who have received at least 1 prior therapy.
CONTRAINDICATIONS:
VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.
WARNINGS AND PRECAUTIONS:
VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic
therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.
Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.
However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with
pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral
neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment
with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation,
hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing
new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE.
Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51%
of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement
in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2
neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The
long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.
Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These
events are observed throughout therapy. Caution should be used when treating patients with a history of
syncope, patients receiving medications known to be associated with hypotension, and patients who are
dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive
medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.
Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of
decreased left ventricular ejection fraction have been reported, including reports in patients with no risk
factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease
should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent
cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.
The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure,
cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and
4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality
has not been established.
Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown
etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress
Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial,
the first two patients given high-dose cytarabine (2 g/m2
per day) by continuous infusion with daunorubicin
and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There
have been reports of pulmonary hypertension associated with VELCADE administration in the absence
of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary
symptoms, a prompt comprehensive diagnostic evaluation should be conducted.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients
receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure,
hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.
Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients
developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously
experiencing RPLS is not known.
Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and
vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and
electrolyte replacement should be administered to prevent dehydration.
Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that
follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering
prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and
recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of
cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately
40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the
relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on
both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each
dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule
of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with
VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.
Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the
complications of tumor lysis syndrome may occur. 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.
Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant
medications and with serious underlying medical conditions. Other reported hepatic events include
increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon
discontinuation of VELCADE. There is limited re-challenge information in these patients.
Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients
with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced
starting doses and closely monitored for toxicities.
Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming
pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis
at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2
post-implantation loss and a decreased number of live fetuses.
based on body surface area caused
VELCADE, MILLENNIUM and
are registered trademarks of Millennium Pharmaceuticals, Inc.
Other trademarks are property of their respective owners.
Millennium Pharmaceuticals, Inc., Cambridge, MA 02139
Copyright © 2011, Millennium Pharmaceuticals, Inc.
All rights reserved.
Printed in USA
V-11-0264a
12/11
ADVERSE EVENT DATA:
Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2
/dose twice weekly for 2 weeks
followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008,
not including the phase 3, VELCADE plus DOXIL®
[doxorubicin HCI liposome injection] study) and previously
treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of
VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.
In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including
fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral
neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%),
thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%),
anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough
and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo);
(each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension
(each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia
(each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of
patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and
neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.
The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%),
and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).
In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination
with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and
melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/
prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%),
nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%),
constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%),
pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%),
asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%),
rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%),
dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain
(14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%),
hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension
(12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%),
arthralgia (11% vs 15%) and pruritus (10% vs 5%).
DRUG INTERACTIONS:
Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of
ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients.
Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4
inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had
no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4
inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction
study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater
than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4
inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving
VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and
should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the
exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure
of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.
USE IN SPECIFIC POPULATIONS:
Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse reactions in nursing infants from
VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother.
Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.
Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65
and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.
Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of
renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal
insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the
dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see
manufacturer’s prescribing information.
Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and
severe hepatic impairment. Starting dose should be reduced in those patients.
Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic
patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may
require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.
Please see full Prescribing Information for VELCADE at VELCADE.com.
Cervantes, Hospital Clinic, Barcelona,
will focus on the diagnosis and
management of ET, the most common
and, in general, the least aggressive
of the three disorders. Yet, a
proportion of patients’ disorders will
evolve into MF or acute leukemia.
Furthermore, treatment of ET with
cytotoxic chemotherapy increases
the risk of transformation to MF or
leukemia. While the prevention of
vascular events is an indication for
therapy, there must be a balance between
preventing thrombosis and
bleeding without increasing the risk
of disease transformation. Dr. Cervantes
states, “Treatment strategy
in ET patients must be driven by
the presence or not of the two factors
… being older than 60 years or
having a history of thrombosis. Patients
with one (or both) risk factors
should be given cytoreductive treatment;
[otherwise] the approach must
be more conservative.”
Dr. Alessandro M. Vannucchi,
University of Florence, the final
speaker, will focus on primary
myelofibrosis (PMF), the most
symptomatic and life-threatening
of the MPNs. Histopathology is
central to diagnosis and the International
Prognostic Scoring System
(IPSS) employs five variables
that are estimated at the time of
diagnosis to be useful for predicting
survival. The only potentially
curative treatment is allogeneic
stem cell transplantation (SCT), so
management for most is primarily
palliative. In the absence of curative
therapy, symptomatic anemia and
splenomegaly must be managed.
Dr. Vannucchi will discuss multiple
effective agents including pomalidomide,
everolimus, and JAK2 inhibitors
of which five are currently under
development.
The so-called “variant” MPNs
share a common stem-cell-derived
clonal heritage with the three “classic”
BCR-ABL-negative MPNs, and
their phenotypic diversity is attributed
to differences in the specific genetic
rearrangements or mutation(s)
that underlie the clonal myeloproliferation.
The Education Program session,
“Diagnosis and Management
of Myeloproliferative Neoplasm
Variants,” which will take place this
morning at 9:30 a.m. and again tomorrow
at 7:30 a.m. in Room 20CD
of the San Diego Convention Center,
will focus on myelodysplastic/
MPNs including chronic myelomonocytic
leukemia (CMML), atypical
CML (BCR-ABL1 negative), and
refractory anemia with ringed sideroblasts
associated with marked
thrombocytosis (RARS-T) as well as
»» MPN Page A-14
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