On June 13, 2015 Celgene, a wholly owned subsidiary of Celgene Corporation reported two analyses of MCL-002 (SPRINT), its multi-center, open-label, phase II randomized trial comparing Revlimid (lenalidomide) with investigators’ choice (IC) in patients with relapsed/refractory mantle cell lymphoma (MCL), were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) annual congress (Press release, Celgene, JUN 13, 2015, View Source [SID:1234505423]).

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In the study, 254 patients were randomized 2:1 to receive either REVLIMID (n=170) or single agent cytarabine, rituximab, gemcitabine, fludarabine or chlorambucil (n=84). The primary efficacy endpoint was progression free survival, defined as the time from randomization to disease progression or death due to any cause. Secondary endpoints, including health-related quality of life (QoL) were analyzed in an exploratory manner.

The primary endpoint, median PFS was significantly improved for lenalidomide vs IC (8.7 vs 5.2 months; HR=0.61, P=0.004). A pre-specified exploratory analysis was presented and examined progression-free survival (PFS) in sub-groups based on prior therapies. Results examining the selected IC treatments in the study showed that REVLIMID provided a reduction in the risk of progression or death vs. each IC treatment. Compared with lenalidomide, and taking into account the small number of patients per IC group, the risk reduction in PFS was 22% vs. rituximab (n=27), 56% vs. gemcitabine (n=20), 42% vs. fludarabine (n=18), 43% vs. chlorambucil (n=11), and 8% vs. cytarabine (n=8).

An exploratory subgroup analysis of PFS based on prior treatment-related subgroups showed statistically improved PFS in several subgroups for REVLIMID over IC, including for patients with for less than 3 years from MCL diagnosis, at least 2 prior systemic therapies or relapses, at least 6 months from last therapy, at least 230 days from last rituximab dose, prior refractory disease, no prior stem cell transplant/high-dose therapy, and prior rituximab.

Treatment group was the main effect associated with significantly better PFS by univariate Cox regression analysis (HR=0.619; P=0.004), and was highly significant in the multivariate analysis (HR=0.384; P= < 0.001). Other factors associated with significantly better PFS by both univariate and multivariate analysis were less than 3 prior systemic anti-lymphoma therapies, and at least 230 days from last prior rituximab.

Also presented was a planned secondary study endpoint of the study. Quality of life (QoL) was measured using the EORTC QLQ-C30 at baseline, after cycles 2, 4, 6 and 8, and at treatment discontinuation. EORTC QLQ-C30 included five functional domains, nine symptom scales, and one global health status/QoL scale.

QoL data completion declined from 93% at screening to 51% at treatment discontinuation during the course of the study, and higher non-compliance rates were seen among IC patients. QoL was maintained (no worsening greater than 10 points) with REVLIMID from baseline through last treatment cycle for evaluated primary and secondary QoL domains. Patients treated with REVLIMID reported similar QoL vs. IC single agents across all domain/scale scores and at each follow-up visit.

A trend toward higher rates of clinically meaningful improvement in QoL was observed in REVLIMID-treated patients across most function and symptom domains/scales at one or more follow-up visits. No significant difference in the QoL was observed between the two arms in the primary endpoint of global health status. Statistically significant QoL differences (at least 10%) comparing REVLIMID vs. IC treatment arms were identified for physical function (24% vs. 8%, respectively; P=0.0025) and pain (29% vs. 18%; P=0.0471).

About REVLIMID

In the United States, REVLIMID is approved in combination with dexamethasone for the treatment of patients with multiple myeloma. REVLIMID is also approved in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy in nearly 70 countries, encompassing Europe, the Americas, the Middle East and Asia, and in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy in Australia and New Zealand.

REVLIMID is also approved in the United States, Canada, Switzerland, Australia, New Zealand and several Latin American countries, as well as Malaysia and Israel, for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities and in Europe for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

In addition, REVLIMID is approved in the United States for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

U.S. Regulatory Information for REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)

REVLIMID is indicated for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib

REVLIMID is not indicated and not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS program (formerly known as the "RevAssist"program).

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism

REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus

Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity:

REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in offspring of female monkeys who received drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy
Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID. Must obtain 2 negative pregnancy tests prior to initiating therapy

Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm

Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID

REVLIMID REMS Program

Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS Program (formerly known as the "RevAssist" Program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. MCL: Patients taking REVLIMID for MCL should have their CBCs monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. MDS: See Boxed WARNINGS

Venous and Arterial Thromboembolism: Venous thromboembolic events (DVT and PE) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and PE (3.7%) occurred in patients with MM after at least one prior therapy, treated with REVLIMID/dex compared to placebo/dex (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In NDMM study, in which nearly all patients received antithrombotic prophylaxis, DVT (3.6%) and PE (3.8%) were reported in the Rd continuous arm. Myocardial infarction (MI,1.7%) and stroke (CVA,2.3%) are increased in patients with MM after at least 1 prior therapy who were treated with REVLIMID/dex therapy compared with placebo/dex (0.6%, and 0.9%) in clinical trials. In NDMM study, MI (including acute) was reported (2.3%) in the Rd Continuous arm. Frequency of serious adverse reactions of CVA was (0.8%) in the Rd Continuous arm. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events occurred in patients with refractory and relapsed MM who were treated with REVLIMID/dex compared to 8.3% thrombosis in the placebo/dex group. Median time to first thrombosis event was 2.8 months. In NDMM study, which nearly all patients received antithrombotic prophylaxis, overall frequency of thrombotic events was 17.4% in combined Rd continuous and Rd18 arms. Median time to first thrombosis event as 4.37 months. Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision. See Boxed WARNINGS

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, 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 risk of death. 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

Second Primary Malignancies: In clinical trials in patients with MM receiving REVLIMID, an increase of invasive second primary malignancies notably AML and MDS have been observed. The increase of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (5.3%) or immediately following high dose intravenous melphalan and ASCT (up to 5.2%). The frequency of AML and MDS cases in the Revlimid/dex 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 and risk of second primary malignancies when considering treatment with REVLIMID

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dex. 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

Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson 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. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance

Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Tumor Flare Reaction: Tumor flare reaction (TFR) 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.

Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. In the MCL trial, approximately 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 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. 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

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 autologous stem cell transplant (ASCT) candidates, referral to a transplant center should occur early in treatment to optimize timing of the stem cell collection.

ADVERSE REACTIONS

Multiple Myeloma

In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.1%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.5%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75%
Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), dyspnea (22.0%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous

After at least one prior therapy most adverse reactions and Grade 3/4 adverse reactions were more frequent in MM patients who received the combination of REVLIMID/dex compared to placebo/dex. Grade 3 or 4 adverse reactions included neutropenia 33.4% vs 3.4%, febrile neutropenia 2.3% vs 0%, DVT 8.2% vs 3.4% and PE 4% vs 0.9% respectively
Adverse reactions reported in ≥15% of MM patients (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%)

Myelodysplastic Syndromes

Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%), thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)
Adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): thrombocytopenia (61.5%), neutropenia (58.8%), diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)

Mantle Cell Lymphoma

Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%)
Serious adverse events reported in ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile colitis, sepsis, basal cell carcinoma, and supraventricular tachycardia
Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin. Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436

Nursing Mothers: It is not known whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother

Pediatric Use: Safety and effectiveness in patients below the age of 18 have not been established

Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis

On June 12, 2015 ARIAD reported long-term follow up from its pivotal Phase 2 trial of Iclusig (ponatinib), its approved BCR-ABL inhibitor, in heavily pretreated patients with resistant or intolerant chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) (Press release, Ariad, JUN 12, 2015, View Source;p=RssLanding&cat=news&id=2058920 [SID:1234505422]). The study now shows that with a median follow-up of approximately 3.5 years for chronic phase CML (CP-CML) patients and a median follow-up of approximately 2.9 years in all patients in the trial, Iclusig continues to demonstrate anti-leukemic activity in patients with limited treatment options. Responses have been maintained long-term in CP-CML patients. Eighty-three percent (83%) of CP-CML patients who achieved a major cytogenetic response (MCyR) are estimated to remain in MCyR at three years.

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Additionally, 95 percent of CP-CML patients who underwent ponatinib dose reductions maintained their responses (MCyR). Benefit-risk evaluations should guide the decision to initiate and maintain Iclusig therapy, particularly in patients who may be at increased risk for arterial occlusive events (AOE).

"These continued responses in the PACE study, with a minimum follow-up of 3.3 years, in such a heavily pretreated patient population are very encouraging. Eighty-three percent of CP-CML patients who achieved the primary endpoint of major cytogenetic response remain in MCyR at three years," stated Jorge E. Cortes, M.D., Professor and Deputy Chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center. "Careful assessment of the benefit and risk of initiating ponatinib therapy, particularly in patients who may be at increased risk for arterial occlusive events, can help identify patients with refractory Ph+ leukemias who can benefit most from this treatment."

The data were featured today at the 20th Conference of the European Hematology Association (EHA) (Free EHA Whitepaper) in Vienna, Austria.

PACE Trial Update

The efficacy and safety of ponatinib in CML and Ph+ ALL patients resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation, were evaluated in the pivotal Phase 2 PACE trial. A total of 449 patients were treated with ponatinib at a starting dose of 45 mg/day. Ninety-three percent of patients had previously received two or more approved tyrosine kinase inhibitors (TKI), and 55 percent had previously received three or more approved TKIs.

Updated data on CP-CML patients (n=270) from the ongoing trial indicate that with a median follow-up of 42.3 months (data as of February 2, 2015), 114 patients (42%) continue to receive ponatinib.

Additional data in CP-CML patients include:

59% of CP-CML patients achieved MCyR (primary endpoint) at any time.

83% of patients who achieved MCyR are estimated to remain in MCyR at 3 years.

39% of patients achieved a major molecular response (MMR) or better.

By Kaplan-Meier analysis, progression-free survival at 3 years is estimated to be 60%.

Overall survival at 3 years is estimated to be 81%.

23% of CP-CML patients experienced an AOE designated a serious adverse event (SAE), and 28 percent of CP-CML patients experienced any AOE. The median time to onset for AOEs in CP-CML patients was 14.1 (0.3–44.0) months.

4% and 5% of CP-CML patients, respectively experienced a venous thromboembolic SAE or AE.

The most common all-grade treatment-emergent adverse events occurring in ≥ 40% of CP-CML patients were abdominal pain (46%), rash (46%), thrombocytopenia (45%), headache (43%), constipation (41%), and dry skin (41%); the discontinuation rate due to adverse events was 18% in CP-CML.

"These data show that the majority of CP-CML patients in the PACE trial retained their anti-leukemic responses, even when lowering the daily dose of Iclusig," stated Frank G. Haluska, M.D., Ph.D., senior vice president of clinical research and development and chief medical officer at ARIAD. "The safety and efficacy of Iclusig at starting doses lower than 45 mg will be studied in the randomized OPTIC (Optimizing Ponatinib Treatment In CML) trial set to begin shortly."

Efficacy Update Following Prospective Dose-Reduction Recommendations
(Data from October 10, 2013 to February 2, 2015)

On October 10, 2013, dose-reduction recommendations were provided by ARIAD to investigators for patients remaining on the PACE trial. The following dose reductions were recommended, unless the benefit-risk analysis warranted treatment with a higher dose:

CP-CML patients who already achieved a MCyR should have their ponatinib dose reduced to 15 mg/day,
CP-CML patients who had not already achieved MCyR should have their dose reduced to 30 mg/day, and
Advanced-phase patients should have their dose reduced to 30 mg/day.

As of February 2015, with 1.3 years (16 months) of follow-up after these recommendations, the rate of maintenance of response in CP-CML was 95% — whether or not patients underwent prospective dose reductions.

Of the 64 patients who were in MCyR as of October 10, 2013 and had a prospective dose reduction, 61 patients (95%) maintained their response at 1.3 years following prospective dose reduction.

Of the 47 patients who were in MMR as of October 10, 2013 and had a prospective dose reduction, 44 patients (94%) maintained their response at 1.3 years following prospective dose reduction.

42 patients in MCyR did not undergo any dose reductions (the majority of which were already at a reduced dose of 30 mg or 15 mg as of October 10, 2013); of these, 39 patients (93%) maintained MCyR after 1.3 more years of ponatinib treatment.

Safety Update Following Prospective Dose-Reduction

Recommendations (Data from October 10, 2013 to February 2, 2015)

Of the patients who underwent prospective dose reduction, 5 of 71 patients (7%) without prior AOEs had a new AOE during the 1.3 year interval following prospective dose reduction.

Of the patients who did not undergo prospective dose reduction, 9 of 67 patients (13%) without prior AOE had a new AOE in the same time interval.

About Iclusig (ponatinib) tablets

Iclusig is approved in the U.S., EU, Australia, Israel, Canada and Switzerland.

In the U.S., Iclusig is a kinase inhibitor indicated for the:

Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.

These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning

Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit risk consideration should guide a decision to restart Iclusig therapy.

Heart Failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.

Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.

Vascular Occlusion: Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can also cause recurrent or multi-site vascular occlusion. Overall, 20% of Iclusig-treated patients experienced an arterial occlusion and thrombosis event of any grade. Fatal and life-threatening vascular occlusion has occurred within 2 weeks of starting Iclusig treatment and in patients treated with average daily dose intensities as low as 15 mg per day. The median time to onset of the first vascular occlusion event was 5 months. Patients with and without cardiovascular risk factors have experienced vascular occlusion although these events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia. Interrupt or stop Iclusig immediately in patients who develop vascular occlusion events.

Heart Failure: Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig-treated patients (22/449). Eight percent of patients (35/449) experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure.

Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with blast phase CML (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Severe hepatotoxicity occurred in all disease cohorts. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Hypertension: Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled.

Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Neuropathy: Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1% grade 3/4). Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase CML (AP-CML), BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage and evaluate.

Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% (25/449) of Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Interrupt Iclusig and evaluate.

Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig.

Most common non-hematologic adverse reactions: (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

On June 12, 2015 Sunesis reported additional results of the VALOR trial, a Phase 3 study of vosaroxin and cytarabine in adult patients with relapsed or refractory acute myeloid leukemia (AML) (Press release, Sunesis, JUN 12, 2015, View Source;p=RssLanding&cat=news&id=2058835 [SID:1234505411]). The results are being presented today, Friday, June 12th from 5:15 p.m. to 6:45 p.m. Central European Time at the acute myeloid leukemia (AML) poster session of the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place in Vienna, Austria.

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VALOR is a randomized, double-blind, placebo-controlled Phase 3 trial which enrolled 711 adult patients with first relapsed or refractory AML at 124 leading sites in 15 countries. Patients were stratified for age, geographic region and disease status and randomized one to one to receive either vosaroxin and cytarabine or placebo and cytarabine. Detailed results of the VALOR trial were presented in the "Late Breaking Abstracts" session of the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2014. Data from the post-hoc analysis of VALOR patients age 60 years and older who received allogeneic transplant after treatment with vosaroxin or placebo plus cytarabine were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in May 2015 and now at the EHA (Free EHA Whitepaper) Congress.

Among the new data presented today are detailed results from the subgroups of patients age 60 years and older (451 out of 711 enrolled in VALOR) with late relapse (n=87) and refractory and early relapse disease (combined n=364).

Among patients with late relapse disease, overall survival (OS) and leukemia-free survival (LFS) were comparable between treatment arms. The complete remission (CR) rate was 57% and 28% (p=0.0064) and event-free survival (EFS) was 5.5 months versus 2.3 months (HR=0.65, p=0.0852) for vosaroxin/cytarabine and placebo/cytarabine, respectively. Thirty- and 60-day all-cause mortality among these patients was 11% and 18% versus 2% and 14% for vosaroxin/cytarabine and placebo/cytarabine, respectively.

Among patients with refractory and early relapse disease (combined n=364), a population known to have poorer outcomes, OS was 6.5 months versus 3.9 months for vosaroxin/cytarabine and placebo/cytarabine, respectively (HR=0.69, p=0.0008). CR rates in this population were 26% and 10% (p=0.0001) for vosaroxin/cytarabine and placebo/cytarabine, respectively. Among these patients, LFS was 9.7 months versus 5.5 months (HR=0.50, p=0.0424) and EFS was 1.7 months versus 1.3 months (HR=0.59, p<0.0001) for vosaroxin/cytarabine and placebo/cytarabine, respectively. Thirty- and 60-day all-cause mortality among these patients was comparable, at 10% and 21% versus 11% and 25% for vosaroxin/cytarabine and placebo/cytarabine, respectively.

In all patients age 60 years and older, Grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin combination arm were gastrointestinal and myelosuppression-related toxicities, consistent with those observed in previous company trials. The rate of serious adverse events related to treatment was 74% and 60% for vosaroxin/cytarabine and placebo/cytarabine, respectively.

"AML is a disease that primarily affects older patients, and clinical outcomes among these patients is abysmal," said Farhad Ravandi, M.D., Professor of Medicine, Department of Leukemia, University of Texas MD Anderson Cancer Center, and a principal investigator of the VALOR study. "These patients have had few options outside of clinical trial enrollment. Results from the analyses presented today show compelling survival and durable responses with comparable early mortality for the vosaroxin and cytarabine treatment arm in the older refractory and early relapse patients. Given these results, I believe vosaroxin represents an important new treatment option."

"In over four decades of research, there has been far too little progress in the treatment of AML," said Patricia J. Goldsmith, CEO of CancerCare. "This need is particularly pronounced in those patients age 60 and older with the fewest options. Progress for these patients cannot wait."

The two poster presentations (Abstracts #4192 and #4693, Hall C), titled "Improved survival in patients ≥60 with first relapsed/refractory acute myeloid leukemia treated with vosaroxin plus cytarabine vs placebo plus cytarabine: results from the Phase 3 VALOR study" and "Allogeneic transplant in patients ≥60 years of age with first relapsed or refractory acute myeloid leukemia after treatment with vosaroxin or placebo plus cytarabine: results from VALOR," will be available on the Sunesis website at www.sunesis.com. In addition, an E-poster, titled "Impact of cytogenetics on clinical outcomes in patients with first relapsed or refractory acute myeloid leukemia treated with vosaroxin plus cytarabine: results from VALOR," is on display at EHA (Free EHA Whitepaper) through tomorrow, Saturday, June 13th at 6:45 p.m. Central European Time.

On June 12, 2015 MEI Pharma reported updated results from a Phase II study of its investigational drug candidate Pracinostat in combination with azacitidine (marketed as Vidaza) in elderly patients with newly diagnosed acute myeloid leukemia (AML) (Press release, MEI Pharma, JUN 12, 2015, View Source [SID:1234505410]). Data from 50 patients treated at 15 centers are being presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress in Vienna. A copy of the poster, entitled "Updated Results from a Phase 2 Study of Pracinostat in Combination with Azacitidine in Elderly Patients with Acute Myeloid Leukemia," is now available at www.meipharma.com.

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To date, 27 of 50 patients (54%) have achieved the primary endpoint of complete response (CR) plus complete response with incomplete blood count recovery (CRi) plus morphologic leukemia-free state (MLFS), including 16 patients (32%) who achieved a CR. The response rate from this study compares favorably with previous studies of azacitidine alone in this population1. Most responses occur within the first two cycles and continue to improve with ongoing therapy.

Median overall survival has not yet been reached in the study, with 32 patients (64%) still being followed (range, 6-15 months). Survival of patients with intermediate-risk cytogenetic abnormalities appears greater than that for patients with high-risk cytogenetics, though neither subset of patients has reached median survival. The 60-day mortality rate, often used as a benchmark in AML clinical studies, was 10% (5 of 50).

Pracinostat in combination with azacitidine was well tolerated in this population of elderly AML patients. The most common treatment-emergent adverse events (AEs) included febrile neutropenia, thrombocytopenia, nausea and fatigue. AEs resulting in dose reductions were frequently due to disease under study. Nearly half of the patients (22 of 50) to date have received study drug beyond six months, reflecting long-term tolerability.

"The combination of Pracinostat and azacitidine continues to demonstrate compelling clinical activity in these elderly patients with newly diagnosed AML," said Daniel P. Gold, Ph.D., President and Chief Executive Officer of MEI Pharma. "While the overall survival trend in this study is encouraging, we believe that longer follow-up is needed to gain an accurate survival estimate. Ultimately, this survival estimate will be critical in determining the development path forward for this combination. We look forward to providing an update when these data mature, which we expect to occur later this year."

About Pracinostat

Pracinostat is an orally available inhibitor of a group of enzymes called histone deacetylases, or HDACs. HDACs belong to a larger set of proteins collectively known as epigenetic regulators that can alter gene expression by chemically modifying DNA or its associated chromosomal proteins. Abnormal activity of these regulators is believed to play an important role in cancer and other diseases. Pracinostat has been tested in multiple Phase I and Phase II clinical studies in advanced hematologic diseases and solid tumor indications with side effects often associated with drugs of this class, the most frequent of which is fatigue. The results of these studies also suggest that Pracinostat has potential best-in-class pharmacokinetic properties when compared to other oral HDAC inhibitors.

MEI Pharma owns exclusive worldwide rights to Pracinostat.

About AML

Acute myeloid leukemia (also known as acute myelogenous leukemia) is the most common acute leukemia affecting adults, and its incidence is expected to increase as the population ages. The American Cancer Society estimates about 20,830 new cases of AML per year in the U.S., with an average age of about 67 years. Treatment options for AML remain virtually unchanged over the past 30 years. Front line treatment consists primarily of chemotherapy, while the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend azacitidine or decitabine (marketed as Dacogen) as low intensity treatment options for AML patients over the age of 60 who are unsuitable for induction chemotherapy.

On June 12, 2015 Celgene International Sàrl, a wholly-owned subsidiary of Celgene reported updated results of its pivotal phase III FIRSTTM (MM-020/IFM 07-01) trial, comparing continuous REVLIMID (lenalidomide) plus low-dose dexamethasone (continuous Rd) to a fixed duration of 18 cycles of Rd (72 weeks) (Rd18) or 12 cycles of melphalan, prednisone and thalidomide (72 weeks) (MPT) for the treatment of transplant ineligible patients with newly diagnosed multiple myeloma (Press release, Celgene, JUN 12, 2015, View Source [SID:1234505409]). The results, as part of the Regulatory submissions which led to the REVLIMID label expansion in the US and EU in February 2015, were presented during the European Hematology Association (EHA) (Free EHA Whitepaper) annual congress.

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In the study, the primary endpoint was progression-free survival (PFS) and the primary analysis was between continuous Rd and MPT. Overall survival was a secondary endpoint, along with response rate, duration of response, time to response, safety, time to second-line anti-myeloma treatment and best response achieved to second-line anti-myeloma treatment.

An updated analysis of progression-free survival (PFS) demonstrated a median of 26.0 months for patients treated with continuous Rd compared with 21.9 months for MPT (HR 0.69 (95% CI, 0.59‐0.80) p=0.00031). The median PFS for Rd18 was 21.0 months.

Continuous Rd treatment (doublet regimen) continued to show an OS advantage, with a 25% reduction in risk of death versus the triple-agent MPT regimen in this updated survival analysis (HR 0.75 (95% CI, 0.62‐0.90), translating into a median OS improvement of 10.4 months (from 48.5 to 58.9 months). The median OS for Rd18 was 56.7 months. The median follow up was 45.5 months.

"The updated results of the FIRST study reinforce the survival advantage for continuous REVLIMID therapy in patients newly diagnosed with multiple myeloma," said Prof. Thierry Facon, MD, University of Lille and primary investigator of the study.

An updated analysis of safety in the continuous Rd arm remained similar with extended follow-up to previously reported data (N Engl J Med 2014). Those data showed that grade 3/4 adverse events that occurred in at least 8% of patients in the continuous Rd arm, Rd18 arm or MPT arm included neutropenia (28%, 26% and 45%, respectively), anemia (18%, 16% and 19%, respectively), thrombocytopenia (8%, 8% and 11%, respectively), febrile neutropenia (1%, 3% and 3%, respectively), leukopenia (5%, 6% and 10%, respectively), infection (29%, 22% and 17%, respectively), pneumonia (8%, 8% and 6%, respectively), deep-vein thrombosis and/or pulmonary embolism (8%, 6% and 5%, respectively), asthenia (8%, 6% and 6%, respectively), fatigue (7%, 9% and 6%, respectively), and peripheral sensory neuropathy (1%, < 1% and 9%, respectively).

An updated analysis of the incidence of invasive second primary malignancies was 3.9% in patients taking continuous Rd, 6.1% in patients taking Rd18 and 5.5% in patients taking MPT. The incidence of solid tumors was similar in the continuous Rd and MPT arms (3.4% and 3.3%, respectively) and 5.9% in the Rd18 arm.

About REVLIMID

In the United States, REVLIMID is approved in combination with dexamethasone for the treatment of patients with multiple myeloma. In the European Union, REVLIMID is approved for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for transplant. REVLIMID is also approved in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy in nearly 70 countries, encompassing Europe, the Americas, the Middle East and Asia, and in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy in Australia and New Zealand.

REVLIMID is also approved in the United States, Canada, Switzerland, Australia, New Zealand and several Latin American countries, as well as Malaysia and Israel, for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities and in Europe for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

In addition, REVLIMID is approved in the United States for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

U.S. Regulatory Information for REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)

REVLIMID is indicated for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib

REVLIMID is not indicated and not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS program (formerly known as the "RevAssist"program).

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism

REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus

Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity:

REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in offspring of female monkeys who received drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy
Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID. Must obtain 2 negative pregnancy tests prior to initiating therapy

Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm

Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID

REVLIMID REMS Program

Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS Program (formerly known as the "RevAssist" Program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. MCL: Patients taking REVLIMID for MCL should have their CBCs monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. MDS: See Boxed WARNINGS

Venous and Arterial Thromboembolism: Venous thromboembolic events (DVT and PE) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and PE (3.7%) occurred in patients with MM after at least one prior therapy, treated with REVLIMID/dex compared to placebo/dex (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In NDMM study, in which nearly all patients received antithrombotic prophylaxis, DVT (3.6%) and PE (3.8%) were reported in the Rd continuous arm. Myocardial infarction (MI,1.7%) and stroke (CVA,2.3%) are increased in patients with MM after at least 1 prior therapy who were treated with REVLIMID/dex therapy compared with placebo/dex (0.6%, and 0.9%) in clinical trials. In NDMM study, MI (including acute) was reported (2.3%) in the Rd Continuous arm. Frequency of serious adverse reactions of CVA was (0.8%) in the Rd Continuous arm. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events occurred in patients with refractory and relapsed MM who were treated with REVLIMID/dex compared to 8.3% thrombosis in the placebo/dex group. Median time to first thrombosis event was 2.8 months. In NDMM study, which nearly all patients received antithrombotic prophylaxis, overall frequency of thrombotic events was 17.4% in combined Rd continuous and Rd18 arms. Median time to first thrombosis event as 4.37 months. Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision. See Boxed WARNINGS

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, 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 risk of death. 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

Second Primary Malignancies: In clinical trials in patients with MM receiving REVLIMID, an increase of invasive second primary malignancies notably AML and MDS have been observed. The increase of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (5.3%) or immediately following high dose intravenous melphalan and ASCT (up to 5.2%). The frequency of AML and MDS cases in the Revlimid/dex 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 and risk of second primary malignancies when considering treatment with REVLIMID

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dex. 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

Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson 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. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance

Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Tumor Flare Reaction: Tumor flare reaction (TFR) 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.

Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. In the MCL trial, approximately 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 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. 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

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 autologous stem cell transplant (ASCT) candidates, referral to a transplant center should occur early in treatment to optimize timing of the stem cell collection.

ADVERSE REACTIONS

Multiple Myeloma

In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.1%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.5%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75%

Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), dyspnea (22.0%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous

After at least one prior therapy most adverse reactions and Grade 3/4 adverse reactions were more frequent in MM patients who received the combination of REVLIMID/dex compared to placebo/dex. Grade 3 or 4 adverse reactions included neutropenia 33.4% vs 3.4%, febrile neutropenia 2.3% vs 0%, DVT 8.2% vs 3.4% and PE 4% vs 0.9% respectively

Adverse reactions reported in ≥15% of MM patients (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%)

Myelodysplastic Syndromes

Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%), thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)

Adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): thrombocytopenia (61.5%), neutropenia (58.8%), diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)

Mantle Cell Lymphoma

Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%)

Serious adverse events reported in ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile colitis, sepsis, basal cell carcinoma, and supraventricular tachycardia

Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin. Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436

Nursing Mothers: It is not known whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother

Pediatric Use: Safety and effectiveness in patients below the age of 18 have not been established

Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis