Black box warning on lenalidomide-associated venous thromboembolism (VTE) in off-label setting: A preemptive and unusual safety initiative

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6074-6074
Author(s):  
C. Angelotta ◽  
A. J. Lurie ◽  
P. R. Yarnold ◽  
S. Singhal ◽  
J. Mehta ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Attorney General ◽  
Package Insert ◽  
Black Box ◽  
Cancer Therapies ◽  
Off Label Use ◽  
Off Label ◽  
Package Inserts ◽  
Thalidomide Analogue ◽  
Label Use

6074 Background: Half of cancer therapies are used off-label, but regulations prohibit package inserts from describing toxicities that occur only in these settings. In 2003, RADAR reported VTE rates of 20% to 62% when thalidomide, approved for leprosy treatment, was used off-label (with dexamethasone) for multiple myeloma. In 2005, the Connecticut attorney general requested that a black box warn of high rates of VTE when thalidomide is used off-label. Subsequently, the thalidomide analogue, lenalidomide, received FDA approval as a myelodysplasia therapy. In phase II/III trials, multiple myeloma response rates were 60% to 92% with lenalidomide/dex therapy. Methods: Published literature, abstracts, and package inserts were reviewed for VTE rates in lenalidomide-treated multiple myeloma. Results: VTE rates were 8.5% to 75% in multiple myeloma treated with lenalidomide and dex or erythropoietin; rates were <3.4% when aspirin prophylaxis was added. The FDA approved package insert for lenalidomide preemptively includes a black box warning describing high VTE rates with off-label use of lenalidomide and advises physicians that VTE prophylaxis should be considered, although the effectiveness of various prophylaxis regimens is unknown. Conclusions: Six months after the attorney general requested that a black box warning describe high VTE rates with off-label use of thalidomide, the manufacturer preemptively included an analogous black box warning in the package insert for the thalidomide analogue, lenalidomide, but did not include similar warnings for this toxicity in the package insert for thalidomide. The FDA should require that package inserts describe severe toxicities that commonly occur with off-label use of cancer therapies. This is especially important for severe class-related toxicities such as lenalidomide- and thalidomide- associated VTE. [Table: see text] No significant financial relationships to disclose.

scholarly journals Off-label use of cancer therapies in women diagnosed with breast cancer in the United States

SpringerPlus ◽  
2015 ◽  
Vol 4 (1) ◽  
Author(s):  
Sophie Hamel ◽  
Douglas S McNair ◽  
Nicholas J Birkett ◽  
Donald R Mattison ◽  
Anthony Krantis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
United States ◽  
The United States ◽  
Cancer Therapies ◽  
Off Label Use ◽  
Off Label ◽  
Label Use

Lenalidomide Administration in Heavily Pretreated Patients with Non Hodgkin Lymphoma – First Report of the REVEAL Study (REVlimid® Effectiveness of Administration in patients with Lymphoma)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4979-4979
Author(s):  
Luigi Rigacci ◽  
Francesco Zaja ◽  
Alberto Fabbri ◽  
Alice Di Rocco ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Hodgkin Lymphoma ◽  
Therapeutic Option ◽  
Stage Iv ◽  
Management Plan ◽  
Off Label Use ◽  
Off Label ◽  
Non Hodgkin Lymphoma ◽  
Heavily Pretreated ◽  
Label Use

Abstract Abstract 4979 Lenalidomide (Revlimid®) is an oral treatment authorized in the US and EU for use in relapse/refractory multiple myeloma. Since March 2008, lenalidomide, in combination with Dexamethasone, is marketed in Italy in the aforementioned indication. The Italian Drug Agency (AIFA) has also granted authorization for the off-label use of lenalidomide in patients with Non Hodgkin Lymphoma (NHL) who have no residual therapeutic option, provided these patients are tracked in a registry, in order to ensure their compliance with the Risk Management Plan (RMP) already in place for the multiple myeloma indication. The authorization was granted based on preliminary published favorable phase 2 data (Wiernik, 2008; Habermann, 2009). April 2008 to November 2010 lenalidomide was prescribed (following the 94/98 Italian law) to over 200 NHL patients, mainly diagnosed as Diffuse Large B Cell Lymphoma (DLBCL) and Mantle Cell Lymphoma (MCL). This retrospective observational study was undertaken to gather clinic-pathological and laboratory data about this cohort of NHL patients, with the objective to evaluate the safety and the efficacy of lenalidomide administered, in the context of routine clinical practice, to a heavily pretreated patient population with no remaining therapeutic alternative. Also, efforts will be done in order to identify prognostic factors which can affect response to lenalidomide treatment. As of today, data on 30 patients treated at 6 sites have been collected and analyzed. Patient demographics and disease characteristics are summarized in Table 1. Patient median age was 70.5 years (range 36.0 – 90.0); median number of previous treatments was 5 (range 1 – 17). Over ninety three per cent (93.3%.) of the patients were previously treated with Rituximab. Forty per cent (40%) had DLBC histology, 16.7% MCL, 13.3% follicular histology and 16.7% were transformed lymphomas. As expected, 60% of the patients had stage IV disease, in keeping with the highly unfavorable characteristics of a heavily pretreated patient population. Responses were assessed according to the International Workshop on Lymphoma Response Criteria (IWRC). The number of lenalidomide cycles administered varied between 1 and 15 in this small patient group; 69.2% of the patients, evaluated at cycle 3, showed an objective response (OR). Table 1 TABLE T3 DEMOGRAPHIC CHARACTERISTICS (EVALUABLE POPULATION) Demographic and Disease Characteristics on evaluable population (N=30) Gender Male 20 (66.7%) Female 10 (33.3%) Age (years) N 30 Mean (SD) 69.8 (11.2) Median 70.5 Range 36.0- 90.0 Time since diagnosis (years) N 22 Mean (SD) 8.82 (8.3) Median 3.30 Range 0.45- 9.0 Histology DLBCL 40% Follicular 13.3% MCL 16.7% Transformed 16.7% Stage Stage III 20% Stage IV 60% Data on approximately 180 patients treated at 46 sites throughout Italy will be analysed and presented. Only subjects who refuse to make their data available for review and analysis, or are currently participating in an interventional clinical study (from the date of enrollment into the interventional study) will be excluded. Although very preliminary, this experience indicates that lenalidomide has interesting anti- lymphoma efficacy, even in patients who have exhausted all available therapeutic options. Disclosures: Off Label Use: The Italian Drug Agency (AIFA) has also granted authorization for the off-label use of lenalidomide in patients with Non Hodgkin Lymphoma (NHL) who have no residual therapeutic option, provided these patients are tracked in a registry, in order to ensure their compliance with the Risk Management Plan (RMP) already in place for the multiple myeloma indication.

Updated Results of a Phase 1/2a, Dose Escalation Study of Pvx-410 Multi-Peptide Cancer Vaccine in Patients with Smoldering Multiple Myeloma (SMM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4246-4246 ◽  
Author(s):  
Ajay K. Nooka ◽  
Michael Wang ◽  
Andrew J. Yee ◽  
Sheeba K. Thomas ◽  
Elizabeth K. O'Donnell ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Post Treatment ◽  
Off Label Use ◽  
Advisory Committees ◽  
Off Label ◽  
Label Use

Methods: As reported previously, PVX-410 Multi-Peptide Vaccine (OncoPep, Inc.) is being developed for the treatment of SMM. PVX-410 consists of 4 human leukocyte antigen-A2 (HLA-A2), synthetic 9-mer peptides from unique regions of 3 multiple myeloma (MM)-associated antigens (XBP1 US184-192; XBP1 SP367-375; CD138260-268; and CS1239-247) emulsified in Montanide® ISA-720 VG (Seppic). Adults with SMM at high risk of progression to active MM and were HLA-A2-positive were eligible. The primary objective of this study was to determine the tolerability of PVX-410, initially as monotherapy. Immune response and change in M protein and free light chain ratio (FLC) were also assessed. PVX-410 alone was safe and immunogenic in the initial 12 patients treated, with all 12 having positive immune response to at least 1peptide, as determined by interferon-gamma enzyme-linked immunosorbent spot (Elispot) and tetramer assays. Given its immunomodulatory properties, it was hypothesized that co-administration of lenalidomide (len; Celgene Corporation) would enhance the T cell-mediated immune response induced by PVX-410. Accordingly, the tolerability, immunogenicity, and anti-MM activity of PVX-410+len was then investigated. Results in the PVX-410 alone cohort were previously reported. In the PVX-410+len cohort, patients received a dose of PVX-410, 0.8mg (0.2mg/peptide / 0.8mg total dose) subcutaneously plus 0.5 mL (1mg) Hiltonol® (poly-ICLC; Oncovir, Inc.) intramuscularly every 2 weeks for a total of 6 doses with 3 standard cycles of len (25 mg orally) on Days 1-21 every 28 days, without dexamethasone. Patients are followed for 12months post-treatment. Blood samples for immune response evaluation are collected at Week 0 (Baseline; pre-dose), 2, 4, and 8 during treatment and at Months 1, 3, 6, 9, and 12 post-treatment. Disease response is assessed at the same time points, except Weeks 0 and 2, using International Myeloma Working Group and modified European Group for Blood and Bone Marrow Transplant criteria. Results: Overall, 22 patients have been enrolled, with ages ranging from 39 to 82 years. Ten patients were enrolled in the PVX-410+len cohort, with 9 evaluable for response. All 10 patients received at least 1 cycle of len; 8 received all 3 cycles; 1 received 1 cycle before discontinuing due to a deviation; and 1 completed 2 cycles as of the cutoff date. One patient had 7 of 21 planned doses held due to neutropenia related to lenalidomide, but resumed the next cycle at a reduced dose (from 25 mg to 20 mg). Immunogenicity data with PVX-410+len and PVX-410 alone, as determined via intracellular cytokine staining and tetramer analysis, will be presented. With PVX-410 alone, 5 patients, 2 of 3 with the low-dose of 0.4 mg (0.1mg/peptide) and 3 of 9 at the target-dose (0.2 mg/peptide), experienced progression to active disease within 9 months post-treatment, and 7 had stable disease (SD) at the last follow up visit in the 12 month follow up period. With PVX-410+len, 5 patients have experienced partial or minimal responses and 3 have experienced SD. Durability of response is assessed through the 12-month study period; 1 patient has progressed to active myeloma during this time. PVX-410 was well-tolerated alone and with len. Most adverse events (AEs) have been ≤Grade 2 and non-serious. AEs seen more frequently with PVX-410+len versus PVX-410 alone are expected with len and include hematologic abnormalities (neutropenia, anemia, thrombocytopenia), gastrointestinal disorders (nausea, diarrhea, constipation), skin and cutaneous disorders (rash, pruritus), and myalgia. There was 1serious AE in the combination cohort (pneumonia), considered possibly related to len and unrelated to PVX-410. Conclusions: Six doses of PVX-410 were well tolerated in 22 patients with SMM. Additional AEs seen with PVX-410+len versus PVX-410 alone were expected with the addition of len to the treatment regimen. An immune response to the vaccine was seen in all patients treated with PVX-410 alone and is expected to be enhanced with PVX-410+len; these data will be presented. Based on the promising findings to date, an evaluation of PVX-410 in combination with an antibody to the programmed cell-death-1-ligand complex (PD1/PDL1) is planned to begin in 2015. Disclosures Nooka: Spectrum Pharmaceuticals: Consultancy; Onyx Pharmaceuticals: Consultancy. Off Label Use: Off label use of lenalidomide. Wang:Janssen: Honoraria; Pharmacyclics, Janssen, Celgene, Oncopep, Kite, Juno: Research Funding. Thomas:Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. O'Donnell:Millennium: Consultancy. Shah:Millenium: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Array: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Kaufman:Milleniumm, Celgene, Novartis, Onyx, Spectrum: Consultancy. Lonial:Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Richardson:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Raje:Takeda: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy; Amgen: Consultancy; Onyx: Consultancy; AstraZeneca: Research Funding; Millenium: Consultancy; Novartis: Consultancy; Acetylon: Research Funding; Eli Lilly: Research Funding.

Using Recombinant Activated Factor VII (rFVIIa) in Refractory Bleeding: A Community Hospital Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4048-4048
Author(s):  
Alaa Muslimani ◽  
Hamed Daw
Keyword(s):  
Multiple Myeloma ◽  
Blood Loss ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Transfusion Requirement ◽  
Factor Vii ◽  
Off Label Use ◽  
Off Label ◽  
Life Threatening ◽  
Label Use

Abstract Introduction: Recently, there has been an increase in using rFVIIa for uncontrolled bleeding in non hemophilic patients. While evidence-based guidelines exist for using rFVIIa in hemophilia, none are available for its off-label use. We report four cases who were treated with rFVIIa for massive uncontrolled hemorrhage. Method: Four [3 female (F) and one male (M)] critically ill patients with a median age of 59.25 years (range 49–78) exhibiting massive, life-threatening bleeding were treated with rFVIIa after conventional therapy [transfusion of fresh frozen plasma (FFP), red blood cell (RBC), platelet (Plt) and cryopreciptate (cryo)] had failed to control the blood loss. The starting dose was 90 μg/kg. If there was no response within 20 minutes, a second dose of 90 μg/kg was given. The median rFVIIa number of treatments were 4 (range 1–8). Treatment efficacy was evaluated after each dose and was based on : the amount of hemorrhage judged visually, and the number of red blood cell units required to maintain a stable hemoglobin level of &gt; 8g/dl. Clinical response was rated as complete (no transfusion requirement, or change from severe to minor type of bleeding), partial (decrease of hemorrhage from severe to moderate), or failure (no change of hemorrhage and/or no change in transfusion requirement). rFVIIa was given in conjunction with transfusion of packed RBC in order to avoid further loss of clotting factors. If there was no response after a total of &gt;200 μg/kg, the indications for rFVIIa administration were re-checked. Results: After administration of rFVIIa, three patients had a complete response with cessation of bleeding. There was a decrease in the transfusion requirements in the single non-responder case who later died of massive myocardial ischemia. Most studies have shown that use of rFVIIa yields better results when given earlier rather than later. Nevertheless, our first patient encounter showed good result despite initiation of the therapy 3 weeks after the onset of bleeding. Finally, patient number 3 showed the first successful reported use of rFVIIa for bleeding associated with multiple myeloma. Conclusion: rFVIIa is effective in the life-threatening emergencies. However, because of the potential thrombotic complications, off-label use should probably be limited to life-threatening blood loss not otherwise controlled by other interventions. Cost/benefit ratio should also be evaluated on a case by case basis. Age (years)/sex details of the caused of bleeding Bleeding sites Period between the bleeding and the rFVIIa infusion dose/frequency Transfusion requirement pre-/post-rFVIIa Transfusion requirement pre-/post-rFVIIa Response after rFVIIa treatment /Response after rFIIa treatement/ 78/F Coumadin toxicity (INR &gt;10) Gross hematuria, epistaxis, hematochezia, hematemesis 3 weeks 90 μg/kg, 4 doses RBC 17/4,Plt 18/3,FFP 26/2,Cry 5/0 6.8/10.2 Complete in 24 hours/Recovered (INR 1.9) 51/F colon adenocarcinoma (Post-surgical) Surgical incision, Intra-abdominal 48 hours 0 μg/kg, 3 doses RBC 16/3, FFP 5/1 4/10 Complete in 48 hours/Recovered 59/M Multiple myeloma, (PT 44.9, INR 4.5, PTT 37) Hematemesis, hematochezia, melena 72 hours 90 μg/kg, 1 dose RBC 13/2, FFP 4/0 6.5/9.8 Complete in 3 hours/Recovered 49/F Hepatitis C cirrhosis (liver failure). Hematemesis, melena 48 hours 90 μg/kg, 8 doses RBC 12/7, FFP 7/3 6/- Partial in 24 hours/Died

Variation In Health-Related Quality of Life (HRQOL) by ISS Stage and ECOG Status Among Multiple Myeloma Patients.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3828-3828
Author(s):  
Chris L Pashos ◽  
Brian G. M. Durie ◽  
Robert M. Rifkin ◽  
Jatin J Shah ◽  
Thomas K. Street ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Self Care ◽  
Off Label Use ◽  
Advisory Committees ◽  
Off Label ◽  
Hrqol Data ◽  
Label Use

Abstract Abstract 3828 Introduction: Attention is being paid to HRQOL when monitoring hematologic disorders or the impact of treatments on those disorders. Minimal HRQOL data have been published on multiple myeloma (MM) patients (pts) in the United States (US). This analysis characterizes variation in the HRQOL of pts with active, symptomatic MM by International Staging System (ISS) stage and ECOG status. Methods: Data were collected as part of Connect MM®, a prospective observational registry initiated in September 2009 involving centers in the US. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was reported by pts in the clinic at enrollment, within two months of diagnosis. Pts completed 3 psychometrically validated instruments: EQ-5D, Brief Pain Inventory (BPI), and Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM). Standard analyses were conducted of each instrument given clinical characteristics at that time. Reported mean BPI, EQ-5D and FACT-MM scores were analyzed by ISS and ECOG status. Statistical significance of score differences among sub-cohorts was ascertained by ANOVA using SAS 9.1. Results: HRQOL data were reported by 328 pts, enrolled from 135 centers. Pts were predominantly male (60%) and white (79%) with mean age at 67.3 (standard deviation [SD] 11.6) yrs. HRQOL scores by evaluable ISS stage (n=236) and ECOG status (n=258) are presented. BPI data (on a scale of 0 [no pain] to 10 [worst pain]) indicate that average reported pain worsens by ISS and ECOG severity. Mean EQ-5D scores (on a scale of 1 [no problem] to 2 [some problems] to 3 [incapacity]) indicate that pain/discomfort, and usual activities are most compromised, and with self care increase in severity as ISS and ECOG worsen. Anxiety/depression level is associated with ECOG, but not with ISS. FACT-MM results indicate that ISS and ECOG severity is associated with greater decrement in physical and functional domains. The associations of HRQOL with ECOG status were stronger than with ISS stage. Specifically, scores on the BPI, all EQ-5D domains, and all FACT-MM domains (except the social/family domain) were statistically significantly associated with more severe ECOG status. Conclusions: Initial results from the Connect MM® Registry indicate that HRQOL worsens with worsening ISS stage and ECOG status, especially in physical and functioning domains, pain/discomfort, and ability to conduct usual activities and to provide self care. These areas should receive attention at diagnosis. Future analyses should be conducted on: (1) more newly diagnosed patients; (2) how HRQOL may be affected over time with changes in disease; and, (3) how HRQOL may be influenced by alternative therapies. Results reported here should serve as useful baseline reference. Disclosures: Pashos: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: CONNECT is a disease registry and includes data on off-label use of anti-myeloma agents. Durie:Celgene & Millennium: Consultancy. Rifkin:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau. Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Street:Celgene: Employment. Sullivan:Celgene: Employment, Equity Ownership. Khan:Celgene Corporation: Employment.

Sign in / Sign up

Export Citation Format

Share Document