Lenalidomide Lenalidomide in transfusion dependant del 5q MDS
O O O O H H N N N O N O N H O 2 Lenalidomide:pharmacological evolution More “potent” immunomodulator than thalidomide • up to 50,000 times more potent inhibitor of TNF- • increased stimulation of T-cell proliferation • augmented stimulation of IL-2 and IFN- production • augmented NK-cell activity Thalidomide Lenalidomide Bartlett JB, et al. Nat Rev Cancer. 2004;4:314-22. Davies FE, et al. Blood. 2001;98:210-6. Stirling D. Semin Oncol. 2001;28:602-6.
Clinical development of lenalidomide in MDS: completed trials MDS-001 N = 43 Phase I/II initiated Feb 2002 del(5q) non-del(5q) MDS-003 N = 148 Phase II initiated July 2003 MDS-002 N = 214 Phase II initiated July 2003
MDS-003: study design Multi-centre phase II study R E G I S T E R R E S P O N S E • Eligibility • RBC transfusion 2 U/8 weeks • 16-week pre-study RBC transfusions • ANC > 0.5 × 109/l • Platelets > 50 × 109/l • De novo MDS withdel(5)(q31.1) Yes Continue • Lenalidomide, p.o. • 10 mg daily • 10 mg for 21 days of each 28-day cycle No Off study Dose reduction 5 mg every day. 5 mg every other day. Week: 0 6 12 18 24 Primary end-point: transfusion independence (Hb ≥ 1 g/dl) Secondary end-points: duration of transfusion independence, frequency of minor erythroid response, cytogenetic response, pathological response, safety List A, et al. N Engl J Med. 2006;355:1456-65.
MDS-003: patientcharacteristics List A, et al. N Engl J Med. 2006;355:1456-65.
MDS-003: cytogenetic features *4 normal metaphases analysed; 85% of 100 interphase nuclei lacked EGR1 signal at 5q31. Data from List A, et al. N Engl J Med. 2006;355:1456-65.
MDS-003: erythroid response at 24 weeks (ITT) *p< 0.001 No significant difference in erythroid response or time to response between the 2 dosing regimens. Data from List A, et al. N Engl J Med. 2006;355:1456-65.
MDS-003: durability of transfusion independence responses • For the 99 del(5q) RBC-TI responders in MDS-003, estimated median duration of response is 115 weeks • 52 (53%) remain on study with ongoing transfusion independence (June 30, 2006) • > 52 weeks for 63 patients • > 78 weeks for 52 patients • > 104 weeks for 36 patients • RBC-TI and major erythroid response to lenalidomide is maintained for a median duration of > 2 years List AF, et al. Presented at ASH Annual Meeting, 2006 [abstract 251].
MDS-003: transfusion-independence rate by cytogenetic pattern *p = 0.068. #Excluding 1 patient whose cytogenetic characteristics were defined by FISH only. Data from List A, et al. N Engl J Med. 2006;355:1456-65.
MDS-003: cytogenetic response by karyotype complexity *p = 0.266. Data from List A, et al. N Engl J Med. 2006;355:1456-65.
MDS-003: pathological response In 106 evaluable patients Data from List A, et al. N Engl J Med. 2006;355:1456-65.
MDS-003: anti-angiogenesisin vivo in del(5q) MDS Markers of angiogenesis in bone marrow biopsies/aspirates from 35 patients with del(5q) MDS: at baseline and 6 and 12 months after start of lenalidomide therapy *Patients with normal bone marrow (n = 20). # Increases were significant (p = 0.0005) but independent of cytogenetic response. Anti-angiogenic inefficacy of lenalidomide in 14/35 patients correlated with disease progression (≥ 5% blasts in blood or bone marrow; p = 0.0005). Data from Buesche G, et al. Blood. 2005;106:113a [abstract 372].
Disease progression in del(5q) MDS patients treated with lenalidomide Retrospective subanalysis of MDS-003 (n = 45) Lenalidomide does not appear to lead to an excess rate of transformation to acute myeloid leukaemia Giagounidis A, et al. Poster presented at EHA Congress, 2007 [abstract 234].
Cytopenias correlate with response to lenalidomide in del(5q) MDS patients Retrospective analysis of MDS-003 study • Baseline characteristics (147 evaluable patients) • neutropenia (< 2.0 × 109/l) 59 (40%) • thrombocytopenia (< 150 × 109/l) 59 (40%) • neutropenia or thrombocytopenia 84 (57%) • Treatment-related neutropenia: ANC reduction ≥ 75% • Treatment-related thrombocytopenia: platelet count reduction ≥ 50% Sekeres MA, et al. Leuk Res. 2007;31 (Suppl 1) [abstract C027].
Multivariate analysis: factors associated with duration of transfusion independence Sekeres MA, et al. Haematologica. 2007;92 (Suppl 1) [abstract 230].
MDS-003:treatment-related adverse events List A, et al. N Engl J Med. 2006;355:1456-65.
MDS-003: dose adjustments according to schedule N = 148 102 *p < 0.05 Patients (n) 46 List A, et al. N Engl J Med. 2006;355:1456-65.
MDS-003: drug discontinuation according to schedule N = 148 102 *p < 0.05 Patients (n) 46 List A, et al. N Engl J Med. 2006;355:1456-65.
MDS-003: medical reason for drug discontinuation in 30 patients • Neutropenia and thrombocytopenia (n = 10) • Rash (n = 5) • AML (n = 3) • n = 1: anaemia, facial oedema, chronic heart failure, urticaria, diarrhoea, weight loss, renal insufficiency, CVA, dementia, dyspnea, pyrexia, pneumonia List A, et al. N Engl J Med. 2006;355:1456-65.
Haematological adverse events in MDS: management recommendations (1) • Monitor FBC weekly for a mandatory 8 weeks • weekly FBC monitoring may be continued for up to 5 months • consider continued biweekly or monthly monitoring on the basis of haematological status • ANC < 1 × 109/l: co-administration of G-CSF is recommended to prevent severe neutropenia • alternatively, lenalidomide treatment can be temporarily discontinued • ANC < 0.5 × 109/l ,interrupt lenalidomide treatment, this can be reintroduced if ANC ≥ 0.75 × 109/l after one week. • Neutropenic sepsis is the only reported drug-related cause of death. Patients should • receive education • receive prophylactic antibiotics at neutrophil counts < 0.5 × 109/l • have all-day access to specialized haematological care • receive broad spectrum antibiotics within 3 hours of fever onset Giagounidis A, et al. Presented at EHA Congress, 2007 [abstract 227].
Haematological adverse events in MDS: management recommendations (2) • If platelet count falls to < 25 × 109/l without platelet support, lenalidomide treatment should be interrupted • thrombocytopenia at baseline is not a contraindication for lenalidomide treatment • consider prophylactic platelet transfusions until counts rise • If, after ≥ 1 week discontinuation, the platelet count is ≥ 50 × 109/l, lenalidomide can be reintroduced Giagounidis A, et al. Presented at EHA Congress, 2007 [abstract 227].
VTE in MDS: management recommendations • VTE is a rare event in lenalidomide-treated MDS (3%)1,2 • VTE prophylaxis is not generally recommended • Patients should be informed about the risk of VTE and monitored for symptoms • Combined lenalidomide and erythropoietin treatment is currently not recommended outside a clinical trial • may increase risk of venous thromboembolism3 • If VTE does occur, interrupt the lenalidomide treatment, treat the VTE, and carefully reintroduce lenalidomide once stable anticoagulation has been established • There is currently no consensus on the role of aspirin or LMWH use3 1. List A, et al. N Engl J Med. 2005;352:549-57. 2. List A, et al. N Engl J Med. 2006;355:1456-65. 3. Giagounidis A, et al. Presented at EHA Congress, 2007 [abstract 227].
Non-haematological adverse events: management recommendations (1) • Most non-haematological adverse events are self-limiting and do not require discontinuation of lenalidomide • Rash • usually resolves within 2–3 weeks • may be treated, if necessary, with unselective antihistamines, topical steroids, or short-course prednisone (10 mg, 14 days) • if rash is severe or persistent despite treatment, lenalidomide treatment should be interrupted until rash resolves • usually does not recur after resolution and resumption of lenalidomide treatment at lower dose level • Diarrhoea • treat symptomatically after ruling out other underlying causes • Fatigue is not considered drug-related Giagounidis A, et al. Presented at EHA Congress, 2007 [abstract 229].
Non-haematological adverse events: management recommendations (2) • Hypothyroidism • screen for thyroid-stimulating hormone triiodothyronine (T3) and thyroxine (T4) and monitor during the course of treatment • in case of hypothyroidism, thyroid hormone replacement therapy may be needed • Other non-haematological adverse events • treat symptomatically after ruling out other underlying causes such as anaemia or autoimmune disorders Giagounidis A, et al. Presented at EHA Congress, 2007 [abstract 229].
Interactions • Lenalidomide is not metabolised through cytochrome P450 pathway and therefore low potential for metabolic interactions • Lenalidomide-warfarin interaction study did not indicate any interaction. However dexamethasone is a weak to moderate enzyme inducer. Close monitoring of warfarin therapy is thereofre recommended. • Lenalidomide –digoxin interaction study showed minor changes in relevent parameters suggesting potential for minor interaction. • Monitoring of digoxin plasma levels is recommended during administration of lenalidomide
Use in patients with impaired hepatic or renal function • Impaired hepatic function • Lenalidomide has not formally been studied in patients with impaired hepatic function and there are no specific dose recommendations • Impaired renal function • Lenalidomide is substantially excreted by the kidney • Care should be taken in dose selection and monitoring of renal function is advised • Dose reductions are recommended at the start of therapy for patients with impaired renal function
Prevention of fœtal exposure • Lenalidomide is structurally related to thalidomide. Currently a teratogenic effect of lenalidomide cannot be ruled out. • Lenalidomide is contraindicated • In pregnancy • In Women of Childbearing Potential (WCBP) unless all the conditions of the Pregnancy Prevention Programme are met
Prevention of fœtal exposure • All patients: • Do not share medication • Do not donate blood during treatment or for one week after cessation of treatment • Male patients • Potential teratogenic risk • Use of condoms during sexual contact with WCBP even if prior vasectomy. • Female partner must consult physician if she becomes pregnant whilst partner on treatment • WCBP (refer to Information Pack for further information) • Potential teratogenic risk • Effective contraception 4 weeks before treatment, during treatment, during dose interruptions and 4 weeks after end of treatment • Negative pregnancy test before treatment and at specific intervals. • If becomes pregnant to stop treatment and consult physician
Adverse Event/Suspected Pregnancy Reporting • Adverse Event: • Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Adverse Event/Suspected Pregnancy Reporting • Report immediately • All Adverse events • Serious and non serious • Regardless of expectedness • All reports of suspected pregnancies • Report by telephone: NEOPHARM Shavit Fragman, Telephone No. : 03-9373753/65 Mobile No. : 054-6777865 Mrs. Ayala Weissman, Telephone No. : 03-9373753 Mobile No. : 052-8696199 Mrs. Keren Moreno, Telephone No. : 03-9373753/0 Mobile No. : 052-8777971