new drugs in haematology
TRANSCRIPT
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EBMT Meeting, France, March 2007
NEW DRUGS
in TRANSPLANTATION
C. PAILLET, Pharmacist, Pharm D.C. RENZULLO, Pharmacist, Pharm D.
Edouard Herriot Hospital, Lyon, FRANCE
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EBMT Meeting, France, March 2007
DEVELOPMENT of NEW DRUGS (1)
RATIONALEMore efficacyNew target
EVALUATIONScientific performanceCost efficiencyToxicity patterns
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EBMT Meeting, France, March 2007
CYTOTOXICCYTOTOXICNON NON
CYTOTOXICCYTOTOXIC
DEVELOPMENT of NEW DRUGS (2)
IMMUNO-
MODULATORY
AGENT
IMMUNO-SUPPRESSIVE
AGENT
GROWTH FACTOR
ANTIFUNGAL AGENT
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EBMT Meeting, France, March 2007
CYTOTOXIC DRUG RECONSTITUTION IN E. HERRIOT HOSPITAL (1)
A Centralized Pharmacy Unit for Cytotoxic drugs Reconstitution
A set up within the Haematology Department
The manpower figures for 15 000 cytotoxic / year
An unit managed by the Pharmacy Department2 pharmacists1 pharmacist student4 pharmacy technicians
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EBMT Meeting, France, March 2007
CYTOTOXIC DRUG RECONSTITUTION IN E. HERRIOT HOSPITAL (2)
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EBMT Meeting, France, March 2007
CYTOTOXIC DRUG RECONSTITUTION IN E. HERRIOT HOSPITAL (3)
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EBMT Meeting, France, March 2007
CYTOTOXIC DRUGS (1)
Conditioning regimens prior to allogeneic stem celltransplantation (SCT)
Treosulfan BusulfanMyeloablative and immunosuppressive effects
Alkylating agents (inhibiting DNA replication )
Tolerance of the conditioning and compliance
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EBMT Meeting, France, March 2007
Injectable drugs (2)CYTOTOXIC DRUGS (2)
Treosulfan
12 g/m²/day over 3 consecutive days (D-6 to D-4)
Single-use vial containing 1000 mg or 5000 mg
Lyophilized powder reconstituted with 20 or 100 ml ofhot sterile water for injection
Difficult to dissolute
CYTOTOXIC
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EBMT Meeting, France, March 2007
Injectable drugs (3)
TreosulfanAdministered pure or diluted (D5W or NS) I.V as a 2 hours infusion
Stable up 4 days at room temperature
SAFETYo Haematotoxicity (thrombocytopenia)o Fatigueo Skin (mild alopecia, skin pigmentation, urticaria…)o Respiratory (allergic alveolitis, pneumonia and pulmonary fibrosis)o Gastrointestinal (nausea +/- vomiting)
CYTOTOXIC DRUGS (3)
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EBMT Meeting, France, March 2007
Injectable drugs (4)CYTOTOXIC DRUGS (4)
Busulfan (BUSILVEX®)New galenic formulation of the existing oral busulfan
0.8 mg/kg every 6 hours for 4 consecutive days(D-4 to D-1)
Single-use ampul containing 60mg (10ml)
Ready to use
CYTOTOXIC
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EBMT Meeting, France, March 2007
Injectable drugs (5)
Busulfan (BUSILVEX®)Diluted in 100ml NS
Administered IV as a 2 hours infusion
Stable up to 12 hours under refrigeration
Cost : o 290 euros / ampul 7.000 euros / dayo 28.000 euros / transplantationo much higher than the oral form(Esperou, EBMT 2005 ; Groves, Proc. British Oncology Pharmacy Association 2005)
CYTOTOXIC DRUGS (5)
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EBMT Meeting, France, March 2007
Injectable drugs (6)CYTOTOXIC DRUGS (6)
Busulfan (BUSILVEX®)Premedication before infusion : anticonvulsant and antiemetic
SAFETYo Haematotoxicity (pancytopenia)o Gastrointestinal (nausea, vomiting, stomatis, diarrhoea) o Skin (alopecia, skin pigmentation, urticaria…)o Significant reduction of VOD (20% to 5%)o Respiratory (tussis, dyspnea)o Fever
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EBMT Meeting, France, March 2007
Chronic lymphoblastic leukaemia
Alemtuzumab (MABCAMPATH®)
Facilitate engraftment and prevent GvHD
Monoclonal antibody
Premedication : antihistamine, antipyretic
CYTOTOXIC
CYTOTOXIC DRUGS (7)
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EBMT Meeting, France, March 2007
CYTOTOXIC DRUGS (8)
Alemtuzumab (MABCAMPATH®)30mg / day, 3 times / weekon alternate days for up to 12 weeks
Escalating dose : 3mg D1, 10mg D2, 30mg D3
Vial containing a 30mg/ml solution
Cost : 445 euros per vialPatient 1.7m² :
1.335 euros / week16.020 euros / treatment
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EBMT Meeting, France, March 2007
CYTOTOXIC DRUGS (9)
Alemtuzumab (MABCAMPATH®)Subcutaneous administration or IV (diluent : D5W or NS)
Stable for 8 hours at room temperature in the dark
SAFETYo Haematotoxicityo Gastrointestinal (nausea, vomiting)o Cardiovascular disorders (hyper or hypo tension)o Skin (prurit, rash…)o Hypersensitivityo Fevero Respiratory (bronchospasm, dyspnea, pneumonia…)
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EBMT Meeting, France, March 2007
CYTOTOXIC DRUGS (10)
Refractory myelomaBortezomib (VELCADE ®)
Prolongate the median time to progression of disease
Proteasoma inhibitor induces apoptosis
CYTOTOXIC
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EBMT Meeting, France, March 2007
CYTOTOXIC DRUGS (11)
Bortezomib (VELCADE ®)
1.3 mg/m² day 1, day 4, day 8 and day 11
Vial containing 3.5mg
Reconstituted with 3.5ml of NS
Cost : 1.170 euros per vialPatient 1.7m² : 4.700 euros/cycle (3.500 euros/cycle if centralized)
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EBMT Meeting, France, March 2007
CYTOTOXIC DRUGS (12)
Bortezomib (VELCADE ®)
Direct IV administration
SAFETYo Haematotoxicityo Peripheral neuropathyo Gastrointestinal (diarrhoea, constipation)o Cardiovascular disorders (hypotension)
San Miguel, Oncologist 2006
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EBMT Meeting, France, March 2007
IMMUNOMODULATORY AGENT (1)
Treatment of multiple myeloma
Lenalidomide (REVLIMID®)
Inhibited the secretion of cytokines from peripheralblood mononuclear cells
Anti-angiogenic properties (thalidomide analogue)
Mutagenic risk
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EBMT Meeting, France, March 2007
IMMUNOMODULATORY AGENT (2)
Lenalidomide (REVLIMID®)25 mg/d, 21 days / month
+ dexamethasone 40mg/day
Capsules for oral administration 5,10, 15, 25 mg
Cost : 310 euros / capsules of 25mgPatient : 6.500 euros / month
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EBMT Meeting, France, March 2007
IMMUNOMODULATORY AGENT (3)
Lenalidomide (REVLIMID®)
Patient should not break, chew or open the capsule
SAFETYo Haematotoxicityo Gastrointestinal toxicity (constipation, diarrhoea)o Teratogenico Deep vein thrombosiso Pulmonary embolism
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EBMT Meeting, France, March 2007
IMMUNOSUPPRESSIVE AGENTS (1)
2 phases of acute Graft versus Host Disease (aGvHD)
Afferent phaseEfferent phase
TreatmentSteroidsCiclosporineAnti-Thymocyte Globulin (THYMOGLOBULINE ®)Inolimomab (LEUKOTAC®)
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EBMT Meeting, France, March 2007
IMMUNOSUPPRESSIVE AGENTS (2)
Rejection prevention and treatment
Anti-thymocyte globulin (THYMOGLOBULIN®)
Suppress immune responses
Polyclonal rabbit antiserum specific for human T cells
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EBMT Meeting, France, March 2007
IMMUNOSUPPRESSIVE AGENTS (3)
Anti-thymocyte globulin (THYMOGLOBULINE®)
2.5 mg/kg/d (D-4 to D-2 or D-1)
Single-use vial containing 25 mg
Lyophilized powder reconstituted with 5 ml ofsterile water for injection
Cost : 155 euros / vialPatient 70 kg : 3.255 euros / 3 days
NON
CYTOTOXIC
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EBMT Meeting, France, March 2007
IMMUNOSUPPRESSIVE AGENTS (4)
Anti-thymocyte globulin (THYMOGLOBULINE®)
Diluted in 50ml per one vial (NS or D5W)Premedication : corticosteroïdes, antihistamine, adapt thethe flow rate of infusion
SAFETYo Haematotoxicityo Peripheral oedema, chills, fever, pain, headache, hypotension,
tachycardia, asthenia
SURVEILLANCE +++
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EBMT Meeting, France, March 2007
Treatment of acute graft versus host disease
Inolimomab (LEUKOTAC®)Specific binding to the IL2 receptorexpressed on activated T cells
Mouse monoclonal IgG1 anti human IL2 receptor
IMMUNOSUPPRESSIVE AGENTS (5)
NON
CYTOTOXIC
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EBMT Meeting, France, March 2007
IMMUNOSUPPRESSIVE AGENTS (6)
Inolimomab (LEUKOTAC®)
0.2 to 0.4 mg/kg/d over 8 consecutive days
Single-use ampul containing 5mg/5ml
Ready to use
Cost : 270 euros / ampulPatient 70 kg : 23.000 euros
(1 week of induction, 2 weeks of maintenance)
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EBMT Meeting, France, March 2007
IMMUNOSUPPRESSIVE AGENTS (7)
Inolimomab (LEUKOTAC®)
IV infusion over 20-30 minutes
Diluted in NS
Used immediately
SAFETYo Well toleratedo No infusion related adverse events recordedo Other events are attributable to immunosuppressive therapy
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EBMT Meeting, France, March 2007
GROWTH FACTOR (1)
Severe oral mucositis
Palifermin (KEPIVANCE®)
Binding the KGF receptor : proliferation, differentiation and migration of epithelial cells
Human keratinocyte growth factor
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EBMT Meeting, France, March 2007
GROWTH FACTOR (2)
Palifermin (KEPIVANCE®)60 µg/kilo/d for a total of 6 doses
Single-use vial containing 6.25 mg
Lyophilized powder (reconstituted with 1.2 ml of sterilewater for injection)
Do not shake or vigourously agitate the vial
Cost : 810 euros per vialPatient 70kg : 5.000 euros / treatment
NON
CYTOTOXIC
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EBMT Meeting, France, March 2007
GROWTH FACTOR (3)
Palifermin (KEPIVANCE ®)IV Bolus Injection
Protect from light
SAFETYo Skin toxicity (rash, erythema, oedema, pruritus)
o Oral toxicity (disesthesia, tong discoloration, tong thickening, alteration taste)
o Pain arthralgias
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EBMT Meeting, France, March 2007
ANTIFUNGAL AGENT (1)
Treatment and prophylaxis of invasive fungalinfections : aspergillosis, fusariosis, zygomycosis, candidiasis andcoccidioidomycosis in patients intolerant of or refractory to other antifungal therapies
Posaconazole (NOXAFIL®)
Triazole antifungal agent
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EBMT Meeting, France, March 2007
ANTIFUNGAL AGENT (2)
Posaconazole (NOXAFIL®)
800 mg/d in 2 or 4 divided doses
Should be taken after meals to ensure maximal absorption
Cost : 660 euros / vialPatient : 4.000 euros / month
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EBMT Meeting, France, March 2007
ANTIFUNGAL AGENT (3)
Posaconazole (NOXAFIL®)PRECAUTIONS
o Hypersensitivity
o Co-administration with tacrolimus or cyclosporin (dosage adjustments may be required)
SAFETYo Gastrointestinal (nausea, vomiting, diarrhoea, abdominal pain)o Headacheo Fatigue o Fever
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EBMT Meeting, France, March 2007
CONCLUSION
An increasing number of molecularly targetedagents are :
already in the pipelineundergoing late experimental testingin early clinical trials
At least some of them will reach clinicalpractice during the coming 5 years