new drugs in haematology

EBMT Meeting, France, March 2007

NEW DRUGS

in TRANSPLANTATION

C. PAILLET, Pharmacist, Pharm D.C. RENZULLO, Pharmacist, Pharm D.

Edouard Herriot Hospital, Lyon, FRANCE

EBMT Meeting, France, March 2007

DEVELOPMENT of NEW DRUGS (1)

RATIONALEMore efficacyNew target

EVALUATIONScientific performanceCost efficiencyToxicity patterns

EBMT Meeting, France, March 2007

CYTOTOXICCYTOTOXICNON NON

CYTOTOXICCYTOTOXIC

DEVELOPMENT of NEW DRUGS (2)

IMMUNO-

MODULATORY

AGENT

IMMUNO-SUPPRESSIVE

AGENT

GROWTH FACTOR

ANTIFUNGAL AGENT

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

EBMT Meeting, France, March 2007

CYTOTOXIC DRUG RECONSTITUTION IN E. HERRIOT HOSPITAL (2)

EBMT Meeting, France, March 2007

CYTOTOXIC DRUG RECONSTITUTION IN E. HERRIOT HOSPITAL (3)

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

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

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)

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

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)

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

EBMT Meeting, France, March 2007

Chronic lymphoblastic leukaemia

Alemtuzumab (MABCAMPATH®)

Facilitate engraftment and prevent GvHD

Monoclonal antibody

Premedication : antihistamine, antipyretic

CYTOTOXIC

CYTOTOXIC DRUGS (7)

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

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…)

EBMT Meeting, France, March 2007

CYTOTOXIC DRUGS (10)

Refractory myelomaBortezomib (VELCADE ®)

Prolongate the median time to progression of disease

Proteasoma inhibitor induces apoptosis

CYTOTOXIC

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)

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

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

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

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

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®)

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

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

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 +++

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

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)

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

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

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

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

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

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

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

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