MabCampath

Therapeutic indication

Patients with B-cell chronic lymphocytic leukaemia (B-CLL)

Mechanism of action

Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibody specific for a 21-28 kD lymphocyte cell surface glycoprotein (CD52) expressed primarily on the surface of normal and malignant peripheral blood B and T cell lymphocytes. Alemtuzumab was generated by the insertion of six complementarity-determining regions from an IgG2a rat monoclonal antibody into a human IgG1 immunoglobulin molecule. Alemtuzumab causes the lysis of lymphocytes by binding to CD52, a highly expressed, nonmodulating antigen which is present on the surface of essentially all B and T cell lymphocytes as well as monocytes, thymocytes and macrophages. The antibody mediates the lysis of lymphocytes via complement fixation and antibody-dependent cell mediated cytotoxicity. The antigen has been found on a small percentage (< 5%) of granulocytes, but not on erythrocytes or platelets. Alemtuzumab does not appear to damage haematopoietic stem cells or progenitor cells.

DRUG

Since 2012, MabCampath (alemtuzumab) no longer has a Marketing Authorization in Europe. However, in very exceptional, urgent cases, the manufacturer (Sanofi) can still provide the medicine on an individual patient basis via the Urgent Situation procedure (fagg.be) based upon the U.S. marketing authorization.

MabCampath 10 mg/ml Medicinal product no longer authorized. Information based on prior SPC.
Each ampoule contains 30 mg of alemtuzumab.

Therapeutic indication

MabCampath is indicated for the treatment of patients with B-cell chronic lymphocytic leukaemia (B-CLL) for whom fludarabine combination chemotherapy is not appropriate.

Reimbursement modalities

Medicinal product no longer authorized.
Patient Access Program via Clinigen, UK. Requests are done via Cliniport, an online portal (Clinigen, UK based).

Administration and dosage

MabCampath should be administered under the supervision of a physician experienced in the use of cancer therapy.

Posology

During the first week of treatment, MabCampath should be administered in escalating doses: 3 mg on day 1, 10 mg on day 2 and 30 mg on day 3 assuming that each dose is well tolerated. Thereafter, the recommended dose is 30 mg daily administered 3 times weekly on alternate days up to a maximum of 12 weeks.

In most patients, dose escalation to 30 mg can be accomplished in 3-7 days. However, if acute

moderate to severe adverse reactions such as hypotension, rigors, fever, shortness of breath, chills,

rashes and bronchospasm (some of which may be due to cytokine release) occur at either the 3 mg or

10 mg dose levels, then those doses should be repeated daily until they are well tolerated before

further dose escalation is attempted (see section 4.4 of the SPC).

Median duration of treatment was 11.7 weeks for first-line patients and 9.0 weeks for previously

treated patients.

Once a patient meets all laboratory and clinical criteria for a complete response, MabCampath should be discontinued and the patient monitored. If a patient improves (i.e. achieves a partial response or stable disease) and then reaches a plateau without further improvement for 4 weeks or more, then MabCampath should be discontinued and the patient monitored. Therapy should be discontinued if there is evidence of disease progression.

Method of administration

The MabCampath solution must be prepared according to the instructions provided in section 6.6. All doses should be administered by intravenous infusion over approximately 2 hours.

Dose modifications

There are no dose modifications recommended for severe lymphopenia given the mechanism of action of MabCampath.

Toxicity

In the event of serious infection or severe haematological toxicity MabCampath should be interrupted until the event resolves. It is recommended that MabCampath should be interrupted in patients whose platelet count falls to < 25,000/µl or whose absolute neutrophil count (ANC) drops to < 250/µl.

MabCampath may be reinstituted after the infection or toxicity has resolved. MabCampath should be

permanently discontinued if autoimmune anaemia or autoimmune thrombocytopenia appears. The

following table outlines the recommended procedure for dose modification following the occurrence

of haematological toxicity while on therapy:

*Haematologic values*	Dose modification*
ANC < 250/μl and/or platelet count ≤25,000/μl
For first occurrence	Withhold MabCampath therapy. Resume MabCampath at 30 mg when ANC ≥ 500/μl and platelet count ≥ 50,000/μl
For second occurrence	Withhold MabCampath therapy. Resume MabCampath at 10 mg when ANC ≥ 500/μl and platelet count ≥ 50,000/μl.
For third occurrence	Discontinue MabCampath therapy.
≥ 50% decrease from baseline in patients initiating therapy with a baseline ANC ≤ 250/μl and/or a baseline platelet count ≤ 25,000/μl
For first occurrence	Withhold MabCampath therapy. Resume MabCampath at 30 mg upon return to baseline value(s).
For second occurrence	Withhold MabCampath therapy. Resume MabCampath at 10 mg upon return to baseline value(s).
For third occurrence	Discontinue MabCampath therapy.

*If the delay between dosing is  7 days, initiate therapy at MabCampath 3 mg and escalate to 10 mg

and then to 30 mg as tolerated

Special populations

Elderly (over 65 years of age)

Recommendations are as stated above for adults. Patients should be monitored carefully (see

section 4.4 of the SPC).

Paediatric population

The safety and efficacy of MabCampath in children aged less than 17 years of age have not been

established. No data are available.

Hepatic impairment
No studies have been conducted.

Renal impairment
No studies have been conducted.

Drug-drug interactions

Although no formal drug interaction studies have been performed with MabCampath, there are no

known clinically significant interactions of MabCampath with other medicinal products. Because

MabCampath is a recombinant humanized protein, a P450 mediated drug-drug interaction would not

be expected. However, it is recommended that MabCampath should not be given within 3 weeks of

other chemotherapeutic agents.

Although it has not been studied, it is recommended that patients should not receive live viral vaccines in, at least, the 12 months following MabCampath therapy. The ability to generate a primary or anamnestic humoral response to any vaccine has not been studied.

Drug-food interactions

None mentioned.

Adverse events of special interest

Acute adverse reactions, which may occur during initial dose escalation and some of which may be

due to the release of cytokines, include hypotension, chills/rigors, fever, shortness of breath and

rashes. Additional reactions include nausea, urticaria, vomiting, fatigue, dyspnoea, headache, pruritus, diarrhoea and bronchospasm. The frequency of infusion reactions was highest in the first week of therapy, and declined in the second or third week of treatment, in patients treated with MabCampath both as first line therapy and in previously treated patients.

If these events are moderate to severe, then dosing should continue at the same level prior to each dose escalation, with appropriate premedication, until each dose is well tolerated. If therapy is withheld for more than 7 days, MabCampath should be reinstituted with gradual dose escalation.

Transient hypotension has occurred in patients receiving MabCampath. Caution should be used in

treating patients with ischaemic heart disease, angina and/or in patients receiving an antihypertensive medicinal product. Myocardial infarction and cardiac arrest have been observed in association with MabCampath infusion in this patient population.

Assessment and ongoing monitoring of cardiac function (e.g. echocardiography, heart rate and body

weight) should be considered in patients previously treated with potentially cardiotoxic agents.

It is recommended that patients be premedicated with oral or intravenous steroids 30 - 60 minutes

prior to each MabCampath infusion during dose escalation and as clinically indicated. Steroids may

be discontinued as appropriate, once dose escalation has been achieved. In addition, an oral

antihistamine, e.g. diphenhydramine 50 mg, and an analgesic, e.g. paracetamol 500 mg, may be given.

In the event that acute infusion reactions persist, the infusion time may be extended up to 8 hours from the time of reconstitution of MabCampath in solution for infusion.

Profound lymphocyte depletion, an expected pharmacological effect of MabCampath, inevitably

occurs and may be prolonged. CD4 and CD8 T-cell counts begin to rise from weeks 8-12 during

treatment and continue to recover for several months following the discontinuation of treatment. In

patients receiving MabCampath as first line therapy, the recovery of CD4+ counts to ≥200 cells/μl

occurred by 6 months post-treatment, however, at 2 months post-treatment the median was 183

cells/µl. In previously treated patients receiving MabCampath, the median time to reach a level of 200 cells/µl is 2 months following last infusion with MabCampath but may take more than 12 months to approximate pretreatment levels. This may predispose patients to opportunistic infections. It is highly recommended that anti-infective prophylaxis (e.g. trimethoprim/sulfamethoxazole 1 tablet twice daily, 3 times weekly, or other prophylaxis against Pneumocystis jiroveci pneumonia (PCP) and an effective oral anti-herpes agent, such as famciclovir, 250 mg twice daily) should be initiated while on therapy and for a minimum of 2 months following completion of treatment with MabCampath or until the CD4+ count has recovered to 200 cells/µl or greater, whichever is the later.

The potential for an increased risk of infection-related complications may exist following treatment

with multiple chemotherapeutic or biological agents.

Because of the potential for Transfusion Associated Graft Versus Host Disease (TAGVHD) it is

recommended that patients who have been treated with MabCampath receive irradiated blood

products.

Asymptomatic laboratory positive Cytomegalovirus (CMV) viraemia should not necessarily be

considered a serious infection requiring interruption of therapy. Ongoing clinical assessment should

be performed for symptomatic CMV infection during MabCampath treatment and for at least 2 months following completion of treatment.

Transient grade 3 or 4 neutropenia occurs very commonly by weeks 5-8 following initiation of

treatment. Transient grade 3 or 4 thrombocytopenia occurs very commonly during the first 2 weeks of therapy and then begins to improve in most patients. Therefore, haematological monitoring of patients is indicated. If a severe haematological toxicity develops, MabCampath treatment should be

interrupted until the event resolves. Treatment may be reinstituted following resolution of the

haematological toxicity (see section 4.2). MabCampath should be permanently discontinued if

autoimmune anaemia or autoimmune thrombocytopenia appears.

Complete blood counts and platelet counts should be obtained at regular intervals during MabCampath therapy and more frequently in patients who develop cytopenias.

It is not proposed that regular and systematic monitoring of CD52 expression should be carried out as routine clinical practice. However, if retreatment is considered, it may be prudent to confirm the

presence of CD52 expression. In data available from first line patients treated with MabCampath, loss

of CD52 expression was not observed around the time of disease progression or death.

Patients may have allergic or hypersensitivity reactions to MabCampath and to murine or chimeric

monoclonal antibodies.

Medicinal products for the treatment of hypersensitivity reactions, as well as preparedness to institute emergency measures in the event of reaction during administration is necessary (see section 4.2 of the SPC).

Males and females of childbearing potential should use effective contraceptive measures during

treatment and for 6 months following MabCampath therapy (see sections 4.6 and 5.3 of the SPC).

No studies have been conducted which specifically address the effect of age on MabCampath

disposition and toxicity. In general, older patients (over 65 years of age) tolerate cytotoxic therapy less well than younger individuals. Since CLL occurs commonly in this older age group, these patients should be monitored carefully (see section 4.2 of the SPC). In the studies in first line and previously treated patients no substantial differences in safety and efficacy related to age were observed; however the sizes of the databases are limited.

Management of adverse events

Appropriate premedication: oral or intravenous steroids 30 - 60 minutes prior to each MabCampath infusion during dose escalation and as clinically indicated. Steroids may be discontinued as appropriate, once dose escalation has been achieved. In addition, an oral antihistamine, e.g. diphenhydramine 50 mg, and an analgesic, e.g. paracetamol 500 mg, may be given. In the event that acute infusion reactions persist, the infusion time may be extended up to 8 hours from the time of reconstitution of MabCampath in solution for infusion.

Dose escalation:

In most patients, dose escalation to 30 mg can be accomplished in 3-7 days. However, if acute moderate to severe adverse reactions such as hypotension, rigors, fever, shortness of breath, chills, rashes and bronchospasm (some of which may be due to cytokine release) occur at either the 3 mg or 10 mg dose levels, then those doses should be repeated daily until they are well tolerated before further dose escalation is attempted (see section 4.4 of the SPC).

Haematological monitoring: see adverse events of special interest.

Initial work-up before start of treatment

Patients should be premedicated with oral or intravenous steroids, an appropriate antihistamine and analgesic 30-60 minutes prior to each MabCampath infusion during dose escalation and as clinically indicated thereafter (see section 4.4 of the SPC).

Concomitant Treatment

Concomitant medicinal products

Other medicinal products should not be added to the MabCampath infusion solution or simultaneously infused through the same intravenous line (see section 4.5 of the SPC).

Premedications

Prophylactic antibiotics

Antibiotics and antivirals should be administered routinely to all patients throughout and following

treatment (see section 4.4 of the SPC).

Response evaluation

First line B-CLL patients
The safety and efficacy of MabCampath were evaluated in a Phase 3, open-label, randomized

comparative trial of first line (previously untreated) Rai stage I-IV B-CLL patients requiring therapy

(Study 4). MabCampath was shown to be superior to chlorambucil as measured by the primary

endpoint progression free survival (PFS)

Cytogenetic analyses in first line B-CLL patients:

The cytogenetic profile of B-CLL has been increasingly recognized as providing important prognostic

information and may predict response to certain therapies. Of the first-line patients (n=282) in whom

baseline cytogenetic (FISH) data were available in Study 4, chromosomal aberrations were detected in 82%, while normal karyotype was detected in 18%. Chromosomal aberrations were categorized

according to Döhner’s hierarchical model. In first line patients, treated with either MabCampath or

chlorambucil, there were 21 patients with the 17p deletion, 54 patients with 11q deletion, 34 patients

with trisomy 12, 51 patients with normal karyotype and 67 patients with sole 13q deletion.

ORR was superior in patients with any 11q deletion (87% v 29%; p<0.0001) or sole deletion 13q (91%

v 62%; p=0.0087) treated with MabCampath compared to chlorambucil. A trend toward improved

ORR was observed in patients with 17p deletion treated with MabCampath (64% v 20%; p=0.0805).

Complete remissions were also superior in patients with sole 13q deletion treated with MabCampath

(27% v 0%; p=0.0009). Median PFS was superior in patients with sole 13q deletion treated with

MabCampath (24.4 v 13.0 months; p=0.0170 stratified by Rai Stage). A trend towards improved PFS

was observed in patients with 17p deletion, trisomy 12 and normal karyotype, which did not reach

significance due to small sample size.

Previously treated B-CLL patients:

Determination of the efficacy of MabCampath is based on overall response and survival rates.

For the full SmPC visit: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000353/WC500025270.pdf