美一公司的抗白血病新药获FDA批准 2001年5月11日
美国Millennium制药公司于本周一宣布，该公司与Ilex
Oncology公司合作研制的抗白血病药物Campath（alemtuzumab）已经获得美国食品和药品管理局（FDA）的批准。
尽管在临床试验中有患者因使用Campath而死亡，但FDA仍批准该药可用于那些烷化剂和氟达拉宾无效的B细胞性慢性淋巴细胞性白血病治疗。
Campath是一种人源性单克隆抗体，主要作用于存在于B和T淋巴细胞上的CD52抗原，从而破坏淋巴细胞。
尽管Campath临床研究中存在30％的死亡率（约半数是治疗相关性死亡，包括血液毒性反应如骨髓增生低下）以及较高的感染率，但是该药总有效率可达到33%，平均有效持续时间为7个月。在2个小规模临床试验中，其有效率分别为21%和29%，平均有效持续时间分别为7和11个月。
在2000年的晚些时候，FDA顾问委员会投票表决，以14票对1票建议加快Campath批准应用，这将允许药物一边在随访研究中搞清未明的问题，一边上市。但是，必须在包装盒上注明应警惕药物的血液毒性、输注反应和治疗相关的感染。
最近该药品已提请欧洲联盟批准以MabCampath的名称在欧盟市场上市，预计在今年下半年可获欧盟的最终批准。
Millennium制药公司称，作为单独用药或联合治疗，Campath正被考虑用于血液肿瘤包括外周和皮肤T细胞淋巴瘤、自体免疫性疾病如多发性硬化的治疗和器官移植排异反应的治疗。
德国Schering AG公司治疗癌症的氟达拉滨新型口服制剂，Fludara
Oral(Ⅰ)已在其第一个市场英国上市，用于B细胞慢性淋巴细胞性白血病(CLL)的二线治疗。静脉注射用氟达拉滨是在烷化剂以后治疗B细胞CLL的金标准二线药，如病人不能上医院去接受静脉注射，则(Ⅰ)是有用的。
在此期间，因FDA顾问委员会于去年年底支持Campath(alemtuzumab),Sche-ring公司的CLL专利业务不久将得到进一步扩大。用烷化剂和氟达拉滨治疗无效的病人可用Campath治疗。该药用于CLL的申报文件正在接受EMEA评审。
另外，Schering已获得Climodien(地诺孕素+雌二醇戊酸酯)的荷兰销售许可证。Climodien是治疗绝经后症状的持续性复合激素替代治疗药。预期今年年底前通过相互承认程序也可获得其余欧盟国家的许可证。
减少器官移植排异新技术Campath
2000-9-30
伦敦消息，英国剑桥大学卡恩教授最近透露，他和同事开发出一种可减少器官移植排异的新技术，在３０名患者身上进行试验获得了良好效果。
植入患者体内的新器官会被患者免疫系统认为是“异物”而遭到排异。为了防止这种情况，医生们在手术中经常同时采用多种药物，对患者免疫系统进行抑制。但这些抑制免疫药物通常副作用较大，并有可能增加患者得癌症和脆骨症等疾病的危险。
英国《独立报》２７日报道说，卡恩教授等研究出的新技术，需要在患者手术前向其体内注入一种名为“坎帕斯”（ＣＡＭＰＡＴＨ）的人工合成抗体。该抗体可暂时清除血液中的淋巴细胞，使免疫系统处于失效状态。这使得器官植入患者体内后，不会马上遭到患者免疫系统的排异。免疫系统在一、两个月的逐渐恢复中，会把被移植器官“误认为”是患者体内原有的组成部分。
研究人员用新技术对３０名接受肾脏移植的患者进行试验后发现，新技术能将被移植器官遭排斥的可能性降低约５０％。另外，采用新技术后患者可只服用一种药物，而药剂量只有原来的一半左右。
(FDA)美國食品藥物管理局 2001年5月批准上市
德國Schering
AG公司治療癌症的氟達拉濱新型口服制劑，用于B細胞慢性淋巴細胞性白血病(CLL)的二線治療。靜脈注射用氟達拉濱是在烷化劑以后治療B細胞CLL的金標准二線藥。
Drug Name: Campath
The following information is obtained from various
newswires, published medical journal articles, and
medical conference
presentations.
Company: Berlex Laboratories
Approval Status: Approved May 2001
Treatment for: Leukemia
General Information
Campath, a humanized monoclonal antibody, has been
approved as an injectable treatment for B-cell chronic
lymphocytic leukemia (B-CLL). Campath is designed for
use in B-CLL patients who have been treated with
alkylating agents and have failed fludarabine therapy.
This drug gives refractory B-CLL patients a new hope for
treatment, as there are no other approved therapeutic
options.
Chronic lymphocytic leukemia is the most prevalent form
of leukemia in adults and affects approximately 120,000
patients in
the United States and Europe. B-CLL is characterized by
an accumulation of leukemic lymphocytes in the bone
marrow, blood, and other body tissues. This
accumulation leads to bone marrow
dysfunction and enlargement of the lymph nodes, liver,
and spleen. Related symptoms of the disease include
fatigue, bone
pain, night sweats, decreased appetite,
and weight loss.
Clinical Results
Campath was evaluated in a multi-center, open-label,
noncomparative study of 93 B-CLL patients previously
treated with alkylating agents, who had failed
fludarabine
treatment. There were also two supportive,
multi-center, open-label, noncomparative trials of
Campath enrolling a total of 56 B-CLL patients. Results
were determined by objective tumor response rates and
duration of response, as defined by the NCI Working
Group Response Criteria.
In the largest of the three trials, an overall response
rate of 33 percent was observed, with a median duration
of seven months. A 30
percent mortality rate was
recorded, either during the study or within six months
of its completion. Half of these deaths were due to
progression of the disease,
while the other half were
related to Campath therapy. Adverse events associated
with Campath therapy included infusion-related events,
infections, and hematological toxicity.
Side Effects
Adverse events associated with the use of Campath
therapy may include (but are not limited to) the
following:
Neurotropenia
· Fever and rigors
· Anemia
· Thrombocytopenia
· Sepsis
· Pneumonia
· Nausea
· Vomiting
· Rash
· Hypotension
Mechanism of Action
Campath (alemtuzumab) works by binding to the CD52
antigen that is present on the surface of the malignant
lymphocytes. After
binding, the drug induces antibody-dependent lysis, or
killing. This causes the removal of malignant
lymphocytes from the blood, bone marrow, and other
affected organs.
Additional Information
For additional information on Campath, please visit
Campath.
FDA专题小组推荐Campath
2001/02/28
美国FDA肿瘤药物顾问委员会已推荐Millenium Pharmaceuticals与Ilex
Dncology公司的人化抗淋巴细胞单克隆抗体Campath(alemtuzumab)(Ⅰ)的加速批准，用于已用过烷化剂治疗和氟达拉滨(fludarabine)(Ⅱ)治疗无效的慢性淋巴
细胞性白血病(CLL)病人。
专题小组会以14对1票通示(Ⅰ)，其决定是依据一项关键的Ⅱ期试验和二项
以前的试验结果。在关键的93例病人的试验中，(Ⅰ)组有33%的病人有效，平均有效期为7个月。23%的病人的客观有效期一年多。
FDA也要求Millenium作进一步试验或从目前的研究中搜寻更多的资料。如果
获批，(Ⅰ)将与(Ⅱ)在美国竞争，后者是Schering公司销售的，于1999年获准用于难治性CLL病人。
在该关键性试验中，病人接受(Ⅰ)递增剂量以尽量减少输液引起的相关副作
用，达每周三次，每次30mg，共4～12周。平均存活时间16个月，比以前的对(Ⅱ)
治疗无效而用其它疗法的CCL病人研究所见到的3～10个月存活时间长些。但不是
所有的病人一样受益，FDA医药评审Genevieve Schechter说，研究6个月结束时，
已有28例死亡，30例因感染、血液学毒性反应或输液相关/反应而中止治疗，还有67%有严重的不良反应。
约30%的病人有3级或4级的机会性感染，其中23例是肺炎。其他感染是系列感染、脓毒症、巨细胞病毒与疱疹。副作用有发热、赛战、恶心呕吐与皮疹，与每周三次的二小时输液相关，见于90%的病人。
(Ⅰ)的半衰期较长，故其已知的免疫抑制与血液学毒性等副作用也较持久，对严重的白血病患者增加了危险。然而，只有一项对比性试验可能确定是(Ⅰ)或基础疾病导致死亡及不良反应。所有病人都是重病人，因过去用过(Ⅱ)故在试验
之前即有广泛的免疫抑制。
Campath(ALEMTUZUMAB)英文说明书
Package Insert
Campath® (ALEMTUZUMAB)
Millennium and ILEX Partners, LP
Table of Contents
Description
Clinical Pharmacology
Clinical Studies
Indications and Usage
Contraindications
Warnings
Precautions
Adverse Reactions
Overdosage
Dosage and Administration
How Supplied
WARNING Campath should be administered under the
supervision of a physician experienced in the use of
antineoplastic therapy. · Hematologic Toxicity: Serious
and, in rare instances fatal, pancytopenia/ marrow
hypoplasia, autoimmune idiopathic thrombocytopenia, and
autoimmune hemolytic anemia have occurred in patients
receiving Campath therapy. Single doses of Campath
greater than 30 mg or cumulative doses greater than 90
mg per week should not be administered because these
doses are associated with a higher incidence of
pancytopenia. · Infusion Reactions: Campath can result
in serious infusion reactions. Patients should be
carefully monitored during infusions and Campath
discontinued if indicated. (See DOSAGE AND
ADMINISTRATION.) Gradual escalation to the recommended
maintenance dose is required at the initiation of
therapy and after interruption of therapy for 7 or more
days. · Infections, Opportunistic Infections: Serious,
sometimes fatal bacterial, viral, fungal, and protozoan
infections have been reported in patients receiving
Campath therapy. Prophylaxis directed against
Pneumocystis carinii pneumonia (PCP) and herpes virus
infections has been shown to decrease, but not
eliminate, the occurrence of these infections.
Return to Table of Contents
Campath® (ALEMTUZUMAB)
DESCRIPTION
Campath® (Alemtuzumab) is a recombinant DNA-derived
humanized monoclonal antibody (Campath-1H) that is
directed against the 21-28 kD cell surface glycoprotein,
CD52. CD52 is expressed on the surface of normal and
malignant B and T lymphocytes, NK cells, monocytes,
macrophages, and tissues of the male reproductive
system. The Campath-1H antibody is an IgG1 kappa with
human variable framework and constant regions, and
complementarity-determining regions from a murine (rat)
monoclonal antibody (Campath-1G). The Campath-1H
antibody has an approximate molecular weight of 150 kD.
Campath is produced in mammalian cell (Chinese hamster
ovary) suspension culture in a medium containing
neomycin. Neomycin is not detectable in the final
product. Campath is a sterile, clear, colorless,
isotonic pH 6.8-7.4 solution for injection. Each single
use ampoule of Campath contains 30 mg Alemtuzumab, 24.0
mg sodium chloride, 3.5 mg dibasic sodium phosphate, 0.6
mg potassium chloride, 0.6 mg monobasic potassium
phosphate, 0.3 mg polysorbate 80, and 0.056 mg disodium
edetate. No preservatives are added.
Return to Table of Contents
CLINICAL PHARMACOLOGY
General:
Alemtuzumab binds to CD52, a non-modulating antigen that
is present on the surface of essentially all B and T
lymphocytes, a majority of monocytes, macrophages, and
NK cells, and a subpopulation of granulocytes. Analysis
of samples collected from multiple volunteers has not
identified CD52 expression on erythrocytes or
hematopoetic stem cells. The proposed mechanism of
action is antibody-dependent lysis of leukemic cells
following cell surface binding. Campath-1H Fab binding
was observed in lymphoid tissues and the mononuclear
phagocyte system. A proportion of bone marrow cells,
including some CD34+ cells, express variable levels of
CD52. Significant binding was also observed in the skin
and male reproductive tract (epididymis, sperm, seminal
vesicle). Mature spermatozoa stain for CD52, but neither
spermatogenic cells nor immature spermatozoa show
evidence of staining.
Human Pharmacokinetics:
The pharmacokinetic profile of Alemtuzumab was studied
in a multicenter rising-dose trial in non-Hodgkin’s
lymphoma (NHL) and chronic lymphocytic leukemia (CLL).
Campath was administered once weekly for a maximum of 12
weeks. Following intravenous infusions over a range of
doses, the maximum serum concentration (Cmax) and the
area under the curve (AUC) showed relative dose
proportionality. The overall average half-life (t1/2)
over the dosing interval was about 12 days. The
pharmacokinetic profile of Campath administered as a 30
mg intravenous infusion three times per week was
evaluated in CLL patients. Peak and trough levels of
Campath rose during the first few weeks of treatment,
and appeared to approach steady state by approximately
week 6, although there was marked inter-patient
variability. The rise in serum Campath concentration
corresponded with the reduction in malignant
lymphocytosis.
Return to Table of Contents
CLINICAL STUDIES
The safety and efficacy of Campath were evaluated in a
multicenter, open-label, noncomparative study (Study 1)
of 93 patients with B-cell chronic lymphocytic leukemia
(B-CLL) who had been previously treated with alkylating
agents and had failed treatment with fludarabine.
Fludarabine failure was defined as lack of an objective
partial (PR) or complete (CR) response to at least one
fludarabine-containing regimen, progressive disease (PD)
while on fludarabine treatment, or relapse within 6
months of the last dose of fludarabine. Patients were
gradually escalated to a maintenance dose of Campath 30
mg intravenously three times per week for 4 to 12 weeks.
Patients received premedication prior to infusion and
anti-Pneumocystis carinii and anti-herpes prophylaxis
while on treatment and for at least 2 months after the
last dose of Campath.
Two supportive, multicenter, open-label, noncomparative
studies of Campath enrolled a total of 56 patients with
B-CLL (Studies 2 and 3). These patients had been
previously treated with fludarabine or other
chemotherapies. In Studies 2 and 3, the maintenance dose
of Campath was 30 mg three times per week with treatment
cycles of 8 and 6 weeks respectively. A slightly
different dose escalation scheme was used in these
trials. Premedication to ameliorate infusional reactions
and anti-Pneumocystis carinii and anti-herpes
prophylaxis were optional.
Objective tumor response rates and duration of response
were determined using the NCI Working Group Response
Criteria (1996). A comparison of patient characteristics
and the results for each of these studies is summarized
in Table 1. Time to event parameters, except for
duration of response, are calculated from initiation of
Campath therapy. Duration of response is calculated from
the onset of the response.
Table 1: Summary of Patient Population and Outcomes
Study 1 (N=93) Study 2 (N=32) Study 3 (N=24)
Median Age in Years (Range) 66 (32 - 68) 57 (46 - 75) 62
(44-77)
Median Number of Prior Regimens (Range) 3 (2 - 7) 3 (1 -
10) 3 (1 - 8)
Prior Therapies: Alkylating Agents
Fludarabine 100% 100% 100% 34% 92% 100%
Disease Characteristics: Rai Stage III/IV
Disease B-Symptoms 76% 42% 72% 31% 71% 21%
Overall Response Rate (95% Confidence Interval)
Complete Response Partial Response 33% (23%,
43%) 2% 31% 21% (8%, 33%) 0% 21% 29% (11%, 47%) 0% 29%
Median Duration of Response (months) (95% Confidence
Interval) 7 (5, 8) 7 (5, 23) 11 (6, 19)
Median Time to Response (months) (95% Confidence
Interval) 2 (1, 2) 4 (1, 5) 4 (2, 4)
Progression-Free Survival (months) (95% Confidence
Interval) 4 (3, 5) 5 (3, 7) 7 (3, 9)
Return to Table of Contents
INDICATIONS AND USAGE
Campath is indicated for the treatment of B-cell chronic
lymphocytic leukemia (B-CLL) in patients who have been
treated with alkylating agents and who have failed
fludarabine therapy. Determination of the effectiveness
of Campath is based on overall response rates. (See
CLINICAL STUDIES.) Comparative, randomized trials
demonstrating increased survival or clinical benefits
such as improvement in disease-related symptoms have not
yet been conducted.
Return to Table of Contents
CONTRAINDICATIONS
Campath is contraindicated in patients who have active
systemic infections, underlying immunodeficiency (e.g.,
seropositive for HIV), or known Type I hypersensitivity
or anaphylactic reactions to Campath or to any one of
its components.
Return to Table of Contents
WARNINGS (See BOXED WARNING.)
Infusion-Related Events:
Campath has been associated with infusion-related events
including hypotension, rigors, fever, shortness of
breath, bronchospasm, chills, and/or rash. In order to
ameliorate or avoid infusion-related events, patients
should be premedicated with an oral antihistamine and
acetaminophen prior to dosing and monitored closely for
infusion-related adverse events. In addition, Campath
should be initiated at a low dose with gradual
escalation to the effective dose. Careful monitoring of
blood pressure and hypotensive symptoms is recommended
especially in patients with ischemic heart disease and
in patients on antihypertensive medications. If therapy
is interrupted for 7 or more days, Campath should be
reinstituted with gradual dose escalation. (See ADVERSE
EVENTS and DOSAGE AND ADMINISTRATION.)
Immunosuppression/Opportunistic Infections:
Campath induces profound lymphopenia. A variety of
opportunistic infections have been reported in patients
receiving Campath therapy (see ADVERSE EVENTS,
Infections). If a serious infection occurs, Campath
therapy should be interrupted and may be reinitiated
following the resolution of the infection.
Anti-infective prophylaxis is recommended upon
initiation of therapy and for a minimum of 2 months
following the last dose of Campath or until CD4+ counts
are ³ 200 cells/mL. The median time to recovery of CD4+
counts to ³ 200/mL was 2 months, however, full recovery
(to baseline) of CD4+ and CD8+ counts may take more than
12 months. (See BOXED WARNING and DOSAGE AND
ADMINISTRATION.
Because of the potential for Graft versus Host Disease
(GVHD) in severely lymphopenic patients, irradiation of
any blood products administered prior to recovery from
lymphopenia is recommended.
Hematologic Toxicity:
Severe, prolonged, and in rare instances fatal,
myelosuppression has occurred in patients with leukemia
and lymphoma receiving Campath. Bone marrow aplasia and
hypoplasia were observed in the clinical studies at the
recommended dose. The incidence of these complications
increased with doses above the recommended dose. In
addition, severe and fatal autoimmune anemia and
thrombocytopenia were observed in patients with CLL.
Campath should be discontinued for severe hematologic
toxicity (see Table 3 Dose Modification and Reinitiation
of Therapy for Hematologic Toxicity) or in any patient
with evidence of autoimmune hematologic toxicity.
Following resolution of transient, non-immune
myelosuppression, Campath may be reinitiated with
caution. (See DOSAGE AND ADMINISTRATION.) There is no
information on the safety of resumption of Campath in
patients with autoimmune cytopenias or marrow aplasia.
(See ADVERSE REACTIONS.)
Return to Table of Contents
PRECAUTIONS
Laboratory Monitoring:
Complete blood counts (CBC) and platelet counts should
be obtained at weekly intervals during Campath therapy
and more frequently if worsening anemia, neutropenia, or
thrombocytopenia is observed on therapy. CD4+ counts
should be assessed after treatment until recovery to ³
200 cells/mL. (See WARNINGS and ADVERSE REACTIONS.)
Drug/Laboratory Interactions:
No formal drug interaction studies have been performed
with Campath. An immune response to Campath may
interfere with subsequent diagnostic serum tests that
utilize antibodies.
Immunization:
Patients who have recently received Campath, should not
be immunized with live viral vaccines, due to their
immunosuppression. The safety of immunization with live
viral vaccines following Campath therapy has not been
studied. The ability to generate a primary or anamnestic
humoral response to any vaccine following Campath
therapy has not been studied.
Immunogenicity:
Four (1.9%) of 211 patients evaluated for development of
an immune response were found to have antibodies to
Campath. The data reflect the percentage of patients
whose test results were considered positive for antibody
to Campath in a kinetic enzyme immunoassay, and are
highly dependent on the sensitivity and specificity of
the assay. The observed incidence of antibody positivity
may be influenced by several additional factors
including sample handling, concomitant medications and
underlying disease. For these reasons, comparison of the
incidence of antibodies to Campath with the incidence of
antibodies to other products may be misleading. Patients
who develop hypersensitivity to Campath may have
allergic or hypersensitivity reactions to other
monoclonal antibodies.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
No long-term studies in animals have been performed to
establish the carcinogenic or mutagenic potential of
Campath, or to determine its effects on fertility in
males or females. Women of childbearing potential and
men of reproductive potential should use effective
contraceptive methods during treatment and for a minimum
of 6 months following Campath therapy.
Pregnancy Category C:
Animal reproduction studies have not been conducted with
Campath. It is not known whether Campath can affect
reproductive capacity or cause fetal harm when
administered to a pregnant woman. However, human IgG is
known to cross the placental barrier and therefore
Campath may cross the placental barrier and cause fetal
B and T lymphocyte depletion. Campath should be given to
a pregnant woman only if clearly needed.
Nursing Mothers:
Excretion of Campath in human breast milk has not been
studied. Because many drugs including human IgG are
excreted in human milk, breast-feeding should be
discontinued during treatment and for at least 3 months
following the last dose of Campath.
Pediatric Use:
The safety and effectiveness of Campath in children have
not been established.
Geriatric Use:
Of the 149 patients with B-CLL enrolled in the three
clinical studies, 66 (44%) were 65 and over, while 15
(10%) were 75 and over. Substantial differences in
safety and efficacy related to age were not observed;
however the size of the database is not sufficient to
exclude important differences.
Return to Table of Contents
ADVERSE REACTIONS
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug
and may not reflect the rates observed in practice. The
adverse reaction information from clinical trials does,
however, provide a basis for identifying the adverse
events that appear to be related to drug use and for
approximating rates.
Safety data, except where indicated, are based on 149
patients with B-CLL enrolled in studies of Campath as a
single agent administered at a maintenance dose of 30 mg
intravenously three times weekly for 4 to 12 weeks.
Table 2 lists adverse events including severe or life
threatening (NCI-CTC Grade 3 or 4) adverse events
reported in > 5% of the patients. More detailed
information and follow-up were available for Study 1 (93
patients), therefore the narrative description of
certain events, noted below, is based on this study.
Infusion-Related Adverse Events:
Infusion-related adverse events resulted in
discontinuation of Campath therapy in 6% of the patients
enrolled in Study 1. The most commonly reported
infusion-related adverse events on this study included
rigors in 89% of patients, drug-related fever in 83%,
nausea in 47%, vomiting in 33%, and hypotension in 15%.
Other frequently reported infusion-related events
include, rash in 30% of patients, fatigue in 22%,
urticaria in 22%, dyspnea in 17%, pruritus in 14%,
headache in 13%, and diarrhea in 13%. Similar types of
adverse events were reported on the supporting studies
(see Table 2). Acute infusion-related events were most
common during the first week of therapy. Antihistamines,
acetaminophen, antiemetics, meperidine, and
corticosteroids as well as incremental dose escalation
were used to prevent or ameliorate infusion-related
events. (See WARNINGS and DOSAGE AND ADMINISTRATION.)
Infections:
On Study 1, all patients were required to receive
anti-herpes and anti-PCP prophylaxis (see DOSAGE AND
ADMINISTRATION) and were followed for infections for 6
months. Forty (43%) of 93 patients experienced 59
infections (one or more infections per patient) related
to Campath during treatment or within 6 months of the
last dose. Of these, 34 (37%) patients experienced 42
infections that were of Grade 3 or 4 severity; 11 (18%)
were fatal. Fifty-five percent of the Grade 3 or 4
infections occurred during treatment or within 30 days
of last dose. In addition one or more episodes of
febrile neutropenia (ANC £ 500 cells/mL were reported in
10% of patients.
The following types of infections were reported in Study
1: Grade 3 or 4 sepsis in 12% of patients with one
fatality, Grade 3 or 4 pneumonia in 15% with five
fatalities, and opportunistic infections in 17% with
four fatalities. Candida infections were reported in 5%
of patients; CMV infections in 8% (4% of Grade 3 or 4
severity); Aspergillosis in 2% with fatal Aspergillosis
in 1%; fatal Mucormycosis in 2%; fatal Cryptococcal
pneumonia in 1%; Listeria monocytogenes meningitis in
1%; disseminated Herpes zoster in 1%; Grade 3 Herpes
simplex in 2%; and Torulopsis pneumonia in 1%. PCP
pneumonia occurred in one (1%) patient who discontinued
PCP prophylaxis.
On Studies 2 and 3 in which anti-herpes and anti-PCP
prophylaxis was optional, 37 (66%) patients had 47
infections while or after receiving Campath therapy. In
addition to the opportunistic infections reported above,
the following types of related events were observed on
these studies: interstitial pneumonitis of unknown
etiology and progressive multifocal leukoencephalopathy.
Hematologic Adverse Events:
Pancytopenia/Marrow Hypoplasia: Campath therapy was
permanently discontinued in six (6%) patients due to
pancytopenia/marrow hypoplasia. Two (2%) cases of
pancytopenia/ marrow hypoplasia were fatal.
Anemia: Forty-four (47%) patients had one or more
episodes of new onset NCI-CTC Grade 3 or 4 anemia.
Sixty-two (67%) patients required RBC transfusions. In
addition, erythropoietin use was reported in nineteen
(20%) patients. Autoimmune hemolytic anemia secondary to
Campath therapy was reported in 1% of patients. Positive
Coombs test without hemolysis was reported in 2%. (See
BOXED WARNING.)
Neutropenia: Sixty-five (70%) patients had one or more
episodes of NCI-CTC Grade 3 or 4 neutropenia. Median
duration of Grade 3 or 4 neutropenia was 28 days (range:
2 – 165 days). (See Infections.)
Thrombocytopenia: Forty-eight (52%) patients had one or
more episodes of new onset Grade 3 or 4
thrombocytopenia. Median duration of thrombocytopenia
was 21 days (range: 2 – 165 days). Thirty-five (38%)
patients required platelet transfusions for management
of thrombocytopenia. Autoimmune thrombocytopenia was
reported in 2% of patients with one fatal case of
Campath-related autoimmune thrombocytopenia. (See BOXED
WARNING.)
Lymphopenia: The median CD4+ count at 4 weeks after
initiation of Campath therapy was 2 (two)/mL, at 2
months after discontinuation of Campath therapy, 207/mL,
and 6 months after discontinuation, 470/mL. The pattern
of change in median CD8+ lymphocyte counts was similar
to that of CD4+ cells. In some patients treated with
Campath, CD4+ and CD8+ lymphocyte counts had not
returned to baseline levels at longer than 1 year post
therapy.
Table 2: Adverse Events in > 5% of the B-CLL Study
PopulationDuring Treatment or Within 30 Days (N = 149)
Adverse Event: B-CLL STUDIES(N = 149)
ANY Grade(%) Grade 3 or 4(%)
Body As A Whole
Rigors 86 16
Fever 85 19
Fatigue 34 5
Pain, Skeletal Pain 24 2
Anorexia 20 3
Asthenia 13 4
Edema, Peripheral Edema 13 1
Back Pain 10 3
Chest Pain 10 1
Malaise 9 1
Temperature Change Sensation 5 --
Cardiovascular Disorders, General
Hypotension 32 5
Hypertension 11 2
Heart Rate & Rhythm Disorders
Tachycardia, SVT 11 3
Central & Peripheral Nervous System Disorders
Headache 24 1
Dysthesias 15 --
Dizziness 12 1
Tremor 7 --
Gastrointestinal Disorders
Nausea 54 2
Vomiting 41 4
Diarrhea 22 1
Stomatitis, Ulcerative Stomatitis, Mucositis 14
1
Abdominal Pain 11 2
Dyspepsia 10 --
Constipation 9 1
Hematologic Disorders
WBC Disorders: Neutropenia 85 64
RBC Disorders: Anemia 80 38
Pancytopenia 5 3
Platelet, Bleeding & Clotting Disorders:
Thrombocytopenia 72 50
Purpura 8 --
Epistaxis 7 1
Musculoskeletal Disorders
Myalgias 11 --
Psychiatric Disorders
Insomnia 10 --
Depression 7 1
Somnolence 5 1
Resistance Mechanism Disorders
Sepsis 15 10
Herpes Simplex 11 1
Moniliasis 8 1
Infection (other viral or unidentified) 7 1
Respiratory System Disorders
Dyspnea 26 9
Cough 25 2
Bronchitis, Pneumonitis 21 13
Pneumonia 16 10
Pharyngitis 12 --
Bronchospasm 9 2
Rhinitis 7 --
Skin & Appendage Disorders
Rash, Maculopapular Rash, Erythematous Rash 40 3
Urticaria 30 5
Pruritus 24 1
Sweating increased 19 1
Serious adverse events:
The following serious adverse events, defined as events
which result in death, requiring or prolonging
hospitalization, requiring medical intervention to
prevent hospitalization, or malignancy, were reported in
at least one patient treated on studies where Campath
was used as a single agent (and are not reported in
Table 2). These studies were conducted in patients with
lymphocytic leukemia and lymphoma (N = 745) and in
patients with non-malignant diseases (N =152) such as
rheumatoid arthritis, solid organ transplant, or
multiple sclerosis.
Body As A Whole: allergic reactions, anaphylactoid
reaction, ascites, hypovolemia, influenza-like syndrome,
mouth edema, neutropenic fever, syncope
Cardiovascular Disorders: cardiac failure, cyanosis,
atrial fibrillation, cardiac arrest, ventricular
arrhythmia, ventricular tachycardia, angina pectoris,
coronary artery disorder, myocardial infarction,
pericarditis
Central and Peripheral Nervous System Disorders:
abnormal gait, aphasia, coma, grand mal convulsions,
paralysis, meningitis
Endocrine Disorders: hyperthyroidism
Gastrointestinal System Disorders: duodenal ulcer,
esophagitis, gingivitis, gastroenteritis, GI hemorrhage,
hematemesis, hemorrhoids, intestinal obstruction,
intestinal perforation, melena, paralytic ileus, peptic
ulcer, pseudomembranous colitis, colitis, pancreatitis,
peritonitis, hyperbilirubinemia, hepatic failure,
hepatocellular damage, hypoalbuminemia, biliary pain
Hearing and Vestibular Disorders: decreased hearing
Metabolic and Nutritional Disorders: acidosis,
aggravated diabetes mellitus, dehydration, fluid
overload, hyperglycemia, hyperkalemia, hypokalemia,
hypoglycemia, hyponatremia, increased alkaline
phosphatase, respiratory alkalosis
Musculoskeletal System Disorders: arthritis or worsening
arthritis, arthropathy, bone fracture, myositis, muscle
atrophy, muscle weakness, osteomyelitis, polymyositis
Neoplasms: malignant lymphoma, malignant testicular
neoplasm, prostatic cancer, plasma cell dyscrasia,
secondary leukemia, squamous cell carcinoma,
transformation to aggressive lymphoma, transformation to
prolymphocytic leukemia
Platelet, Bleeding, and Clotting Disorders: coagulation
disorder, disseminated intravascular coagulation,
hematoma, pulmonary embolism, thrombocythemia
Psychiatric Disorders: confusion, hallucinations,
nervousness, abnormal thinking, apathy
White Cell and RES Disorders: agranulocytosis, aplasia,
decreased haptoglobin, lymphadenopathy, marrow
depression
Red Blood Cell Disorders: hemolysis, hemolytic anemia,
splenic infarction, splenomegaly
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