Alemtuzumab

Alemtuzumab See also Monoclonal antibodies

GENERAL INFORMATION Alemtuzumab (campath-1H) is a humanized monoclonal antibody specific for the CDw52 antigen, present on cell membranes of lymphocytes and monocytes. It has been used for treatment of patients with rheumatoid arthritis and vasculitis, is being investigated for the treatment of chronic lymphocytic leukemia, and has been used to deplete circulating lymphocytes in patients with multiple sclerosis [1]. In 2001, alemtuzumab was approved in Europe for the treatment of chronic B cell lymphocytic leukemia that had been treated previously with alkylating agents and was refractory to fludarabine [2]. It has also been used for induction of immunosuppression/tolerance in liver transplant recipients [3,4] and kidney/pancreas transplant recipients [5]. The major adverse effects (fever, nausea, skin rash, and hypotension) may well be related to the release of cytokines as a consequence of lysis of the target lymphocytes [6]. Of four patients treated with alemtuzumab, three developed antibodies against it, but without affecting the plasma concentrations and without obvious clinical consequences. Other adverse effects have included mild renal impairment and transient thrombocytopenia.

DRUG STUDIES Observational studies On 19 September 2007 alemtuzumab was approved by the FDA as a single agent for the treatment of B-cell chronic lymphocytic leukemia. The common reported adverse effects in the CAM 307 trial include lymphopenia (99%), neutropenia (77%), anemia (76%), thrombocytopenia (71%), pyrexia (69%), chills (53%), cytomegalovirus viremia (56%), and cytomegalovirus infection (16%) [7]. Other infections were reported in 90% of subjects. Skin manifestations included urticaria (16%), other rashes (13%), and erythema (4%). There was also hypotension (16%), hypertension (14%), headache (14%), tremor (3%), dyspnea (14%), diarrhea (10%), insomnia (10%), anxiety (8%), and tachycardia (10%).

A 26-year-old man with Alport’s syndrome underwent re-transplantation with a renal allograft and was subsequently treated with a single intravenous dose of alemtuzumab 30 mg; on the second post-operative day he developed diffuse alveolar hemorrhage [9]. A patient with chronic lymphocytic leukemia received alemtuzumab for 3 weeks as salvage therapy and developed interstitial pneumonitis, which was not associated with either infection or the neoplasm [10].

Endocrine Nine of 27 patients with multiple sclerosis developed antibodies against the thyrotropin receptor and carbimazoleresponsive autoimmune hyperthyroidism after a 5-day pulse of alemtuzumab, a finding that was not reported in patients treated for other disorders [1].

Hematologic In 50 patients with advanced, low-grade, non-Hodgkin’s lymphoma alemtuzumab produced marked lymphopenia and neutropenia, which were the probable cause of frequent severe infections [11]. Seven patients developed opportunistic infections and nine had bacterial septicemia; three patients died from infectious complications. Severe resistant autoimmune thrombocytopenia has also been noted in one patient, but the evidence that alemtuzumab was involved was limited [12]. Of 357 pancreas transplant recipients 20 developed red cell aplasia, autoimmune hemolytic anemia, and/or idiopathic thrombocytopenic purpura during therapy with alemtuzumab, daclizumab, and mycophenolate mofetil [13]. Alemtuzumab was used as induction therapy immediately before surgery in a man who received a living donor real transplant; during surgery he developed a severe coagulopathy, which improved after 24 hours but recurred within 3 hours after a second dose of alemtuzumab, given exactly 24 hours after the first [14].

Immunologic Reactivation of cytomegalovirus is a frequent complication during treatment with alemtuzumab in patients with chronic lymphocytic leukemia [15], and other organisms are occasionally described.
A 52-year-old man with B cell chronic lymphocytic leukemia

ORGANS AND SYSTEMS Respiratory Of 22 patients, median age 61 years, who had received a median of three previous types of therapy for mycosis fungoides or Se´zary syndrome and were given alemtuzumab in increasing doses (from 3 to 30 mg three times a week for 12 weeks), 11 had no infectious complications, one had fatal pulmonary aspergillosis 2.5 months after the end of treatment, and another contracted fatal Mycobacterium pneumonia 10 months after the end of treatment [8]. ã 2016 Elsevier B.V. All rights reserved.

had weight loss and a steadily rising blood lymphocyte count [16]. He received alemtuzumab as first-line treatment as part of a clinical trial. After 12 weeks the leukemia completely remitted. Three years later he received chlorambucil for progressive disease and had a partial remission. After another 2 years his chemotherapy regimen was change to fludarabine and cyclophosphamide. After a further year his disease became rapidly progressive, with anemia, splenomegaly, and lymphadenopathy. Alemtuzumab was reintroduced and standard prophylaxis treatment was started with co-trimoxazole, valaciclovir, and fluconazole. After 8 weeks he developed fever up to 39  C. There was no evidence of bacterial or viral infection. His general condition worsened rapidly and he showed signs of acute hepatitis, renal insufficiency, disseminated intravascular

Alemtuzumab 135 coagulation, and finally respiratory failure. He died 14 days after the start of the fever. Adenovirus 5 was recovered from the lung, spleen, liver, and blood.

Among 18 patients with chronic lymphocytic leukemia, one with a long-lasting lymphocytopenia died 3 months after treatment, owing to progressive multifocal leukoencephalopathy; papovavirus was isolated from the cerebrospinal fluid [17]. Immune reconstitution syndrome has been reported in two cases after the use of alemtuzumab [18,19].
A 53-year-old man with Se´zary syndrome received alemtuzu-

mab 30 mg thrice weekly for 3 months. The disease response, but 3 months later he developed sarcoidosis, which was thought to have resulted from T-cell reconstitution.
A 55-year-old man received alemtuzumab thrice weekly for T-cell prolymphocytic leukemia and went into remission after 26 doses. A few weeks later, while he still had profound cellular immunodeficiency, he had a cryptococcal infection. After 10 months in remission he developed what was thought to be an immune reconstitution inflammatory response specific to Cryptococcus neoformans.

Nine of 27 patients with multiple sclerosis developed antibodies against the thyrotropin receptor and carbimazoleresponsive autoimmune hyperthyroidism after a 5-day pulse of alemtuzumab, a finding that was not reported in patients treated for other disorders [1].

Infection risk From July 2001 to December 2003, all patients who received alemtuzumab for lymphoproliferative disorders at one institution were evaluated retrospectively to document infectious complications until death or the end of follow-up in October 2004 [20]. Alemtuzumab recipients who underwent allogeneic hemopoietic stem cell transplantation were compared with a concurrent cohort who also underwent allogeneic stem cell transplantation but did not receive alemtuzumab. There were 27 patients, 21 with chronic lymphocytic leukemia and six with plasma cell disorders. Overall mortality was 37%, seven of 10 deaths being related to infection. There were significant opportunistic infections in nine patients with chronic lymphocytic leukemia, including cytomegalovirus and adenovirus infections, progressive multifocal leukoencephalopathy, toxoplasmosis, and acanthamebiasis. There were also 30 non-opportunistic infections in 22 patients, with three deaths, all involving Enterococcus species bacteremia. Of nine patients who received alemtuzumab six had cytomegalovirus reactivation compared with only 10 of 27 patients who did not receive alemtuzumab. Post-transplant opportunistic infections (excluding herpesviruses) occurred in 12/27 patients given alemtuzumab compared with 8/27 controls. Of 449 consecutive transplant recipients who received alemtuzumab 69 had at least one episode of bloodstream infection [21]. However, none had bacteremia with Streptococcus pneumoniae, Listeria monocytogenes, nontyphoidal Salmonella, or Mycobacterium avium complex. Fungemia occurred in 1.5% of patients. The most common organisms isolated from the blood were Staphylococcus aureus (21 episodes), coagulase-negative Staphylococcus (14), Klebsiella pneumoniae (12), Enterococcus faecium (11), Pseudomonas aeruginosa (10), Enterococcus ã 2016 Elsevier B.V. All rights reserved.

faecalis (9), and Escherichia coli (7). The authors concluded that although alemtuzumab is associated with profound CD4 positive T lymphocyte depletion, it does not seem to be associated with an increased risk of bloodstream infection with pathogens that are typically seen in other disorders of CD4 cell depletion, such as acquired immunodeficiency syndrome.
A 40-year-old Caucasian man with rheumatoid arthritis

received infliximab [22] and 40 days after the 10th dose developed an acutely swollen, painful, erythematous left knee. Direct Gram stain showed Gram-negative pleomorphic coccobacilli in pairs or groups. The synovial fluid culture yielded a slow-growing Gram-negative coccobacillus, with pink pigmented mucoid colonies. The PCR product was sequenced as a strain of Roseomonas mucosa.
A 42-year-old man with a 13-year history of ankylosing spondylitis was enrolled in a randomized controlled trial of the efficacy of infliximab. After four doses he developed an orbital cellulitis. Culture of a swab from the left eye grew a flucloxacillin-sensitive Staphylococcus aureus [23].

Of 547 organ transplant recipients 65% of whom received induction therapy with alemtuzumab only, 56 developed subsequent opportunistic infections, including infections with cytomegalovirus (n ¼ 16), BK virus (12), Candida (12), invasive molds (4), Nocardia (4), mycobacteria (3), Cryptococcus neoformans (2), and HHV 6, parvovirus, Balamuthia mandrillaris, and Toxoplasma (one each) [24]. Patients who received alemtuzumab for allograft rejection were significantly more likely to develop an opportunistic infection than patients who received alemtuzumab for induction therapy only (4.5% versus 21%). Of 113 patients with chronic lymphoproliferative disorders who received alemtuzumab-based therapy. 25 had reactivation of cytomegalovirus; the only significant difference between the groups was a low serum albumin concentration in those in whom reactivation occurred [25]. In a study of 67 patients with chronic lymphocytic leukemia, 33% of those who received salvage therapy developed an infection while none of those who received consolidation therapy had a similar response [26]. Of 67 patients who were Toxoplasma IgG-positive when they were given alemtuzumab at the time of hemopoietic stem cell transplantation, and were therefore classified as being at high risk of Toxoplasma reactivation, and were covered with co-trimoxazole prophylaxis after transplantation, two developed Toxoplasma invasive disease with cerebral involvement at 2 and 4 months after transplantation [27]. Comparing these results with those of studies of other T-cell replete cohorts receiving hemopoietic stem cell transplantation, there was no significant difference in the incidence of Toxoplasma reactivation. In 477 patients who received induction with alemtuzumab for renal transplantation the incidences of subsequent fungal and tuberculous infections were 0.6% and 0.4% respectively [28].

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ã 2016 Elsevier B.V. All rights reserved.

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