Administration Of Alemtuzumab Research Articles

In‐vivo purging of the circulating clonal T‐cells with Alemtuzumab prior to autologous peripheral blood hematopoietic cell mobilization and transplantation

<i>In‐vivo</i> purging of the circulating clonal T‐cells with Alemtuzumab prior to autologous peripheral blood hematopoietic cell mobilization and transplantation

Successful alemtuzumab retreatment in progressive B-cell chronic lymphocytic leukemia: a multicenter survey in 30 patients

Although retreatment with alemtuzumab in relapsing B-cell chronic lymphocytic leukemia (CLL) may be beneficial, there has thus far been no thorough analysis available on this topic. Data were collected from 30 chemotherapy-pretreated patients with progressive CLL who had received alemtuzumab twice in consecutive, distinct therapy lines. The median dose of alemtuzumab retreatment was 402mg (range, 43-1,090mg). Retreatment with alemtuzumab induced an overall response rate of 47%. From the start of alemtuzumab retreatment, median progression-free survival (PFS) and overall survival (OS) were 6.3 and 20.0months, respectively. Response rates, PFS and OS upon alemtuzumab retreatment were correlated with response to initial alemtuzumab treatment, the time interval between the initial course of alemtuzumab and start of retreatment, and the hemoglobin concentration prior to retreatment. Reported toxicities from 24 cases included infections (50%), febrile reactions upon alemtuzumab administration (38%), exanthema (21%), and grade 4 neutropenia (13%) and thrombocytopenia (17%). We conclude that alemtuzumab retreatment represents an effective and tolerable therapeutic option for selected patients with CLL.

A Phase I Study of Escalated Dose Subcutaneous Alemtuzumab Given Weekly with Rituximab In Relapsed CLL/SLL.

Abstract Abstract 1381 Alemtuzumab is an anti-CD52 antibody originally approved for intravenous administration three times per week to CLL patients refractory to fludarabine and previously exposed to alkylators. Since that time subcutaneous administration three times per week has become widespread because of its reduced infusional toxicity and recently demonstrated equivalent efficacy. In this study we assessed the tolerability, efficacy and pharmacokinetics of administering alemtuzumab subcutaneously weekly at up to 90 mg per dose following an initial 3+3 dose escalation (see table); we further added weekly rituximab in hopes of enhancing activity in lymph nodes. Treatment was administered in up to two eight week blocks with response evaluation between; the second 8 week block continued the dose and schedule used in weeks 5–8. No more than 45 mg was given per subcutaneous injection site. 28 patients were enrolled on this study between 7/2006 and 1/2010. The median age was 62 (range 47–76), and 75% were male. The median time from diagnosis to starting study therapy was 94 mos (14-236 mos). A majority of patients (82%) had Rai stage 3–4 disease and the median number of prior therapies was 4 (1-11). 20/28 patients (71%) had high risk deletions of 17p or 11q. 13/16 (81%) had unmutated IGVH, and 14/19 (74%) were positive for ZAP70. Early study withdrawals occurred due to pre-existing and persistent thrombocytopenia requiring study therapy to be held (n=2), persistent fever attributed to alemtuzumab (n=1), PML in retrospect present prior to study entry (n=1), and a DLT (grade 3 rituximab reaction) which was observed on dose level 2 prior to dose escalation of alemtuzumab. Overall, therapy was well tolerated; injection site reactions were minimal, primarily grade 1 (n=11) with only two grade 2 events. Other toxicities were as expected with alemtuzumab in this patient population, including grade 3–4 neutropenia (54%), grade 3–4 thrombocytopenia (57%), and single cases each of grade 3 rash, AIHA, pulmonary embolism, MRSA bacteremia, diverticular abscess, pulmonary Cryptococcus, EBV lymphoma and metastatic colon cancer. The ORR by NCI-WG criteria at wk 8 was 61% (95% CI 42–76%), with CR rate 11% (95% CI 4–27%). Two of 14 patients who completed a second eight week cycle improved their response (one PR from SD, and one CR from PR). A planned endpoint of this study was to compare lymph node staging by CT to PE, and we found that using CT scans to evaluate nodal response at 8 weeks decreased the ORR rate to 14% (95% CI 6–31%), with no CRs. Bone marrow was completely cleared of disease by 8 weeks in 8 patients and by 16 weeks in an additional 4 patients. The median PFS for the entire population was 13 months with a median follow-up of 9 months in patients who have not progressed. 10 patients have died, 5 of disease, 3 of second malignancies, 1 of PML and 1 of SCT complications. The median OS from study entry is 47 months, with 10 patients having undergone subsequent SCT. Following initiation of therapy we observed a &gt;1,700X decrease in the median CD19+5+ cell count in peripheral blood by the start of week 3. Similar rapid depletion of all T and NK cell subsets was also observed, with first signs of recovery at week 28, and more definite recovery at week 40. Preliminary pharmacokinetic data demonstrated lower maximum levels of rituximab (p=0.06) and alemtuzumab (p=0.05) in patients with &gt;80% bone marrow replacement by CLL but not in those with bulky lymphadenopathy. A trend toward higher alemtuzumab levels was observed in those patients with complete bone marrow clearance (p=0.1) but not in those with objective response. In conclusion, we found that administration of alemtuzumab at 90 mg subcutaneously weekly in combination with rituximab was well-tolerated, convenient and resulted in sustained adequate blood levels of both drugs in most patients. Response rates were high although in this relapsed refractory CLL population, abdominal lymphadenopathy was common, resulting in a decreased response rate when CT scans were included in staging. PFS and OS were favorable for this novel combination regimen and many patients went on to SCT. Disclosures: Brown: Genzyme: Research Funding; Celgene: Consultancy, Research Funding; Calistoga: Consultancy; Genentech: Consultancy. Off Label Use: alternative schedule of alemtuzumab. Kipps:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding; Memgen: Research Funding; Igenica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Research Funding; Abbott Laboratories: Research Funding.

Isolated left-sided pulmonary edema caused by alemtuzumab (Campath®) during kidney transplantation

Alemtuzumab is a novel anti-CD-52 monoclonal antibody for immunosuppression. Although cost effective and efficacious, alemtuzumab is not without risk. Interestingly, intraoperative complications caused by alemtuzumab have rarely been reported. We describe a case of intraoperative pulmonary edema following administration of alemtuzumab. A 22-year-old man underwent kidney transplantation and received alemtuzumab intraoperatively. To provide better surgical exposure for transplantation, the operation table was tilted to the right. At the end of 3.5-h uneventful procedure, a sudden oxygen desaturation was noted after the bed was flattened. The postoperative chest X-ray showed opacification of the entire left lung field. After 4 days of bi-level positive airway pressure treatment, the lung field was cleared. This case is unique in that pulmonary edema developed during surgery after administration of alemtuzumab, and that the edema developed only in the nondependent lung. Transplant anesthesiologists should be aware of the risk of this complication with these novel anti-CD-52 monoclonal antibodies.

The number of circulating recent thymic emigrants is severely reduced 1 year after a single dose of alemtuzumab in renal transplant recipients

To better understand the kinetics of the delayed reconstitution of peripheral CD4+ T-cells after depletion with a single administration of alemtuzumab (AL) for renal transplantation, we evaluated in these patients the percentage and absolute number of recent thymic emigrants (RTEs) CD4+ T cells, together with naive and memory subsets, defined by the analysis of CD31, CD45RA and CCR7 expression, and compared with patients treated with a nondepleting protocol based on basiliximab, and with healthy controls. In AL-treated patients, the number of circulating CD4+ T cells was greatly reduced 1 year after the infusion (P < 0.01), but the proportions of central memory, effector memory and terminally differentiated effector memory subsets among CD4+ cells were significantly increased. On the contrary, the proportion and the absolute number of naïve CD4+ T cells, although progressively increasing with time, were severely reduced. In particular, the absolute number of RTEs had only very slight increase with time (P = 0.049) and was dramatically low 1 year after the therapy (P < 0.01 vs. healthy controls; P < 0.05 vs. basiliximab-treated transplant recipients). These data suggest that a prolonged defective thymic output after AL therapy in renal transplant recipients is one of the main causes of the persistent CD4+ T-cell lymphopenia observed in these patients.

Immune reconstitution syndrome and the thyroid

Reconstitution Graves' disease occurs in three settings. First, bone marrow transplantation from a donor with Graves' disease may cause this disease to appear in the recipient, as a result of adoptive immunity, although disordered immunoregulation secondary to graft-versus-host disease may also play a role. Second, alemtuzumab treatment for multiple sclerosis leads to the development of Graves' disease in up to a third of patients during the phase of naive T-cell expansion, which follows therapeutic lymphocyte depletion. Other reconstitution autoimmune phenomena, including immune thrombocytopaenic purpura, are also recognised after alemtuzumab administration. Finally, reconstitution Graves' disease may occur during a similar phase of CD4(+) T-cell expansion, which follows highly active antiretroviral therapy for human immunodeficiency virus infection. Again, this complication is part of a broader spectrum of immunoregulatory disturbances, which can arise after immune reconstitution. The mechanisms responsible for reconstitution Graves' disease are at present unclear, but may include a relative bias towards a Th2-mediated immune response and reduced competition for autoreactive lymphocytes to expand during the time when recovery from lymphopenia commences.

Preliminary Results of Bilateral Arm Transplantation

Preliminary Results of Bilateral Arm Transplantation

Subcutaneous alemtuzumab plus cyclosporine for the treatment of aplastic anemia

Aplastic anemia (AA) is most frequently due to autoimmune attack on its own stem cells. Alemtuzumab is a monoclonal antibody which recognizes the CD52 antigen on the surface of T and B cells. It has proved useful in autoimmune diseases, lymphoproliferative conditions, and graft versus host disease. Based on its immunosuppressive properties, we treated 14 AA patients with alemtuzumab. Median age was 23 years. Ten milligrams of alemtuzumab were injected subcutaneously each day for five consecutive days. Cyclosporine A was also administered orally at a dose of 2 mg/kg every 12 h for 3 months, and then gradually tapered. Response to alemtuzumab was followed for a median of 20 months. There were eight responses (57.1%), two complete and six partial. Whereas six (42.8%) patients were non-responders. Median complete blood count values on alemtuzumab responders were Hb 13.1 mg/dL, absolute neutrophil count 2.4 x 10(9)/L, and platelets 97.5 x 10(9)/L. A good response was produced in 57% of AA patients with the administration of alemtuzumab, who lacked a stem cell donor.

Favorable outcomes with alemtuzumab-conditioned unrelated donor stem cell transplantation in adults with high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in first complete remission

Approximately 40% of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia achieve long-term survival following unrelated donor hematopoietic stem cell transplantation in first complete remission but severe graft-versus-host disease remains a problem affecting survival. Although T-cell depletion abrogates graft-versus-host disease, the impact on disease-free survival in acute lymphoblastic leukemia is not known. We analyzed the outcome of 48 adults (median age 26 years) with high-risk, Philadelphia-chromosome-negative acute lymphoblastic leukemia undergoing T-cell depleted unrelated donor-hematopoietic stem cell transplantation (67% 10 of 10 loci matched) in first complete remission reported to the British Society of Blood and Marrow Transplantation Registry from 1993 to 2005. T-cell depletion was carried out by in vivo alemtuzumab administration. Additional, ex vivo T-cell depletion was performed in 21% of patients. Overall survival, disease-free survival and non-relapse mortality rates at 5 years were 61% (95% CI 46-75), 59% (95% CI 45-74) and 13% (95% CI 3-25), respectively. The incidences of grades II-IV and III-IV acute graft-versus-host disease were 27% (95% CI 16-44) and 10% (95% CI 4-25), respectively. The actuarial estimate of extensive chronic graft-versus-host disease at 5 years was 22% (95%CI 13-38). High-risk cytogenetics at diagnosis was associated with a lower 5-year overall survival (47% (95% CI 27-71) vs. 68% (95% CI 44-84), p=0.045). T-cell depleted hematopoietic stem cell transplantation from unrelated donors can result in good overall survival and low non-relapse mortality for adults with high-risk acute lymphoblastic leukemia in first complete remission and merits prospective evaluation.

Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia

The consensus views of an expert roundtable meeting are presented as updated management guidelines for using alemtuzumab in chronic lymphocytic leukemia. Since the publication of previous management guidelines in 2004, clinical experience with alemtuzumab has grown significantly, especially regarding its efficacy and safety, management of cytomegalovirus (CMV) reactivation, identification of patient subgroups likely to benefit from alemtuzumab therapy and subcutaneous administration of alemtuzumab. The updated recommendations include (1) alemtuzumab monotherapy can be safely used as first-line therapy; (2) suitable patient subgroups for alemtuzumab therapy include elderly patients, patients with 17p deletion, patients with refractory autoimmune cytopenias and patients with profound pancytopenia at baseline due to heavily infiltrated bone marrow; (3) alemtuzumab treatment should be continued for 12 weeks (36 doses) whenever possible, and bone marrow examination may be considered at week 12 to evaluate response; (4) monitoring CMV reactivation by weekly PCR is mandated during therapy; when CMV reactivation becomes symptomatic or viremia increases, alemtuzumab therapy should be interrupted and anti-CMV therapy started; (5) subcutaneous administration is safe, easy to perform and appears equally effective compared with intravenous infusion and (6) our strong recommendation is that alemtuzumab combination therapy and consolidation therapy shall not be used outside carefully controlled clinical studies.

Fludarabine followed by alemtuzumab consolidation for previously untreated chronic lymphocytic leukemia: final report of Cancer and Leukemia Group B study 19901

The humanized anti-CD52 monoclonal antibody alemtuzumab is an effective therapy for chronic lymphocytic leukemia (CLL). We examined the impact of alemtuzumab treatment after initial fludarabine treatment for feasibility and safety. Patients (N = 85) with previously untreated symptomatic CLL received fludarabine (25 mg/m2/day) for 5 days every 4 weeks for four cycles followed by 2 months of observation. Patients with stable disease or better response then received alemtuzumab 30 mg three times weekly for 6 weeks either intravenously (IV; cohort 1; N = 39) or subcutaneously (SC; cohort 2; N = 20). Of the 85 evaluable patients enrolled on our study, four (5%) attained a complete response (CR) and 43 (51%) attained a partial response after fludarabine induction for an overall response rate (ORR) of 55%. Thirty-nine patients received IV alemtuzumab for consolidation with improvement in CR to 27% and ORR to 73%. Twenty patients received SC alemtuzumab consolidation with improvement in CR to 17% and ORR to 69%. Toxicity from IV alemtuzumab included infusion-related reactions and infection. Mild local inflammation was common from SC alemtuzumab but there were virtually no systemic side effects. Nine of 59 (15%) patients had cytomegalovirus (CMV) infections; one patient died. The administration of alemtuzumab as consolidation therapy following an abbreviated fludarabine induction is feasible but requires close monitoring for CMV infection and other infectious events.

Islet Transplantation with Alemtuzumab Induction and Calcineurin-Free Maintenance Immunosuppression Results in Improved Short- and Long-Term Outcomes

Only a minority of islet transplant recipients maintain insulin independence at 5 years under the Edmonton protocol of immunosuppression. New immunosuppressive strategies are required to improve long-term outcomes. Three subjects with unstable type 1 diabetes mellitus underwent islet transplantation with alemtuzumab induction and sirolimus-tacrolimus maintenance for 3 months and then sirolimus-mycophenolic acid maintenance thereafter. Follow-up was more than 2 years. Comparison was with 16 historical subjects transplanted under the Miami version of the Edmonton protocol. Insulin independence was achieved in 2 of 3 alemtuzumab and 14 of 16 historical subjects. Those who did not achieve insulin independence only received a single islet infusion. Insulin-independence rates remained unchanged in the alemtuzumab group, but decreased from 14 of 16 (88%) to 6 of 16 (38%) in the historical group over 2 years. Insulin requirements increased in the historical group while remaining stable in the alemtuzumab group. Comparison of functional measures at 3 months suggested better engraftment with alemtuzumab (P=NS). Further comparison of alemtuzumab versus historical groups, up to 24 months, demonstrated significantly better: Mixed meal stimulation index (24 months, 1.0+/-0.08 [n=3] vs. 0.5+/-0.06 pmol/mL [n=6], P<0.01), mixed meal peak C-peptide (24 months, 5.0+/-0.5 [n=3] vs. 3.1+/-0.3 nmol/mL [n=6], P<0.05), HbA1c (24 months, 5.4+/-0.15 [n=3] vs. 6.3+/-0.12 pmol/mL [n=10], P<0.01). Administration of alemtuzumab was well tolerated. There was no increased incidence of infections in alemtuzumab subjects despite profound, prolonged lymphocyte depletion. Islet transplantation with alemtuzumab induction was well tolerated and resulted in improved short- and long-term outcomes. Further investigation is underway for validation.

The Use of Low-Dose Alemtuzumab as Single Agent in the Treatment of Complication in Advanced Chronic Lymphocytic Leukaemia

There are some report in literature about the use of Alemtuzumab in patients affected by advanced B-cell chronic lymphocytic leukaemia who developed severe transfusion-dependent autoimmune haemolytic anaemia (AIHA) resistant to conventional therapy or cutis involvement. We report the use of low-dose Alemtuzumab in 4 AIHA patients and in 1 case of eyelid leukaemia cutis. Alemtuzumab was given subcutaneously at 10 mg three times weekly for 30 administrations (10 weeks). Treatment was stopped for progression disease, grade IV thrombocytopenia and/or infections or Cytomegalovirus (CMV) reactivation. Prophylaxis consiste on co-trimoxazole and aciclovir from the start of the treatment until 2 months after the end of treatment. Peripheral blood count, biochemical screening, antigenemia and CMV DNA analysis, reticulocyte count were conducted weekly. DAT and IAT were studied every two weeks during the treatment. Patient with eyelid leukaemia cutis underwent to histological examination before and after the end of treatment. AIHA response, was defined as the independence from RBC transfusion and a concomitant > 2.0 g/dl rise in Hb concentration. Four male patients developed DATpositive AIHA at a median of 44.5 months from the B-CLL diagnosis. Previous treatment for B-CLL, stage and haemoglobin (Hb) values at Alemtuzumab administration are shown in table 1. Three patients underwent to RBCu transfusion before Alemtuzumab treatment, and one also during the treatment (2RBCu). The median haemoglobin value at first Alemtuzumab administration was 8.25 gr/dl. (table1) Two patients showed CMV reactivation at 5th and 6th week of therapy and were treated with oral ganciclovir for 14 and 21 days respectively. AIHA response was reached at median of 7 weeks of Alemtuzumab therapy in all patients while the median duration time of response to Alemtuzumab therapy was 10 months. Two patients underwent to further treatment for DAT negative progressive disease after 9 and 10 months from the end of Alemtuzumab therapy respectively, one patients was treated after 26 months for AIHA relapse, while the last patients even if showed AIHA remission is currently at 6th week of Alemtuzumab treatment (Hb 8g/dl). At the end of Alemtuzumab administrations the median Hb concentration was 12.7 g/dl regarding clinical responses, the patient no.1 obtained SD, the other 2 PR. Patient with leukemia cutis (LC) showed a constant reduction of eyelid involvement until clinical resolution after 240 mg of Alemtuzumab. Now a day, a manteinance therapy is ongoing with Alemtuzumab 30 mg monthly maintaining complete remission of eyelid localization and partial remission of CLL 10 months after induction therapy. In All patients the therapy has been well tolerated, with mild haematological and extra-haematological side effects (grade I). No episode of febrile neutropenia or bacterial/fungal infection occurred during the treatment. Our data confirmed the literature data about the use of Alemtuzumab, even if with low-dose, as salvage treatment for transfusion-dependent and resistant AIHA in pre-treated B-CLL patients and show a new indication for LC involvement.Table 1: Patient's clinical characteristicsAge/SexBinet/Rai StageMonths from B-CLL diagnosis and AIHA/LCPrevious treatment for B-CLL (number of cycles)Biological ParameterMonths between last B-CLL therapy-AIHA/LCHb at baseline Alemtuzumab treatment (gr/dl)DAT/IAT68/MC/IV9CHOP(6), CVP(3)Unmutated IgVH Zap-70 + CD38 + Del17p19.4DAT 4+ (IgG 4+) IAT 4+53/MC/IV31Chl/Pdn(6), FC(6), Pdn(6), Ig, SplenectomyMutated Zap-70 − Normal karyotipe37.1DAT 2+ (IgG 1+) IAT 2+46/MC/III58CHOP(8), HD-CTX, aPBSCTUnmutated IgVH Normal Kariotype3810.1DAT 4+ (IgG 3+; C3d 1+) IAT −56/MC/IV64FC, chl, fludarabine, RIC transplantUnmutated IgVH Zap-70 + CD38 −Del 17p, Del 13q284.9DAT 4+ (IgG 4+) IAT 2+61/MB/II108Fludarabine, CHOP, INFa, chl/pdnMutated IgVH Zap-70 + CD38 + Del 17p, +122414.3NegativeM: male, Chl: chlorambucil, Pdn: prednisone, FC: fludarabine+cyclophosphamide, Ig: intravenous immunoglobulin, HD-CTX: high dose-cyclophosphamide, aPBSCT: autologous peripheral blood stem cell transplantation.

Alemtuzumab Administered by Subcutaneous Route Is Less Effective Than Intravenous Route for First Line Therapy of T-Cell Prolymphocytic Leukaemia: Results of a Pilot Study (UKCLL05)

T-cell prolymphocytic leukaemia (T-PLL) is a rare aggressive post thymic lymphoid disorder with distinctive clinical and pathological features. It is resistant to conventional chemotherapy and has a short median survival of 7 months. Intravenous (IV) alemtuzumab is an effective and well tolerated therapy for this disease, inducing remission in 76% of patients in the relapsed and refractory setting and increasing median survival to 24 months in responders. The aim of this study was to determine the efficacy of subcutaneous (SC) administration of alemtuzumab in previously untreated T-PLL patients. After an initial week of dose escalation, patients were treated with a dose of 30 mg 3 times weekly. Patients could be switched to the IV route if they had local side effects or showed a lack of response. Nine patients were enrolled. Male: female ratio was 2:1; median age was 61 years. All cases were centrally reviewed and confirmed to have a diagnosis of T-PLL. Eight had an immunophenotype typical of T-PLL (CD2, CD3, CD4, CD5 and CD 7 positive). One patient was unusually CD7 negative and also did not have an abnormality of chromosome 14. Seven had a complex karyotype and 8 had chromosome 14 abnormalities. Patients were treated on trial for a median of 7 weeks (range 3–13 weeks); 55% required a change to IV treatment due to a lack of response. This resulted in an increase in overall response (OR) from 33% (1 complete response [CR], 2 partial response [PR]) to 44 %.(2 CR, 2 PR). Five patients required addition of pentostatin to alemtuzumab at a dose of 4 mg/m2 IV weekly to augment response. This increased OR to 77% (1 additional CR and 2 PR). 5 patients had haemopoietic progenitor cell transplants (HPCT) as consolidation; 1 was autologous and 4 were allogeneic. Median overall survival was 20 months (range 1–26 months) and disease free survival was 12 months (range 0–20 months). The treatment was well tolerated; however 2 patients had skin reactions to the SC injections. One patient required treatment for CMV reactivation and 2 patients had grade 4 haematologic toxicity which was related to disease and not treatment. Four patients remain alive and well in CR with a follow up of between 12 and 23 months, of whom 3 had allogeneic HPCT. The study was terminated early as a data safety monitoring review felt that SC treatment was not efficacious and patients should not be offered SC treatment. This pilot study suggests that the SC route of administration of alemtuzumab is not as effective as IV in the treatment of T-PLL; our series of 16 patients receiving first line therapy with IV alemtuzumab has shown an OR of 94% with 88% CR. It is therefore advisable that IV treatment should be used. Pentostatin is an effective agent to augment response. Allogeneic HPCT should be used as consolidation therapy when possible.

Economic Analysis of Alemtuzumab in Fludarabine-Refractory and Relapsed Chronic Lymphocytic Leukemia in Canada

Background: Alemtuzumab (ALEM), a humanized antibody that recognizes the CD52 antigen, is indicated for the treatment of B-cell chronic lymphocytic leukemia (CLL) in patients who have been treated with alkylating agent and who had failed fludarabine therapy. The objective of this economic analysis was to determine the incremental cost-effectiveness of ALEM in patients with fludarabine-refractory and relapsed CLL from the perspective of a publicly funded health care system in Canada. ALEM was compared to accepted treatments for this patient population.Methods: A two-year time horizon was used. Effectiveness and adverse event information was obtained from an extensive literature review process. Resource utilization was based on guidelines, literature and expert opinion. Costs were obtained from provincial sources and presented in 2008 Canadian dollars. Only direct medical costs were considered. A number of comparators were used to represent standard treatment: salvage therapy, which included a variety of literature-based treatment options for fludarabine-refractory patients, fludarabine+cyclophosphamide (FC), flud arabine+cyclophosphamide+rituximab (FCR), and best supportive care (BSC). BSC included the palliative costs for caring for individuals previously treated with FC.Results: Mean survival for ALEM was 20.89 months (1.74 years), salvage therapy 16.32 months (1.36 years), FC 17.44 months (1.45 years), FCR 20.06 months (1.67 years). The incremental cost-effectiveness ratio (ICER) for the base case-ALEM vs. salvage therapy was Canadian $52,021/life year gained (LYG); ALEM vs. FC $68,165/LYG; ALEM vs. FCR $20,886/LYG. For ALEM vs. BSC, there was increased survival and cost savings with ALEM. Base case ICERs were sensitive to four variables: treatment duration of FC; treatment duration of FCR; treatment duration of ALEM; and additional survival due to rituximab for FCR patients compared to FC. Sensitivity analyses of the remaining variables showed minimal change to the base case ICERs. These variables were: ALEM administration (proportion of intravenous to subcutaneous); cytomegalovirus (CMV) complication rate for ALEM; discount rate; neutropenia and thrombocytopenia rates for ALEM; and neutropenia and thrombocytopenia rates for FCR.Conclusion: The results show that ALEM has a favourable ICER and provided good economic value for patients with fludarabine-refractory and relapsed CLL when compared to salvage therapy, FC and FCR. ALEM was found to be dominant over BSC.

Alemtuzumab (Campath 1-H) in Patients with HTLV-1 Associated Adult T-Cell Leukemia/Lymphoma.

This study investigated the antitumor activity of alemtuzumab (Campath 1-H) with regard to response rate, time to progression, overall survival and adverse events in patients with human T-cell lymphotrophic virus-1 (HTLV-1)-associated adult T-cell leukemia/ lymphoma (ATL). In a single institution non-randomized open-label phase II trial, 24 patients with chronic (n=2), acute (n=13) and lymphomatous (n=9) ATL were treated with intravenous alemtuzumab 30 mg three times weekly for a maximum of 12 weeks. Patients received antimicrobial prophylaxis from the initiation of treatment continuing for a minimum of 2 months after treatment, or until the peripheral blood CD4+ T-cells were ≥ 200 cells/μL. Tumor responses were assessed at the end of 4, 8, and 12 weeks. All patients were evaluable for toxicity and one patient was not evaluable for response due to early withdrawal. The overall objective response rate was 10 out of 23 patients (95% CI: 23 to 66%). Based on the 10 patients who responded, median time to response was 1.1 months (range, 1.0 to 3.0 months). The median response duration was 3.9 months. Median progression free survival of patients with chronic subtype was 2.0 months, 1.0 month for lymphomatous subtype and 2.4 months for acute subtype. Median time to treatment failure was 1.7 months. At data cut-off, (April 24, 2008), 6 (25%) patients were alive. Overall median survival was 5.9 months. Median overall survival by subtypes was 3.9 months for chronic, 4.8 months for lymphomatous, and 7.6 months for acute. Median survival for all responders from on study date was 8.4 months. Clinical benefit was observed both in responders and in patients with stable disease. The most common adverse events were related to infusion and were generally grade 1 or 2, occurring mainly in the first week of alemtuzumab administration. All patients developed CMV antigenemia; however, only 3 (12.5%) were symptomatic. Grade 3 or 4 infections were reported in 6 (25%) patients. Median time to recovery of ALC to >200 cells/μL was 1.9 months.

The Effect of In Vivo T Cell Depletion with Alemtuzumab on Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia

Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation is increasingly considered for patients with chronic lymphocytic leukemia (CLL). To investigate the impact of in vivo T cell depletion with alemtuzumab on the incidence of graft-versus-host disease (GVHD), nonrelapse mortality (NRM), progression-free survival (PFS), and overall survival (OS), we retrospectively analyzed the outcomes of 62 consecutive CLL patients conditioned with fludarabine and melphalan at 4 institutions. For GVHD prophylaxis, 41 patients (cohort 1) received alemtuzumab and cyclosporin; and 21 patients (cohort 2) received cyclosporin plus methotrexate or mycophenolate. Donors were 50 siblings and 12 unrelated volunteers. Twenty-two (36%) patients received donor lymphocyte infusions (DLI), 20 (49%) from cohort 1 and 2 (10%) from cohort 2 (P=.002). Grade III-IV acute GVHD (aGVHD) was observed in 20% and 38% of patients from cohorts 1 and 2, respectively (P=.14). Extensive chronic GVHD (cGVHD) was observed in 10% and 48% of patients from cohorts 1 and 2, respectively (P=.03). There was a trend toward a higher viral infection rate in cohort 1 compared to cohort 2 (68% versus 43%, P=.062), but the incidence of cytomegalovirus (CMV) reactivation was not significantly different. The 3-year OS, PFS, NRM, and relapse rates were 65%, 39%, 28%, and 32%, respectively, for cohort 1; and 57%, 47%, 34%, and 20%, respectively, for cohort 2 (P=.629, P=.361, P=.735, and P=0.112, respectively). In conclusion, both methods of GVHD prophylaxis were equivalent in terms of survival. The administration of alemtuzumab led to reduced cGVHD, possibly improving quality of life.

Alemtuzumab Induction and Steroid-Free Maintenance Immunosuppression in Pancreas Transplantation

Alemtuzumab is a humanized anti-CD52 antibody that depletes lymphocytes and has been increasingly used as induction agent in transplantation. The impact of alemtuzumab induction immunosuppression in pancreas transplantation was evaluated, with particular reference to steroid avoidance in maintenance. A total of 100 patients who received 102 pancreas transplants (83 simultaneous kidney-pancreas [SPK], 15 pancreas after kidney transplantation [PAK] and 4 pancreas transplant alone [PTA]) were included. All patients received two doses of 30-mg alemtuzumab i.v. with tacrolimus (trough level 8-12 ng/mL) and mycophenolate mofetil (MMF,1g/day) with no maintenance steroids. This analysis included 62 male and 38 female recipients, with mean (+/-SD) age of 42 (+/-7.6) years. Median follow-up was 17 months (range 8-41 months). One-year patient, pancreas and kidney graft survival (actuarial) was 97%, 89% and 94%, respectively. Overall incidence of rejection was 25%. Side effects of alemtuzumab administration included thrombocytopenia (14%), pulmonary edema (2%) and rash (1%). Twenty-five percent required reoperations (12% for bleeding). Infectious complications included Cytomegalovirus (CMV,6.8%) BK viruria (3.8%), fungal infections (4%), primary varicella (1%) and posttransplant lymphoproliferative disorders (PTLD,1%). Eighty-three percent did not require any steroids posttransplant. These results indicate that alemtuzumab is safe and enables pancreas transplantation to be carried out without maintenance steroids in 83% of cases and acceptable rejection rate.

Morbidity and mortality in rheumatoid arthritis patients with prolonged therapy‐induced lymphopenia: Twelve‐year outcomes

To assess immunologically relevant outcomes in a cohort of rheumatoid arthritis (RA) patients with prolonged therapy-induced lymphopenia. Morbidity (infection or malignancy) and mortality were assessed in 53 RA patients who were treated with the lymphocytotoxic monoclonal antibody alemtuzumab between 1991 and 1994. Data were obtained by interview, medical record review, and Office for National Statistics mortality monitoring. Lymphocyte subsets were enumerated by flow cytometry. A retrospective, matched-cohort study of mortality was performed with 102 control subjects selected from the European League Against Rheumatism database of patients with rheumatic disorders. Lymphopenia persisted in the patients: median CD3+CD4+, CD3+CD8+, CD19+, and CD56+ lymphocyte counts measured at a median followup of 11.8 years from the first administration of alemtuzumab were 0.50 x 10(9)/liter, 0.26 x 10(9)/liter, 0.11 x 10(9)/liter, and 0.09 x 10(9)/liter, respectively. Twenty-seven of 51 cases and 46 of 101 controls with available data had died, yielding a mortality rate ratio of 1.20 (95% confidence interval 0.72-1.98). Causes of death were similar to those that would be expected in a hospital-based RA cohort. No opportunistic infections were noted, and only 3 infections were documented following 36 elective orthopedic procedures. Despite continued lymphopenia 11.8 years after therapy, our patient cohort did not exhibit excess mortality or unusual infection-related morbidity, and surgery was well tolerated. These data should be reassuring for clinicians and patients who are considering lymphocytotoxic or other immunomodulatory therapy for RA.

Subcutaneous Administration of Alemtuzumab in Simultaneous Pancreas-Kidney Transplantation

Alemtuzumab (MabCampath, Campath-1H) is a potent lymphocyte-depleting monoclonal antibody increasingly used at induction in solid organ transplantation. Previously, it had been given by intravenous infusion; such administration is associated with a first-dose cytokine release syndrome characterized by fever and hypotension. Subcutaneous administration of alemtuzumab avoids this first-dose reaction while achieving a similar concentration to intravenous administration. The avoidance of infusion-associated hypotension is particularly important in pancreas transplantation where venous thrombosis is a major problem. We therefore treated 21 recipients of combined pancreas and kidney transplants with two 30-mg doses of alemtuzumab administered subcutaneously on days 0 and 1. No patient suffered a first-dose reaction. Lymphocyte depletion after subcutaneous alemtuzumab was profound and comparable to that seen in a group of renal transplant recipients who had received intravenous alemtuzumab. Subcutaneous alemtuzumab was associated with similar rates of acute rejection (14% at 1 year), patient survival (100%), and pancreas and kidney graft survival (95% and 100%, respectively) to those observed in centers using intravenous alemtuzumab in simultaneous pancreas kidney transplantation. There was no excess incidence of adverse events. We therefore recommend this route of administration to all transplant centers using alemtuzumab.