Courses Of Alemtuzumab Research Articles

ACTRIMS 2019 – Posters

Background: In the 2-year (y) CARE-MS II phase 3 trial (NCT00548405), alemtuzumab (12 mg/day; baseline: 5 consecutive days; 12 months later: 3 consecutive days) significantly improved clinical and MRI outcomes versus SC IFNB-1a in RRMS patients with inadequate response to prior therapy. In a 4-y extension (NCT00930553), patients could receive additional courses of alemtuzumab (12 mg/day on 3 consecutive days; ⩾12 months apart) as needed for disease activity or receive other disease-modifying therapy (DMT) per investigator’s discretion. Efficacy on clinical/MRI outcomes was maintained through Y6, with 50% receiving no additional alemtuzumab or other DMTs in the extension. Following the initial 4-y extension, patients could continue in TOPAZ (NCT02255656), an additional 5-y extension study, for further evaluation. Objectives: To evaluate 8-y efficacy and safety outcomes in alemtuzumab-treated CARE-MS II patients. Methods: At the investigator’s discretion, patients in TOPAZ can receive additional as-needed alemtuzumab (⩾12 months apart; no criteria) or receive other DMT (at any time). Results: Of 435 alemtuzumab-treated CARE-MS II patients, 300 (69%) completed 8-y total follow-up; 44% received neither additional courses of alemtuzumab nor another DMT. Of 393 patients who entered the extension, 200 (51%) received ⩾3 courses of alemtuzumab (3 courses, 29%; 4 courses, 16%; 5 courses, 3%, >5 courses, 3%). Course 3 was given in Y3 (20%), Y4 (11%), Y5 (9%), Y6 (5%), Y7 (2%), and Y8 (3%). In Y8, the annualized relapse rate was 0.18, with 85% of patients relapse-free. Compared with core study baseline, 70% of patients had stable/improved EDSS scores at Y8, and mean change in EDSS score was 0.17. Over 8 y, 64% of patients were free of 6-month confirmed disability worsening, and 47% had 6-month confirmed disability improvement. In Y8, 58% of patients achieved no evidence of disease activity, and 70% were free of MRI disease activity. Median percent cumulative brain volume loss (BVL) from baseline through Y8 was −1.06%; median annual BVL from Y3 to Y8 was ⩽−0.19%. The safety profile in Y8 was consistent with the previous years; incidence of AEs, infections, and thyroid AEs continued to decline. No new cases of immune thrombocytopenia or nephropathy were seen. Conclusion: Alemtuzumab efficacy on clinical, MRI, and BVL outcomes was maintained over 8 y, with 44% of CARE-MS II patients receiving no additional treatment. Safety was consistent and manageable through Y8.

Immune thrombocytopenia in alemtuzumab-treated MS patients: Incidence, detection, and management

Background: Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk. Objective: To examine ITP incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials. Methods: CAMMS223 and Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion. Results: Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 [2.0%]; alemtuzumab 24 mg, 9 [3.3%]) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials. Conclusion: Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.

PACTRIMS 2018

Background: In CARE-MS II (NCT00548405), 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months [M] later: 3 days) significantly improved clinical/MRI outcomes versus SC IFNB-1a over 2 years (y) in RRMS patients with inadequate response to prior therapy. Efficacy was maintained in a 4-y extension (NCT00930553), wherein patients could receive additional alemtuzumab (12 mg/day; 3 days; ⩾12M apart) as needed for disease activity or other disease-modifying therapy (DMT). Patients could continue in an additional 5-y extension (TOPAZ; NCT02255656). Aims: To evaluate 8-y efficacy/safety of alemtuzumab in CARE-MS II patients. Methods: At investigator’s discretion, patients in TOPAZ can receive as-needed additional alemtuzumab (⩾12M apart; no criteria) or other DMT (any time). Results: 300/435 (69%) patients completed TOPAZ Y2 (Y8 after initiating alemtuzumab); 44% received neither additional alemtuzumab nor another DMT. At Y8, annualised relapse rate was 0.18, 85% were relapse-free, 70% had stable/improved EDSS versus baseline, and mean EDSS change was 0.17. Through Y8, 64% were free of 6-month confirmed disability worsening, and 47% achieved 6-month confirmed disability improvement. In Y8, 58% achieved no evidence of disease activity, and 70% were free of MRI disease activity. Median percent brain volume loss (BVL) from baseline through Y8 was –1.06%; BVL was –0.19% or less annually in Y3–8. Safety remained consistent through Y8, with no new immune thrombocytopenia or nephropathy cases. Conclusion: Efficacy of alemtuzumab on clinical, MRI, and BVL outcomes was maintained through Y8 in absence of continuous treatment in CARE-MS II patients, with a consistent and manageable safety profile.

LACTRIMS 2018

Background: In CARE-MS II (NCT00548405), alemtuzumab (two courses; 12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis (RRMS) patients with inadequate response to prior therapy. In a 4-year extension (NCT00930553), patients could receive additional alemtuzumab courses (12 mg/day on 3 days; at least 12 months apart) as needed for disease activity or receive another disease-modifying therapy (DMT; investigator discretion); efficacy was maintained with 50% receiving no additional alemtuzumab or DMT through Year 6. Following this extension, patients could continue in TOPAZ (NCT02255656), an additional 5-year extension. Objectives: Evaluate alemtuzumab efficacy/safety through Year 8 in CARE-MS II patients. Methods: In TOPAZ, patients can receive as-needed alemtuzumab (at least 12 months apart) or receive another DMT. Results: 300/435 (69%) patients completed TOPAZ Year 2 (Year 8 post-alemtuzumab); 44% received neither additional alemtuzumab nor another DMT. In Year 8, annualized relapse rate was 0.18; 85% were relapse-free. From baseline through Year 8, 70% had stable/improved EDSS, mean change in EDSS was +0.17, 64% were free from 6-month confirmed disability worsening, and 47% achieved 6-month confirmed disability improvement. In Year 8, 70% were free of magnetic resonance imaging (MRI) disease activity; 58% achieved no evidence of disease activity. Median percent cumulative brain volume loss from baseline through Year 8 was −1.06%. Safety remained consistent through Year 8. Conclusion: Alemtuzumab efficacy and safety were maintained through Year 8 in the absence of continuous treatment, with 69% of patients completing Year 8 post-alemtuzumab and 44% receiving no additional treatment after the initial two courses.

Infection risk with alemtuzumab decreases over time: pooled analysis of 6-year data from the CAMMS223, CARE-MS I, and CARE-MS II studies and the CAMMS03409 extension study

Background: Reduced MS disease activity with alemtuzumab versus subcutaneous interferon beta-1a (SC IFNB-1a) in core phase 2/3 studies was accompanied by increased incidence of infections that were mainly nonserious and responsive to treatment. Alemtuzumab efficacy was durable over 6 years. Objective: To evaluate infections over 6 years in alemtuzumab-treated patients. Methods: Three randomized trials (CAMMS223, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I, and CARE-MS II) compared two courses of alemtuzumab 12 mg with SC IFNB-1a 44 μg in patients with active relapsing-remitting MS. An extension study (CAMMS03409) provided further evaluation and as-needed alemtuzumab retreatment. Results: Infections occurred more frequently with alemtuzumab 12 mg than SC IFNB-1a during Years 1 (58.7% vs 41.3%) and 2 (52.6% vs 37.7%), but declined for alemtuzumab-treated patients in Years 3 (46.6%), 4 (42.8%), 5 (40.9%), and 6 (38.1%). Serious infections were uncommon (1.0%–1.9% per year). Infections were predominantly (>95%) mild to moderate and included upper respiratory tract infections, urinary tract infections, and mucocutaneous herpetic infections. Prophylactic acyclovir reduced herpetic infections. Lymphocyte counts after alemtuzumab therapy did not predict infection risk. Conclusion: Infections with alemtuzumab were mostly mild to moderate and decreased over time, consistent with preservation of components of protective immunity.

A.03 Durable clinical and MRI efficacy of alemtuzumab over 6 years in CARE-MS II patients with RRMS who relapsed between Courses 1 and 2

Background: In RRMS patients with inadequate response to prior therapy, 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved outcomes over 2 years (y) versus SC IFNB-1a (CARE-MS II [NCT00548405]), with durable efficacy over a 4-y extension (NCT00930553). We present 6-y efficacy (2-y core study plus 4-y extension) in patients with relapse (relapsers) between Courses (C) 1 and 2. Methods: Annualized relapse rate (ARR); 6-month confirmed disability worsening (CDW); MRI disease activity (Gd-enhancing lesions; new/enlarging T2 hyperintense lesions); brain volume loss (BVL; derived by relative change in brain parenchymal fraction). Results: 105/435 (24%) patients relapsed between C1 and C2; 33% (relapsers) versus 55% without relapse (non-relapsers) received neither alemtuzumab retreatment nor another disease-modifying therapy through Y6. ARR (Y1: 1.2) declined post-C2 (0.5), remaining low through Y6 (0.2 [0.1, non-relapsers]; 10/105 [10%] relapsed). Through Y6, patients remained CDW-free (60% [relapsers]; 75% [non-relapsers]), Gd-enhancing lesion-free (94% [relapsers]; 90% [non-relapsers]), new/enlarging T2 hyperintense lesion-free (68% [relapsers]; 69% [non-relapsers]), and MRI disease activity-free (68% [relapsers]; 69% [non-relapsers]). Alemtuzumab slowed median percent yearly BVL (Y6: -0.13% [relapsers]; -0.10% [non-relapsers]). Conclusions: Patients relapsing between C1 and C2 improved post-C2 through Y6. These findings support administering 2 alemtuzumab courses to achieve optimal and durable benefit.

P.027 Efficacy of a fourth alemtuzumab course in RRMS patients from CARE-MS II who experienced disease activity after three prior courses

Background: In RRMS patients with inadequate response to prior therapy, 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved outcomes versus SC IFNB-1a over 2 years (CARE-MS II [NCT00548405]). Efficacy remained durable in a 4-year extension (NCT00930553); patients could receive as-needed alemtuzumab retreatment (≥12 months apart) for disease activity, or another disease-modifying therapy (DMT). Through Year 6, 88% remained on study; 50% received neither alemtuzumab retreatment nor another DMT; 16% received ≥4 courses; 3% received ≥5 courses. We evaluated Course 4 (C4) efficacy in patients receiving ≥4 courses. Methods: Annualized relapse rate (ARR); improved/stable Expanded Disability Status Scale (EDSS) score (versus baseline); 6-month confirmed disability improvement (CDI). 11% of patients met inclusion criteria: ≥4 courses within 60 months of baseline; no DMT. Those receiving C5 were censored at that time. Results: ARR decreased after C4 (12 months pre-C4 [-12M]: 0.75; 12 months post-C4 [+12M]: 0.19; P<0.0001), remaining low (0.23) at Year 3 post-C4. More patients had stable/improved EDSS scores +12M (67.5%) versus at C4 administration (53.5%). Percentage with CDI increased post-C4 (-12M: 10.0%; +12M: 26.7%). Conclusions: C4 reduced relapses and stabilized/improved disability in patients with disease activity after initial treatment (C1, C2) plus one additional course (C3).

Understanding the positive benefit:risk profile of alemtuzumab in relapsing multiple sclerosis: perspectives from the Alemtuzumab Clinical Development Program.

The introduction of high-efficacy therapies for relapsing–remitting multiple sclerosis has driven re-evaluation of treatment goals and benefit:risk considerations in treatment choice. In the alemtuzumab Phase II and III clinical trials, patients treated with alemtuzumab 12 mg versus subcutaneous interferon beta-1a demonstrated significantly reduced annualized relapse rates and improved magnetic resonance imaging outcomes, and were significantly more likely to achieve no evidence of disease activity and reduction in brain volume loss. In two of the studies, alemtuzumab-treated patients had a significantly reduced risk of 6-month confirmed disease worsening, compared with subcutaneous interferon beta-1a. Benefits were maintained throughout 5 years, with a majority of patients receiving no alemtuzumab retreatment or other disease-modifying therapy. Trial results support alemtuzumab’s manageable, consistent safety profile in relapsing–remitting multiple sclerosis. Infusion-associated reactions, the most frequent adverse events (AEs), can be minimized by corticosteroid pretreatment, monitoring, and symptomatic management. Other AEs include infections and autoimmune events. Oral anti-herpes prophylaxis should be initiated on the first day of each alemtuzumab treatment course and continued according to local guidelines. Overall cancer risk was lower in the alemtuzumab clinical trials than in a reference population; however, continuing surveillance will determine if alemtuzumab may be associated with certain malignancies such as thyroid papillary carcinoma and melanoma, which are currently identified as potential risks. The post-approval risk management strategy includes a safety monitoring program. Autoimmune AEs (thyroid events, immune thrombocytopenia, nephropathies) can be detected in a timely manner with the monitoring program, which includes physician and patient education about the signs and symptoms, monthly renal and hematologic monitoring, and quarterly thyroid function monitoring for 48 months after the last alemtuzumab course. Education, vigilance by physicians and patients, and monthly laboratory monitoring are recommended to maintain alemtuzumab’s positive benefit:risk profile.

Alemtuzumab improves quality-of-life outcomes compared with subcutaneous interferon beta-1a in patients with active relapsing-remitting multiple sclerosis

Background: Alemtuzumab was superior on clinical and magnetic resonance imaging (MRI) outcomes versus subcutaneous interferon beta-1a in phase 3 trials in patients with relapsing-remitting multiple sclerosis. Objective: To examine quality-of-life (QoL) outcomes in the alemtuzumab phase 3 trials. Methods: Patients who were treatment naive (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I [CARE-MS I]) or had an inadequate response to prior therapy (CARE-MS II) received annual courses of alemtuzumab 12 mg/day at baseline (5 days) and Month 12 (3 days) or subcutaneous interferon beta-1a 44 µg three times/week. QoL was measured every 6 or 12 months using Functional Assessment of Multiple Sclerosis (FAMS), European Quality of Life-5 Dimensions (EQ-5D) and its visual analog scale (EQ-VAS), and 36-Item Short-Form Survey (SF-36). Results: Statistically significant improvements from baseline with alemtuzumab were observed on all three QoL instruments at the earliest post-baseline assessment and sustained through Year 2. Statistically significant greater QoL improvements over subcutaneous interferon beta-1a were seen at all time points in CARE-MS II with FAMS, EQ-VAS and SF-36 physical component summary, and in CARE-MS I with FAMS. Conclusion: Patients treated with alemtuzumab had improvements in physical, mental, and emotional QoL regardless of treatment history. Improvements were significantly greater with alemtuzumab versus subcutaneous interferon beta-1a on both disease-specific and general measures of QoL.

Alemtuzumab for multiple sclerosis.

Alemtuzumab for multiple sclerosis.

Durable Efficacy in RRMS Patients Receiving Two Annual Courses of Alemtuzumab and No Additional Treatment for 4 Years: Pooled Analysis of CARE-MS I and II (S51.005)

Durable Efficacy in RRMS Patients Receiving Two Annual Courses of Alemtuzumab and No Additional Treatment for 4 Years: Pooled Analysis of CARE-MS I and II (S51.005)

No Evidence of Disease Activity for 4 Years Following 2 Courses of Alemtuzumab and No Further Treatment: Long-Term Responders from the CARE-MS II Study (P3.059)

No Evidence of Disease Activity for 4 Years Following 2 Courses of Alemtuzumab and No Further Treatment: Long-Term Responders from the CARE-MS II Study (P3.059)

Long-Term Responders from the CARE-MS I Study: No Evidence of Disease Activity for 4 Years Following 2 Courses of Alemtuzumab and No Further Treatment (P3.054)

Long-Term Responders from the CARE-MS I Study: No Evidence of Disease Activity for 4 Years Following 2 Courses of Alemtuzumab and No Further Treatment (P3.054)

Alemtuzumab improves neurological functional systems in treatment-naive relapsing-remitting multiple sclerosis patients

BackgroundIndividual functional system scores (FSS) of the Expanded Disability Status Scale (EDSS) play a central role in determining the overall EDSS score in patients with early-stage multiple sclerosis (MS). Alemtuzumab treatment improves preexisting disability for many patients; however, it is unknown whether improvement is specific to certain functional systems. ObjectiveWe assessed the effect of alemtuzumab on individual FSS of the EDSS. MethodsCAMMS223 was a 36-month, rater-blinded, phase 2 trial; treatment-naive patients with active relapsing-remitting MS, EDSS ≤3, and symptom onset within 3years were randomized to annual courses of alemtuzumab or subcutaneous interferon beta-1a (SC IFNB-1a) 44μg three times weekly. ResultsAlemtuzumab-treated patients had improved outcomes versus SC IFNB-1a patients on most FSS at Month 36; the greatest effect occurred for sensory, pyramidal, and cerebellar FSS. Among patients who experienced 6-month sustained accumulation of disability, clinical worsening occurred most frequently in the brainstem and sensory systems. For patients with 6-month sustained reduction in preexisting disability, pyramidal and sensory systems contributed most frequently to clinical improvement. ConclusionsAlemtuzumab demonstrated a broad treatment effect in improving preexisting disability. These findings may influence treatment decisions in patients with early, active relapsing-remitting MS displaying neurological deficits. ClinicalTrials.gov Identifier NCT00050778.

P058 - Efficacy and safety of Alemtuzumab in treatment-naive patients with relapsing-remitting multiple sclerosis: Four-year follow-up of the Care-MS I study

Background/objectives Alumtzumab is approved in over 30 countries for relapsing-remitting multiple sclerosis. In the 2-year, phase 3 CARE-MS I study (NCT00530348), Alemtuzumab significantly reduced relapses compared with subcutaneous interferon beta-1a, with manageable safety in treatment-naive patients with active relapsing-remitting multiple sclerosis. Durable efficacy of Alemtuzumab was demonstrated at 3-year follow-up. Here we report results for years 3 and 4 after Alemtuzumab initiation, and for years 1 and 2 after Alemtuzumab initiation in patients initially treated with subcutaneous interferon beta-1a (crossover cohort). Design and methods In CARE-MS I, patients received Alemtuzumab (12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later) or subcutaneous interferon beta-1a (44 μg 3 times/week). In the extension study (NCT00930553), patients could receive as-needed Alemtuzumab re-treatment (12 mg/day on 3 consecutive days) ≥1 year apart or other disease-modifying therapy. Crossover patients received 2 Alemtuzumab courses (5 days then 3 days) 12 months apart. Results The extension enrolled 349 (95%) eligible patients from the core study Alemtuzumab arm. Through 4 years, 73% of these patients received only 2 annual courses, while 21% and 5% received 1 or 2 additional courses, respectively; <5% of patients received another disease-modifying therapy during the extension. Nine patients (3%) discontinued from the study, none due to adverse events. Among patients who received subcutaneous interferon beta-1a in CARE-MS I, 144 (83%) entered the extension and 132 (92%) received 2 courses of Alemtuzumab. There were 8 withdrawals (6%) in the crossover group during the 2-year extension period, none due to adverse events. Efficacy and safety data will be reported. Conclusions Most patients receiving Alemtuzumab during the core study required no re-treatment during the 2-year extension period; few sought alternative therapies or withdrew from the study. Among crossover patients, most received both treatment courses and remained in the study. Alumtzumab is approved in over 30 countries for relapsing-remitting multiple sclerosis. In the 2-year, phase 3 CARE-MS I study (NCT00530348), Alemtuzumab significantly reduced relapses compared with subcutaneous interferon beta-1a, with manageable safety in treatment-naive patients with active relapsing-remitting multiple sclerosis. Durable efficacy of Alemtuzumab was demonstrated at 3-year follow-up. Here we report results for years 3 and 4 after Alemtuzumab initiation, and for years 1 and 2 after Alemtuzumab initiation in patients initially treated with subcutaneous interferon beta-1a (crossover cohort). In CARE-MS I, patients received Alemtuzumab (12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later) or subcutaneous interferon beta-1a (44 μg 3 times/week). In the extension study (NCT00930553), patients could receive as-needed Alemtuzumab re-treatment (12 mg/day on 3 consecutive days) ≥1 year apart or other disease-modifying therapy. Crossover patients received 2 Alemtuzumab courses (5 days then 3 days) 12 months apart. The extension enrolled 349 (95%) eligible patients from the core study Alemtuzumab arm. Through 4 years, 73% of these patients received only 2 annual courses, while 21% and 5% received 1 or 2 additional courses, respectively; <5% of patients received another disease-modifying therapy during the extension. Nine patients (3%) discontinued from the study, none due to adverse events. Among patients who received subcutaneous interferon beta-1a in CARE-MS I, 144 (83%) entered the extension and 132 (92%) received 2 courses of Alemtuzumab. There were 8 withdrawals (6%) in the crossover group during the 2-year extension period, none due to adverse events. Efficacy and safety data will be reported. Most patients receiving Alemtuzumab during the core study required no re-treatment during the 2-year extension period; few sought alternative therapies or withdrew from the study. Among crossover patients, most received both treatment courses and remained in the study.

P045 - Efficacy and safety of alemtuzumab in patients with relapsing-remitting multiple sclerosis who relapsed on prior therapy: Four-year follow-up of the Care-MS II study

Background/objectives Alemtuzumab is approved in over 30 countries for relapsing-remitting multiple sclerosis. In the 2-year, phase 3 CARE-MS II study (NCT00548405), alemtuzumab had superior efficacy over subcutaneous interferon beta-1a and manageable safety over 2 years; follow-up at Year 3 showed durable efficacy of alemtuzumab. Here we report results for years 3 and 4 after alemtuzumab initiation, and for years 1 and 2 after alemtuzumab initiation in patients initially treated with subcutaneous interferon beta-1a (crossover cohort). Design and methods In CARE-MS II, patients with active relapsing-remitting multiple sclerosis who relapsed on prior therapy received 2 courses of alemtuzumab (12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later) or subcutaneous interferon beta-1a (44 ?g 3 times/week). In the extension study (NCT00930553), alemtuzumab-treated patients could receive as-needed re-treatment (12 mg/day intravenously on 3 consecutive days) ?1 year apart or other disease-modifying therapy. Crossover patients received 2 alemtuzumab courses (5 days then 3 days) 12 months apart. Results The extension enrolled 393 (93%) eligible patients from the core study alemtuzumab arm. Through 4 years, 68% received the first 2, but no additional courses; 24% and 7% received 1 or 2 additional courses, respectively; 5% received another disease-modifying therapy during the extension. Twenty-five patients (6%) discontinued study, none from adverse events. Among former interferon beta-1a patients, 146 (83%) entered the extension; 131 (90%) received 2 alemtuzumab courses. Seven extension withdrawals (5%) occurred in crossover patients, 1 from an adverse event. Efficacy and safety data will be reported. Conclusions Most patients receiving alemtuzumab in the core study required no re-treatment during the first 2 extension years; few received alternative therapies or withdrew from study. Among crossover patients, most received both treatment courses and remained in the study.

Valganciclovir suppressed Epstein Barr virus reactivation during immunosuppression with alemtuzumab

BackgroundReactivation of latent herpes viruses occurs with immunosuppression. Alemtuzumab is an antibody targeting CD52, which is expressed on all B- and T-cells. Treatment with alemtuzumab leads to profound T-cell suppression, and reactivation of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) occurs. Valganciclovir is used as an anti-CMV prophylaxis during alemtuzumab therapy. ObjectiveTo determine if EBV reactivation is decreased with valganciclovir prophylaxis. Study designPlasma EBV DNA was serially quantified by quantitative polymerase chain reaction with a World Health Organization EBV standard in patients receiving alemtuzumab therapy with valganciclovir as anti-CMV prophylaxis. ResultsTwenty-nine patients were studied. A total of 258 samples were quantified, at a median of 7 (3–25) specimens per patient. Twenty-four patients never had any quantifiable EBV DNA. Five patients (17%) developed EBV reactivation. Two patients had EBV reactivation at very low levels of about 103IU/mL, 3–4 logs lower than those typically found in post-transplant lymphoproliferative diseases. Three patients had EBV reactivation at higher levels of 104IU/mL, which only occurred after two courses of alemtuzumab were administered. EBV reactivation subsided spontaneously in four cases. One patient developed EBV-positive Hodgkin lymphoma, but he had also received previously another potent T-cell suppressing drug fludarabine. ConclusionValganciclovir suppressed EBV reactivation during alemtuzumab therapy. It might be a useful prophylaxis in immunocompromized patient populations at high risk of EBV reactivation.

The successful use of alemtuzumab for treatment of steroid‐refractory acute graft‐versus‐host disease in pediatric patients

SR-aGVHD remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Alemtuzumab has been used with success in adult patients but has not been studied in the pediatric setting. To estimate the effectiveness of alemtuzumab for the treatment of SR-aGVHD in pediatric patients, we retrospectively reviewed the charts of 19 patients (median age 4 yr, range 0.5-28 years) with grades II (n = 3), III (n = 10), or IV (n = 6) SR-aGVHD who received alemtuzumab treatment. Patients received a median dose of 0.9 mg/kg alemtuzumab (range 0.3-2 mg/kg) divided over 2-6 days. Eighty-nine percent of patients received additional courses. A complete response, defined as GVHD of grade 0 at four wk following the first alemtuzumab course, was observed in nine patients (47%). A partial response, defined as an improvement in grade after four wk, was observed in five patients (26%). There was no response in five patients (26%). The overall response rate at four wk was 73%. Infectious complications included bacteremia (47%), presumed or documented fungal infections (21%), adenovirus viremia (52%), EBV viremia (36%), and CMV viremia (36%). We conclude that alemtuzumab is effective for SR-aGVHD in pediatric patients with a tolerable spectrum of complications.

Alemtuzumab in the treatment of IVIG-dependent chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an idiopathic immune mediated neuropathy causing demyelination and conduction block thought to occur as the result of an aberrant autoimmune response resulting in peripheral nerve inflammation mediated by T cells and humoral factors. Diagnosis commonly prompts initial treatment with steroids or intravenous immunoglobulin (IVIG) on which 5-35% subsequently become dependent to maintain function. Despite a number of small scale trials, the role for alternative long-term immunosuppression remains unclear. Alemtuzumab is a humanised monoclonal antibody targeting the CD52 antigen present on the surface of lymphocytes and monocytes. A single intravenous infusion results in rapid and profound lymphopoenia lasting >12 months. We report its use and clinical outcome in a small series of patients with severe IVIG-dependent CIDP. Seven patients (4 Males; 3 Females) who had failed to respond to conventional immunosuppression were treated in 5 centres receiving 9 courses of alemtuzumab (dose range 60-150 mg). Following treatment, mean monthly IVIG use fell 26% from 202 to 149 g and IVIG administration frequency from 22 to 136 days. Two patients had prolonged remission, two patients had a partial response and no clear benefit was observed in the remaining three patients (2 Males, 1 Females). Responding patients had a younger age at onset (19.5 years) and shorter disease duration than non-responders. Three patients developed autoimmune disease following treatment. Alemtuzumab may offer an alternative treatment for a subset of early onset IVIG dependent CIDP patients failing conventional immunosuppressive agents, but concerns about toxicity may limit its use.

Sustained, Durable Responses with Alemtuzumab in Refractory Angioimmunoblastic T-Cell Lymphoma.

Abstract 2730 Poster Board II-706 Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype representing 2% of Non-Hodgkin's Lymphoma characterized by lymphadenopathy, hepatosplenomegaly, anemia, hypergammaglobulinemia and immune dysfunction. Prognosis is poor with a median survival of less than 36 months. There is no standard treatment for AITL. Most patients initially respond to treatment, but relapse within short time intervals. Alemtuzumab is a humanized monoclonal antibody that binds to CD52 antigen, a cell surface glycoprotein with high expression on T-cells. We report three patients with refractory AITL, with confirmed T-cell receptor gene rearrangements, who achieved sustained, durable responses with alemtuzumab. The table below lists the treatment regimens, duration of remissions and complications for all 3 cases. Infectious and autoimmune complications were effectively treated in all.PatientPrevious Treatment (Response duration, months)Alemtuzumab (Response duration)InfectionsAutoimmune manifestationsACHOP (10) Cytoxan-P (1) Gemzar-P (1)24 monthsCMVBCHOPE (10) ICE (0) Gemcitabine-P followed by Cyclosporine maintenance (1)&gt;24 monthsAspergillusAgranulocytosis Autoimmune hemolytic anemiaCCHOP (1)&gt;14 monthsCMV Legionella Patient A was a 73 year-old female who presented with lymphadenopathy and biopsy proven AITL. Her longest remission was 10 months following CHOP. She was started on alemtuzumab 30 mg 3 times per week for 4 weeks in June 2007 after relapsing. Her only complication from treatment was CMV infection. She remained in remission until June 2009 when she relapsed in her liver and colon. She was treated with alemtuzumab and prednisone for 2 weeks, but developed neutropenic fever, CMV and died July 2009. Patient B is a 73 year-old male with a history of ITP who presented in July 2005 with fevers, lymphadenopathy and anemia, and biopsy proven AITL. His longest remission was 10 months with CHOPE. In June 2007, the patient was treated with alemtuzumab for 7 weeks after relapsing. Treatment complications included Aspergillus pneumonia, agranulocytosis and autoimmune hemolytic anemia. He achieved a complete response as evidenced by PET/CT scan. He remains in remission 2 years later. Patient C is a 62 year-old woman with a history of MGUS who presented in 2007 with rapidly growing lymphadenopathy and a biopsy that revealed AITL. She never achieved a sustained remission with chemotherapy. June 2008, the patient was treated with alemtuzumab for 6 weeks, complicated by CMV and Legionella pneumonia. She remains in remission now over 14 months. Here we have shown remarkable success with short courses of alemtuzumab. Three patients remained disease free for an average of 21 months; two remissions are on-going. This report demonstrates sustained responses for patients with AITL, suggesting that alemtuzumab is a valid and rational treatment choice in heavily pretreated patients. We propose using anti-CD52 therapy as consolidation after primary response to conventional chemotherapy in patients with AITL. Disclosures: Off Label Use: Alemtuzumab is not licensed for use in Angioimmunoblastic T-cell Lymphoma.