Study Of Alemtuzumab Research Articles

Early beginning of alemtuzumab: Changing the multiple sclerosis treatment paradigm. Interim analysis of the LEMVIDA study

IntroductionLEMVIDA is a real-world prospective study of 3-year follow-up on quality of life of patients with multiple sclerosis (MS) receiving alemtuzumab in Spain. MethodsThis is an interim analysis evaluating the baseline characteristics of patients who started alemtuzumab between October 2016-September 2018. For 3 additional subanalysis patients were categorised by baseline EDSS score; time of alemtuzumab initiation during the recruitment period (cohort 1: October 2016-March 2017, cohort 2: April-September 2017, cohort 3: October 2017-March 2018 and cohort 4: April-September 2018); and the presence of highly active MS criteria. Results161 patients were analysed: 67.1% female, age 38.7 ± 9.4 years, MS duration 8.5 ± 6.0 years, EDSS 3.3 ± 1.7 and number of relapses in the previous 2 years 1.8 ± 1.3. 48.3% of patients presented gadolinium-enhanced (Gd+) lesions (mean: 5.2 ± 6.9) and 63.1% had received prior treatment with fingolimod or natalizumab. Baseline EDSS scores and number of Gd+ lesions were higher in cohort 1 than in cohort 4 (4.1 ± 1.8 vs 3.2 ± 1.7; P = .040 and 10.9 ± 11.9 vs 4.5 ± 5.7; P = .020). The frequency of prior treatment with fingolimod and natalizumab was lower in cohort 4 (60.6%) than in cohort 1 (70.6%) (comparison between groups not analysed). ConclusionsUnlike phase 3 studies of alemtuzumab, the patients included in LEMVIDA are older, have a longer duration of MS, higher disability and have received previous immunosuppressants. However, throughout the recruitment period, there is a tendency towards an early beginning of treatment with alemtuzumab, probably due to the evidence of higher effectiveness in the early stages of MS.

A real-world study of alemtuzumab in a cohort of Italian patients.

Background and purposeReal‐world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease‐modifying therapies (DMTs). Our aim was to provide real‐world data on the impact of clinical variables and previous DMTs on clinical response to alemtuzumab.MethodsSixteen Italian multiple sclerosis centers retrospectively included patients who started alemtuzumab from January 2015 to December 2018, and recorded demographics, previous therapies, washout duration, relapses, Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging data. Negative binomial regression models were used to assess the effect of factors on annualized relapse (ARR) after alemtuzumab initiation.ResultsWe studied 322 patients (mean age 36.8 years, median EDSS score 3, median follow‐up 1.94 years). Previous treatments were: fingolimod (106), natalizumab (80), first‐line oral agents (56), first‐line injectables (interferon/glatiramer acetate; 30), and other drugs (15). Thirty‐five patients were treatment‐naïve. The pre‐alemtuzumab ARR was 0.99 and decreased to 0.13 during alemtuzumab treatment (p < 0.001). The number of previous‐year relapses was associated with alemtuzumab ARR (adjusted risk ratio [RR] 1.38, p = 0.009). Progression‐free survival was 94.5% after 1 year, and 89.2% after 2 years of alemtuzumab treatment. EDSS score improvement occurred in 13.5% after 1 year, and 20.6% after 2 years. Re‐baselining patients after 6 months of alemtuzumab treatment, led to no evidence of disease activity status in 71.6% after 1 year and 58.9% after 2 years.ConclusionsAlemtuzumab decreases ARR independent of previous therapy, including patients with disease activity during natalizumab treatment. Overall, 90% of patients showed no disease progression, and 20% an improvement after 2 years of alemtuzumab.

Inicio temprano de alemtuzumab: cambio en el paradigma de tratamiento en esclerosis múltiple. Análisis intermedio del estudio LEMVIDA

IntroductionLEMVIDA is a real-world prospective study of 3-year follow-up on quality of life of patients with multiple sclerosis (MS) receiving alemtuzumab in Spain. MethodsThis is an interim analysis evaluating the baseline characteristics of patients who started alemtuzumab between October 2016-September 2018. For 3 additional subanalysis patients were categorized by baseline EDSS score; time of alemtuzumab initiation during the recruitment period (cohort 1: October 2016-March 2017, cohort 2: April-September 2017, cohort 3: October 2017-March 2018 and cohort 4: April-September 2018); and the presence of highly active MS criteria. Results161 patients were analyzed: 67.1% female, age 38.7±9.4 years, MS duration 8.5±6.0 years, EDSS 3.3±1.7 and number of relapses in the previous 2 years 1.8±1.3. 48.3% of patients presented gadolinium-enhanced (Gd+) lesions (mean: 5.2±6.9) and 63.1% had received prior treatment with fingolimod or natalizumab. Baseline EDSS scores and number of Gd+lesions were higher in cohort 1 than in cohort 4 (4.1±1.8 vs. 3.2±1.7; p=0.040 and 10.9±11.9 vs 4.5±5.7; p=0.020). The frequency of prior treatment with fingolimod and natalizumab was lower in cohort 4 (60.6%) than in cohort 1 (70.6%) (comparison between groups not analyzed). ConclusionsUnlike phase 3 studies of alemtuzumab, the patients included in LEMVIDA are older, have a longer duration of MS, higher disability and have received previous immunosuppressants. However, throughout the recruitment period, there is a tendency towards an early beginning of treatment with alemtuzumab, probably due to the evidence of higher effectiveness in the early stages of MS.

Abstract 5765: Epidemiology and clinicopathology prognostic factors of T-cell prolymphocytic leukemia: Analysis and met-analysis of updated pooled databases

Abstract TPLL is a rare and aggressive T-cell lymphoid malignancy. It typically presents with leukocytosis, hepatosplenomegaly, lymphadenopathy, and skin involvement. The post-thymic malignant lymphocytes often express CD2, CD3, CD4, CD5, and occasionally CD8. CD52 is also frequently and densely expressed and serves as a therapeutic target for the monoclonal antibody, Alemtuzumab. Inv(14) and chromosome 14 translocations (tchr14) are the most frequent cytogenetic abnormalities contributing to the overexpression of the TCL-1 gene product. This analysis was conducted to update and expand our existing knowledge of this rare disease. To study the demographic characteristics, cytogenetic and molecular signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 91 cases. Kaplan-Meier survival curves were constructed. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathology factors on survival. A search of online databases identified all available comparative studies of Alemtuzumab in TPLL to conduct a meta-analysis using an inverse variance method with a fixed-effects model. The median age was 65 (27-89) years, with a peak incidence between ages 71 and 81. Males were 1.8 times more afflicted than females. The median overall survival of the whole group was 21 months. Sex did not impact the overall survival of the group. When compared to supportive care, chemotherapy significantly improved survival (HR:0.29, p=0.0016). Allogeneic stem cell transplant did not confer any survival advantage. Moreover, the presence of SAMHD1 and JAK-STAT mutations did not affect survival. The median survival of inv(14), tchr14, and TCL-1 expression were 29, 12, and 11 months respectively. When compared to tchr14 and TCL-1 expression combined, inv(14) seems to have a borderline significant survival advantage (HR:0.52, p=0.06). Patients who were treated with Alemtuzumab had higher median survival, though not significant, compared to those who did not (29 vs 12 months, p=0.6). To study further the effect of Alemtuzumab on TPLL survivorship, we conducted a meta-analysis of four retrospective comparative series with a total of 144 patients including ours. Alemtuzumab was found to be significantly associated with a survival benefit in patients with TPLL (HR 0.54, p=0.001). This study presents an updated epidemiologic and clinicopathologic data from a pooled cohort of patients with TPLL. It identifies the potential prognostic impact of inv(14), tchr14, and TCL-1 on survival. Furthermore, it confirms the survival advantage conferred by Alemtuzumab in TPLL. Citation Format: Philip A. Haddad, Kevin Gallagher, Dalia Hammoud. Epidemiology and clinicopathology prognostic factors of T-cell prolymphocytic leukemia: Analysis and met-analysis of updated pooled databases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5765.

Preapproval and postapproval evidence on drugs for multiple sclerosis.

To review the evidence supporting the European Union marketing authorization of drugs for multiple sclerosis (MS) and assess how far postmarketing research addresses information gaps at the time of approval. Through its database, we identified drugs approved by the European Medicines Agency and gathered data on pivotal trials from the European Public Assessment Reports and corresponding publications. We searched Medline, Embase, Cochrane Library, and trial registries for postmarketing randomized controlled trials testing the drugs identified in any form of the disease. Since approval of interferon and glatiramer up to 2017, the Agency has examined 10 drugs for the treatment of MS, and 8 were included in this study: alemtuzumab, daclizumab, dimethyl fumarate, fampridine, fingolimod, peginterferon-β-1a, natalizumab, and teriflunomide. We analyzed 16 pivotal trials enrolling almost 16,000 participants. Eleven compared new drugs to placebo, 5 to interferon-β-1a. Annualized relapse rate was the primary outcome in two-thirds and coprimary with disability progression in the 2 studies of alemtuzumab. Of the 52 postmarketing trials, 24 reported final results and 28 were ongoing, terminated, or completed but no results were available. None directly compared the approved drugs, thus leaving their respective therapeutic values unknown. Data on the prevention of disease progression were scarce: none of the disease-modifying drugs showed any effect on disability progression. The lack of comparative evidence and data on clinical effectiveness hamper the assessment of therapeutic value and place in therapy of drugs approved for MS.

A Phase 2 Trial of Fludarabine Combined With Subcutaneous Alemtuzumab for the Treatment of Relapsed/Refractory B-Cell Chronic Lymphocytic Leukemia

Alemtuzumab is effective in fludarabine-refractory patients with chronic lymphocytic leukemia. We performed a phase 2 study of alemtuzumab in combination with fludarabine in patients with relapsed disease. Patients received alemtuzumab and fludarabine daily on days 1 to 5 of a 28-day cycle for up to 6 cycles with the primary objective of determining the rate of complete response. Of 60 enrolled patients, 51 had previously received fludarabine, and 60% had received 3 or more prior therapies. Five patients experienced complete response (8.3%) and 12 experienced partial response, yielding an overall response rate of 28.3% for the intention-to-treat population. Among the 41 patients who completed at least 4 cycles of therapy, the complete response rate was 20%. Median progression-free survival was 211 days. Forty-seven percent of patients experienced cytomegalovirus viremia, including 4 patients with symptomatic cytomegalovirus disease. All patients responded to antiviral therapy. Despite some evidence of efficacy in this setting, the primary end point for the study was not met. In the era of targeted agents that are well tolerated, the combination of fludarabine and alemtuzumab should be used rarely for a select group of fit patients who are refractory to standard therapies.

Alemtuzumab Is Safe and Associated With High Response Rates In Selected Patients With Myelodysplastic Syndrome

▪In a subgroup of patients with myelodysplastic syndrome (MDS) an immune mechanism is believed to cause bone marrow failure. In these individuals immunosuppressive treatment (IST) can restore marrow function. We previously reported a 68% response rate in a phase I/II study of alemtuzumab in 31 patients with low to int-2 risk MDS (Sloand etal JCO Dec 10, 2010:5166-5173). Patients were enrolled according to their predicted probability of response based on an algorithm that incorporated HLA-DR15 positivity, age and transfusion burden (Blood 2003 Oct 15; 102(8):3025-7). We now report updated efficacy data on our cohort of 40 patients and long term follow up data on responders. The first 37 patients received 10mg of alemtuzumab for 10 days intravenously. Alemtuzumab was administered subcutaneously in the subsequent 3 patients. Primary endpoints were changes in peripheral blood counts. Secondary endpoints included improvement in the transfusion requirements (in transfusion- dependent patients), duration of response, and late effects of treatment, relapse and survival. Thirty nine patients were evaluable. One patient discontinued treatment after one dose because of severe hypotension and was excluded from analysis. Median follow-up time was 25 months (3-64 months). Median age was 56 years (23-71 years). The overall response rate (ORR) was 64% (25/39) with 21% of patients having a complete response (8/39). Twenty of 29 (69%) int-1 patients; 4 of 7 (57 %) int-2 patients and 1 of 3 (33%) low risk patients responded following alemtuzumab treatment. Median time to response was 3 months with median duration of response 9 months (range 1-69 months). Eight of 11 patients who relapsed regained their response with addition of cyclosporine and one patient was lost to follow up. The median duration of response in patients rescued with cyclosporine is 37 months (1-42 months). The median duration of response to immunosuppressive treatment (alemtuzumab +/- cyclosporine) is 22.2 months (range 3-69 months). All responding patients who were previously transfusion dependent became transfusion independent after alemtuzumab treatment. One of three patients who received subcutaneous alemtuzumab administration responded. The median survival for all patients was 34 months (range 1-72 months) (figure 1a) with median survival of 36 months (6-72 months) in responding group compared to 16 months (1-56 months) in non-responding group (p<0.001) (figure 1b). Five of twelve patients with abnormal cytogenetics at the start of treatment had a complete cytogenetic remission at one year. One patient with monosomy 7 and another with del 13 were in cytogenetic remission for 4.5 years and 4 years respectively. Decline in their blood counts correlated with re-emergence of initial clone. Three patients with del 13, 5q- and del 5 continue to remain in cytogenetic remission at 4, 2 and 1 years respectively. The absolute neutrophil count at baseline was significantly associated with overall survival on univariate analysis. On multivariate analysis, factors significantly associated with overall survival were male sex, bone marrow hypocellularity/normocellularity, prior immunosuppressive treatment, baseline absolute neutrophil count and platelet count. All patients became lymphopenic after alemtuzumab administration and most patients continued to be lymphopenic at 3 years. Baseline absolute lymphocyte count, ratio of CD4/CD8 cell count, absolute CD4 and NK cell counts and kinetics of lymphocyte recovery were not predictive for response. Alemtuzumab was generally well tolerated with most patients having manageable infusion reactions with the first dose. Sixteen of the 39 patients became transiently positive for EBV DNA and 6 of 29 CMV seropositive patients had reactivation but no patient developed clinically significant viral disease. Alemtuzumab is well tolerated and is effective in a subset of patients with MDS. Long term responses with cytogenetic remissions are possible. Patients who relapse can be rescued with cyclosporine. Immunosuppresion should be considered in patients likely to respond based on a simple algorithm and alemtuzumab is an alternative to ATG based regimens. [Display omitted] [Display omitted] Disclosures:Off Label Use: Alemtuzumab use as immunosuppresive agent in myelodysplastic syndrome.

Efficacy of alemtuzumab (ALZ) in combination with dose-adjusted EPOCH (DA-EPOCH) in untreated nodal peripheral T-cell lymphoma (PTCL).

8051 Background: The survival of patients (pts) with PTCL (excluding ALCL) is disappointing following anthracycline-based therapy and novel approaches are needed. In diffuse large B-cell lymphoma, the addition of anti-CD20 therapy to CHOP has significantly improved outcome and we investigated if in PTCL, adding ALZ – which targets CD52, expressed on most PTCLs – was feasible and improved outcome. Methods: This was a single-center phase I/II trial of ALZ, in combination with DA-EPOCH in patients with treatment-naïve CD52+ PTCL. The MTD of 30 mg ALZ was combined with DA-EPOCH for phase II evaluation resulting in an intention-to-treat population (ITTP) of 30 pts. Results: Patient (n=30) characteristics: median (range) age 50 (17-77); M:F 1:1; Stage III/IV 27 (90%); IPI ≥2 22 (73%). Histologies: ATLL 11 (37%), PTCL NOS 6 (20%), AITL 5 (16%), Hepatosplenic 3 (10%), Peripheral T NK cell 2 (7%), Other 3 (10%). At 67 months median follow-up, 11 patients were alive, 10 disease-free. Median overall (OS) and event-free survivals (EFS) were 15.4 and 6.7 months respectively. Outcome was substantially better for pts with ‘nodal’ (AITL, PTCL-NOS, Other) compared to ‘non-nodal’ (ATLL and ‘extranodal’ histologies) PTCL subtypes. 3-year OS for the two groups was 58.3% and 27.8% respectively (p=0.082); 3-yrs EFS was 50% (median 27.0 months) and 22.2% (median: 5 months) respectively (p=0.041). Half of the ‘nodal’ PTCL pts had sustained long-term complete remissions demonstrated by a plateau in the EFS curve at 27 months. There were 3 treatment related deaths: 2 from neutropenic sepsis; 1 from toxoplasma. Other toxicities included CMV and BK virus reactivation in 53% and 30% respectively. Febrile neutropenia was seen in 20% and grade 4 thrombocytopenia in 12 % of cycles. Conclusions: Although it has significant infectious toxicity, ALZ 30mg and DA-EPOCHin untreated PTCL is feasible and associated with a long-term favorable outcome in nodal but not extranodal or leukemic PTCL. A phase III study of ALZ 30mg with anthracycline-based therapy is ongoing and we await the results with interest.

A single‐arm, open‐label study of alemtuzumab in treatment‐refractory patients with multiple sclerosis

Alemtuzumab (CD52-specific humanized monoclonal antibody) was found to be an effective therapy for treatment-naive patients with relapsing-remitting multiple sclerosis. Evaluate alemtuzumab's effects in patients with treatment-refractory relapsing-remitting multiple sclerosis. Forty-five relapsing-remitting multiple sclerosis patients who experienced ≥2 relapses during 2 years prior to the study entry whilst receiving interferon therapy were administered 24 mg i.v. alemtuzumab/day for 5 days at baseline and 3 days 12 months later. Patients received premedication with 1 g i.v. methylprednisolone on days 1-3 at both times. After 2-year follow-up, the annualized relapse rate was reduced by 94% compared to pre-treatment levels, from 1.6 (2 years prior to treatment) to 0.17 for the 2 years following (P<0.0001). Moreover, 86% of patients showed stable or improved scores on the Expanded Disability Status Scale, and only 1 experienced an increase in disability lasting ≥6 months. The majority (70-88%) showed stable or improved leg, arm and cognitive function as measured by the Multiple Sclerosis Functional Composite. Serious adverse events observed in single patients were transient neutropenia and pneumonia, pulmonary emboli and deep vein thrombosis. Five patients developed clinical thyroid disorders but no opportunistic infections or cases of immune thrombocytopenic purpura were observed. Alemtuzumab effectively reduced relapse rates and improved clinical scores in patients with active relapsing-remitting multiple sclerosis not controlled by interferon therapy.

Emerging role of Alemtuzumab in renal and renal–pancreas transplantation

Background: Alemtuzumab is a humanized anti-CD52 monoclonal antibody that is increasingly used in solid organ transplantation. Objective: The novel mechanism by which alemtuzumab works was used to provide an understanding of its clinical efficacy and adverse effects. Methods: Human studies of alemtuzumab in adult renal and pancreas transplantation were reviewed. These studies looked at the role of alemtuzumab as a tolerogenic and induction agent as well as its role in the treatment of acute rejection. Results/conclusions: Overall, alemtuzumab induction resulted in patient and graft outcomes comparable to other induction strategies but studies failed to show development of true tolerance. Economic benefit is a major attraction for alemtuzumab use. Future studies will further identify the optimal use of alemtuzumab.

Phase II study of alemtuzumab in lymphoplasmacytic lymphoma: Results of WMCTG trial 02–079

7523 Background: Alemtuzumab (Campath-1H) is a fully humanized anti-CD52 antibody used to treat B and T-cell disorders. CD52 is widely expressed on bone marrow lymphoplasmacytic cells and growth supporting mast cells in patients with lymphoplasmacytic lymphoma (LPL), including Waldenstrom’s macroglobulinemia (WM). We therefore examined the activity of alemtuzumab in LPL. Methods: 28 patients with LPL, including 27 WM patients were enrolled in this multicenter study. 23 patients were previously treated. Median age was 60 (range 33–75 years), median prior therapies was 2 (range 0–5), and median time from diagnosis was 2.9 (range 0.1–9.0 years). Baseline median bone marrow involvement was 30% (range 5–90%), median serum IgM was 3510 (range 622–12,000 mg/dL) and hematocrit was 35.1 (range 24.4–42.8%). Patients received 3 test doses of alemtuzumab (3, 10, and 30mg IV) followed by 30 mg TIW for up to 12 weeks. All patients received acyclovir and bactrim or equivalent prophylaxis. Results: Twenty-five patients are evaluable for response. 24/25 patients demonstrated a decrease in serum IgM levels (median change -40.5%), for an overall response rate of 76%, which included 8 (32%) partial responders (≤50% decrease in serum IgM), and 11 (44%) minor responders (≥25% decrease in serum IgM). Hematological toxicities were common among previously treated (but not untreated) patients and included G3/4 neutropenia 39%; thrombocytopenia 18%; anemia 7%. G3/4 non-hematological toxicity for all patients included dermatitis 11%; fatigue 7%; and infection 7%. CMV reactivation and infection was commonly seen among previously treated patients and may have been etiological for one death on study. Two other patients also succumbed on study, one related in part to drug therapy for CMV infection and another due to complications of therapy induced thrombocytopenia and Von Willebrand disease. With a median follow-up of 8.5+ months, 11/19 responding patients remain free of progression. Conclusions: Alemtuzumab is highly active in patients with LPL. Hematological and non-hematological toxicities, including CMV reactivation and infection are common among previously treated patients. Further exploration of this agent in LPL, including upfront therapy is warranted. No significant financial relationships to disclose.

Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sézary syndrome

AbstractThis phase 2 study evaluated the safety and efficacy of alemtuzumab in 22 patients with advanced mycosis fungoides/Sézary syndrome (MF/SS). Most patients had stage III or IV disease, reduced performance status, and severe itching. The overall response (OR) rate was 55%, with 32% of patients in complete remission (CR) and 23% in partial remission (PR). Sézary cells were cleared from the blood in 6 of 7 (86%) patients, and CR in lymph nodes was observed in 6 of 11 (55%) patients. The effect was better on erythroderma (OR, 69%) than on plaque or skin tumors (OR, 40%) and in patients who had received 1 to 2 previous regimens (OR, 80%) than in those who had received 3 or more prior regimens (OR, 33%). Itching, self-assessed on a 0 to 10 visual analog scale, was reduced from a median of 8 before treatment to 2 at end of therapy. Median time to treatment failure was 12 months (range, 5-32+ months). Cytomegalovirus (CMV) reactivation (causing fever without pneumonitis and responding to ganciclovir) occurred in 4 (18%) patients. Six additional patients had suspect or manifest infection (fever of unknown origin, 3; generalized herpes simplex, 1; fatal aspergillosis, 1). One patient had fatal Mycobacterium pneumonia at 10+ months. All serious infectious adverse events (except CMV) occurred in patients who had received 3 or more prior regimens. Progression of squamous cell skin carcinoma was noted in 1 patient. Alemtuzumab shows promising clinical activity and an acceptable safety profile in patients with advanced MF/SS, particularly in patients with erythroderma and severe itching and those who were not heavily pretreated.