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Gavin Giovannoni - One of the best experts on this subject based on the ideXlab platform.
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long term safety data from the Cladribine tablets clinical development program in multiple sclerosis
Multiple sclerosis and related disorders, 2020Co-Authors: Thomas Leist, Doris Damian, Gavin Giovannoni, Xavier Montalban, Stuart D. Cook, Axel Nolting, G Comi, Sana Syed, Andrew GalazkaAbstract:Abstract Background Long-term safety data are of particular interest for any newly approved treatment in multiple sclerosis such as Cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as Cladribine tablets 3.5 mg/kg), which is approved in Europe and the USA. Here we provide the final report on the integrated analysis of the safety profile of Cladribine tablets 3.5 mg/kg from the clinical development program, including final data from the PREMIERE registry. Methods Safety data for Cladribine tablets 3.5 mg/kg from three previously reported Phase III studies (CLARITY, CLARITY Extension and ORACLE-MS), as well as the prospective, observational PREMIERE registry (which ran from November 2009 to October 2018; consisting of patients who had participated in at least one of the Phase III trials) were combined to provide the Monotherapy Oral cohort. Serious adverse events (SAEs) and predefined SAEs of special interest were recorded. Observation-adjusted incidence rates per 100 patient-years (Adj-AE per 100 PY) were used to assess adverse events (AEs). Standardized incidence ratios for malignancies were calculated in relation to a matched GLOBOCAN reference population, and risk differences (Cladribine tablets versus placebo) were estimated. Results The Monotherapy Oral cohort comprised 923 patients who received Cladribine tablets 3.5 mg/kg and 641 patients who received placebo. Overall, the reported number of SAEs was higher in the Cladribine tablets 3.5 mg/kg group (133/923 [14.4%] patients with at least 1 SAE), versus the placebo group (68/641 [10.6%] patients with at least 1 SAE). Four patients in the Cladribine tablets 3.5 mg/kg group had lymphopenia classified as a serious event (resulting in an Adj-AE of 0.10 per 100 PY) and 2 patients had serious herpes zoster (resulting in an Adj-AE of 0.05 per 100 PY). There were no cases in the corresponding placebo groups. There was no difference between the Cladribine tablets 3.5 mg/kg group and placebo in the overall incidence of infections. However herpetic infection AEs occurred more frequently in the Cladribine tablets 3.5 mg/kg group (driven primarily by herpes zoster, followed by oral herpes and herpes simplex). Overall, there was a numerical imbalance in malignancy incidence between Cladribine tablets 3.5 mg/kg and placebo, with an Adj-AE of 0.26 and 0.12 per 100 PY, respectively; however the difference was not statistically significant. The rate of malignancies observed with Cladribine tablets 3.5 mg/kg in the final integrated safety analysis was not different from the expected rate in the matched GLOBOCAN reference population (standardized incidence ratio, 0.88; 95% CI, 0.44–1.69). Conclusion Additional patient-years of observation do not significantly alter the conclusions of earlier interim analyses, and no new major safety findings were identified in this consolidated analysis of safety data of Cladribine tablets 3.5 mg/kg monotherapy in patients with relapsing-remitting multiple sclerosis.
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Pregnancy Outcomes During the Clinical Development Program of Cladribine in Multiple Sclerosis: An Integrated Analysis of Safety.
Drug safety, 2020Co-Authors: Gavin Giovannoni, Doris Damian, Thomas Leist, Giancarlo Comi, Andrew Galazka, Regina Schick, Xavier Montalban, Fernando Dangond, Stuart D. CookAbstract:Although use of contraception was pre-specified during Cladribine clinical trials for multiple sclerosis, some pregnancies did occur. This analysis reports on pregnancy outcomes in the Cladribine clinical development program. Pregnancy outcomes in female patients (direct pregnancies) and those arising from partner pregnancies (i.e., female partners of male study participants with multiple sclerosis) were evaluated from an integrated safety analysis of ten studies of Cladribine in multiple sclerosis (nine clinical trials and a long-term safety registry), with patients treated with Cladribine tablets, parenteral Cladribine, or placebo (all-exposed cohort; 1976 patients received Cladribine and 802 received placebo). Pregnancies that occurred during the ‘at-risk’ period for Cladribine (during treatment or within 6 months thereafter) are reported as a separate group. In the all-exposed cohort, 70 direct pregnancies occurred among 62 female patients (Cladribine, n = 49; placebo, n = 21). Pregnancy outcomes were: live births (Cladribine, n = 19 [38.8%]; placebo, n = 9 [42.9%]), elective terminations (Cladribine, n = 14 [28.6%]; placebo, n = 4 [19.0%]), spontaneous abortions (Cladribine, n = 11 [22.4%]; placebo, n = 5 [23.8%]), and therapeutic terminations (Cladribine, n = 5 [10.2%]; placebo, n = 2 [9.5%]); in the remaining placebo recipient, the pregnancy outcome was unknown. There were two reports of congenital malformations (Cladribine, n = 1; placebo, n = 1), both of which occurred with pregnancies arising > 2 years after exposure to the last dose of study medication. Sixteen direct pregnancies occurred during the ‘at-risk’ period for Cladribine; outcomes for these were: live births, n = 3 (18.8%); elective terminations, n = 10 (62.5%); spontaneous abortions, n = 2 (12.5%); and therapeutic terminations, n = 1 (6.2%). Corresponding findings for direct pregnancies among placebo recipients were (n = 11): live births, n = 5 (45.5%); elective terminations, n = 2 (18.2%); spontaneous abortions, n = 3 (27.3%); and unknown, n = 1 (9.1%). No cases of congenital malformation were reported for pregnancies during the ‘at-risk’ period. There were an additional nine partner pregnancies in female partners of Cladribine-treated male patients, all of which resulted in live births; of these, two pregnancies occurred within the ‘at-risk’ period for Cladribine. While limited by the small number of pregnancies and related data from the Cladribine clinical development program, highlighting the need for further study, the observations made in the present analysis were generally consistent with epidemiological data on pregnancy outcomes for the general population or women with multiple sclerosis. There were no congenital malformations in pregnancies that occurred during Cladribine treatment or within 6 months after the last dose. As the data available for Cladribine-exposed pregnancies in patients with multiple sclerosis are limited, a non-interventional post-authorization safety study has been initiated to obtain more information on this subject. CLARITY: NCT00213135; CLARITY Extension: NCT00641537; ORACLE MS: NCT00725985; ONWARD: NCT00436826; PREMIERE: NCT01013350.
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Severe skin reactions associated with Cladribine in people with multiple sclerosis.
Multiple sclerosis and related disorders, 2020Co-Authors: M. Mateo-casas, Gavin Giovannoni, David Baker, Kimberley Allen-philbey, Joela Mathews, Saúl Reyes, Ea O'toole, S. De Trane, Özlem Yildiz, Klaus SchmiererAbstract:Abstract Objective To report three cases of severe skin reactions in patients treated with Cladribine for multiple sclerosis. Methods Case study. Results Patients developed severe rash 3–192 days after receiving Cladribine. All were effectively treated with steroids and antihistamines. Additional doses of Cladribine were administered after pretreatment with steroids and anti-histamines. One patient developed mild recurrence following re-exposure, which resolved within three days, whilst another patient tolerated re-exposure without further adverse reaction. Conclusion Severe skin reactions, well described in patients receiving Cladribine for treatment of haematological conditions, may occur in patients treated with this compound for multiple sclerosis. Neurologists need to be aware of this rare, but significant adverse reaction. Re-exposure may be safe with standard pre-treatment against allergic reactions.
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efficacy of Cladribine tablets in high disease activity subgroups of patients with relapsing multiple sclerosis a post hoc analysis of the clarity study
Multiple Sclerosis Journal, 2019Co-Authors: Gavin Giovannoni, Giancarlo Comi, Fernando Dangond, Stuart D. Cook, Christine Hicking, P Rieckmann, Per Soelberg Sorensen, K Rammohan, P VermerschAbstract:Background:In the CLARITY (Cladribine Tablets treating multiple sclerosis orallY) study, Cladribine Tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis.Objective:Describe two clinically relevant definitions for patients with high disease activity (HDA) at baseline of the CLARITY study (utility verified in patients receiving placebo) and assess the treatment effects of Cladribine Tablets 3.5 mg/kg compared with the overall study population.Methods:Outcomes of patients randomised to Cladribine Tablets 3.5 mg/kg or placebo were analysed for subgroups using HDA definitions based on high relapse activity (HRA; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not) or HRA plus disease activity on treatment (HRA + DAT; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not, PLUS patients with ⩾1 relapse during the year prior to s...
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effect of Cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis
Multiple sclerosis and related disorders, 2019Co-Authors: Giancarlo Comi, P Vermersch, Gavin Giovannoni, Andrew Galazka, Stuart D. Cook, Axel Nolting, Christine Hicking, P Rieckmann, Per Soelberg Sorensen, Fernando DangondAbstract:Abstract Background Immune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19+ B cells and T cells, followed by reconstitution of adaptive immune function. Objective To characterize long-term lymphocyte count changes in pooled data from the 2-year CLARITY and subsequent 2-year CLARITY Extension studies, and the PREMIERE registry (Long-term CLARITY cohort). Methods Data from patients randomized to placebo (n = 435) or Cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as Cladribine tablets 3.5 mg/kg; n = 685) in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry were pooled to provide long-term follow-up data. The study investigated absolute lymphocyte counts (ALC) up to 312 weeks and B and T cell subsets up to 240 weeks after the first dose, in patients receiving placebo or Cladribine tablets 3.5 mg/kg administered as two short (4 or 5 days) weekly treatments at the start of months 1 and 2 in each treatment year, followed by no further active treatment. Results Treatment with Cladribine tablets 3.5 mg/kg resulted in selective reductions in B and T lymphocytes. Lymphocyte recovery began soon after treatment in each of years 1 and 2. Median ALC recovered to the normal range and CD19+ B cells recovered to threshold values by week 84, approximately 30 weeks after the last dose of Cladribine tablets in year 2. Median CD4+ T cell counts recovered to threshold values by week 96 (approximately 43 weeks after the last dose of Cladribine tablets in year 2). Median CD8+ cell counts never dropped below the threshold value. Conclusion These results show the dynamics of lymphocyte count changes following treatment with Cladribine tablets 3.5 mg/kg. The immune cell repopulation results provide further evidence that Cladribine tablets may represent a form of IRT.
Klaus Schmierer - One of the best experts on this subject based on the ideXlab platform.
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Severe skin reactions associated with Cladribine in people with multiple sclerosis.
Multiple sclerosis and related disorders, 2020Co-Authors: M. Mateo-casas, Gavin Giovannoni, David Baker, Kimberley Allen-philbey, Joela Mathews, Saúl Reyes, Ea O'toole, S. De Trane, Özlem Yildiz, Klaus SchmiererAbstract:Abstract Objective To report three cases of severe skin reactions in patients treated with Cladribine for multiple sclerosis. Methods Case study. Results Patients developed severe rash 3–192 days after receiving Cladribine. All were effectively treated with steroids and antihistamines. Additional doses of Cladribine were administered after pretreatment with steroids and anti-histamines. One patient developed mild recurrence following re-exposure, which resolved within three days, whilst another patient tolerated re-exposure without further adverse reaction. Conclusion Severe skin reactions, well described in patients receiving Cladribine for treatment of haematological conditions, may occur in patients treated with this compound for multiple sclerosis. Neurologists need to be aware of this rare, but significant adverse reaction. Re-exposure may be safe with standard pre-treatment against allergic reactions.
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Cladribine: mechanisms and mysteries in multiple sclerosis.
Journal of neurology neurosurgery and psychiatry, 2018Co-Authors: Benjamin Meir Jacobs, Gavin Giovannoni, Francesca Ammoscato, David Baker, Klaus SchmiererAbstract:Objectives The aims of this manuscript were to review the evidence for the efficacy and safety of Cladribine in multiple sclerosis (MS) and to review the molecular and cellular mechanisms by which Cladribine acts as a disease-modifying therapy in MS. Methods This is a narrative review of the available clinical and preclinical data on the use of Cladribine in MS. Results Clinical trial data argue strongly that Cladribine is a safe and effective therapy for relapsing MS and that it may also be beneficial in progressive MS. The pharmacology of Cladribine explains how it is selectively toxic towards lymphocytes. Immunophenotyping studies show that Cladribine depletes lymphocyte populations in vivo with a predilection for B cells. In vitro studies demonstrate that Cladribine also exerts immunomodulatory influences over innate and adaptive immunity. Conclusions Cladribine is a safe and effective form of induction therapy for relapsing MS. Its mechanism of benefit is not fully understood but the most striking action is selective, long-lasting, depletion of B lymphocytes with a particular predilection for memory B cells. The in vivo relevance of its other immunomodulatory actions is unknown. The hypothesis that Cladribine’s action of benefit is to deplete memory B cells is important: if correct, it implies that selective targeting of this cell population and sparing of other lymphocytes could modify disease activity without predisposing to immunosuppression-related complications.
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Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells.
Journal of neurology, 2018Co-Authors: Bryan Ceronie, Gavin Giovannoni, Benjamin Meir Jacobs, Francesca Ammoscato, David Baker, Zhifeng Mao, Nicolas Dubuisson, Helen Lock, Hilary Longhurst, Klaus SchmiererAbstract:The mechanism of action of oral Cladribine, recently licensed for relapsing multiple sclerosis, is unknown. To determine whether Cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells. A cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable Cladribine. The relative proportions and absolute numbers of peripheral blood B lymphocyte subsets were measured using flow cytometry. Cell-subtype expression of genes involved in Cladribine metabolism was examined from data in public repositories. Cladribine markedly depleted class-switched and unswitched memory B cells to levels comparable with alemtuzumab, but without the associated initial lymphopenia. CD3+ T cell depletion was modest. The mRNA expression of metabolism genes varied between lymphocyte subsets. A high ratio of deoxycytidine kinase to group I cytosolic 5′ nucleotidase expression was present in B cells and was particularly high in mature, memory and notably germinal centre B cells, but not plasma cells. Selective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by Cladribine. These may offer a new target, possibly with potential biomarker activity, for future drug development.
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PO134 Personalised dosing of Cladribine to treat multiple sclerosis
Journal of Neurology Neurosurgery & Psychiatry, 2017Co-Authors: Zhifeng Mao, Gavin Giovannoni, David Baker, Cesar Alvarez-gonzalez, Kimberley Allen-philbey, Joela Mathews, Benjamin Turner, Sharmilee Gnanapavan, Monica Marta, Klaus SchmiererAbstract:Background Evidence suggests Cladribine is an effective, safe and convenient disease modifying therapy (DMT) for people with multiple sclerosis (pwMS). Objective To report our clinical experience using Cladribine in pwMS using a dosing scheme adapted to individual total lymphocyte count (TLC) thereby addressing a key safety concern raised in the rejection of oral Cladribine by the European Medicines Agency in 2011. Methods Subcutaneous Cladribine 10 mg/day was administered on up to seven days in five weeks to pwMS who had clinical and/or MRI disease activity. The number of injections was adjusted to individual TLC to avoid depletion below 0.5 × 10* 9/L (WHO Grade 3 or 4). Efficacy and safety were assessed. Results Forty-nine pwMS (31 women and 18 men, aged 44 years (SD=9 )) were followed up for a mean of 6 months after their first Cladribine injection. Median EDSS at baseline was 5 (1–8, n=46). No serious treatment-related adverse event was observed, and neither any clinical disease activity. TLC dropped to between 0.5 and 1 × 10* 9/L while other white cells remained within normal range. Conclusion Cladribine was well tolerated and led to controlled TLC depletion leaving other cell lines largely unaffected. So far no new disease activity has been detected. Follow-up continues.
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Positive impact of Cladribine on quality of life in people with relapsing multiple sclerosis.
Multiple sclerosis (Houndmills Basingstoke England), 2017Co-Authors: Dayo Afolabi, David Baker, Lukasz Zalewski, Christo Albor, Daniel R. Altmann, Klaus SchmiererAbstract:Background:A number of elements of the pivotal ‘Cladribine tablets treating multiple sclerosis orally’ (CLARITY) trial have remained unpublished.Objective:To report the impact of Cladribine on heal...
Giancarlo Comi - One of the best experts on this subject based on the ideXlab platform.
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Pregnancy Outcomes During the Clinical Development Program of Cladribine in Multiple Sclerosis: An Integrated Analysis of Safety.
Drug safety, 2020Co-Authors: Gavin Giovannoni, Doris Damian, Thomas Leist, Giancarlo Comi, Andrew Galazka, Regina Schick, Xavier Montalban, Fernando Dangond, Stuart D. CookAbstract:Although use of contraception was pre-specified during Cladribine clinical trials for multiple sclerosis, some pregnancies did occur. This analysis reports on pregnancy outcomes in the Cladribine clinical development program. Pregnancy outcomes in female patients (direct pregnancies) and those arising from partner pregnancies (i.e., female partners of male study participants with multiple sclerosis) were evaluated from an integrated safety analysis of ten studies of Cladribine in multiple sclerosis (nine clinical trials and a long-term safety registry), with patients treated with Cladribine tablets, parenteral Cladribine, or placebo (all-exposed cohort; 1976 patients received Cladribine and 802 received placebo). Pregnancies that occurred during the ‘at-risk’ period for Cladribine (during treatment or within 6 months thereafter) are reported as a separate group. In the all-exposed cohort, 70 direct pregnancies occurred among 62 female patients (Cladribine, n = 49; placebo, n = 21). Pregnancy outcomes were: live births (Cladribine, n = 19 [38.8%]; placebo, n = 9 [42.9%]), elective terminations (Cladribine, n = 14 [28.6%]; placebo, n = 4 [19.0%]), spontaneous abortions (Cladribine, n = 11 [22.4%]; placebo, n = 5 [23.8%]), and therapeutic terminations (Cladribine, n = 5 [10.2%]; placebo, n = 2 [9.5%]); in the remaining placebo recipient, the pregnancy outcome was unknown. There were two reports of congenital malformations (Cladribine, n = 1; placebo, n = 1), both of which occurred with pregnancies arising > 2 years after exposure to the last dose of study medication. Sixteen direct pregnancies occurred during the ‘at-risk’ period for Cladribine; outcomes for these were: live births, n = 3 (18.8%); elective terminations, n = 10 (62.5%); spontaneous abortions, n = 2 (12.5%); and therapeutic terminations, n = 1 (6.2%). Corresponding findings for direct pregnancies among placebo recipients were (n = 11): live births, n = 5 (45.5%); elective terminations, n = 2 (18.2%); spontaneous abortions, n = 3 (27.3%); and unknown, n = 1 (9.1%). No cases of congenital malformation were reported for pregnancies during the ‘at-risk’ period. There were an additional nine partner pregnancies in female partners of Cladribine-treated male patients, all of which resulted in live births; of these, two pregnancies occurred within the ‘at-risk’ period for Cladribine. While limited by the small number of pregnancies and related data from the Cladribine clinical development program, highlighting the need for further study, the observations made in the present analysis were generally consistent with epidemiological data on pregnancy outcomes for the general population or women with multiple sclerosis. There were no congenital malformations in pregnancies that occurred during Cladribine treatment or within 6 months after the last dose. As the data available for Cladribine-exposed pregnancies in patients with multiple sclerosis are limited, a non-interventional post-authorization safety study has been initiated to obtain more information on this subject. CLARITY: NCT00213135; CLARITY Extension: NCT00641537; ORACLE MS: NCT00725985; ONWARD: NCT00436826; PREMIERE: NCT01013350.
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efficacy of Cladribine tablets in high disease activity subgroups of patients with relapsing multiple sclerosis a post hoc analysis of the clarity study
Multiple Sclerosis Journal, 2019Co-Authors: Gavin Giovannoni, Giancarlo Comi, Fernando Dangond, Stuart D. Cook, Christine Hicking, P Rieckmann, Per Soelberg Sorensen, K Rammohan, P VermerschAbstract:Background:In the CLARITY (Cladribine Tablets treating multiple sclerosis orallY) study, Cladribine Tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis.Objective:Describe two clinically relevant definitions for patients with high disease activity (HDA) at baseline of the CLARITY study (utility verified in patients receiving placebo) and assess the treatment effects of Cladribine Tablets 3.5 mg/kg compared with the overall study population.Methods:Outcomes of patients randomised to Cladribine Tablets 3.5 mg/kg or placebo were analysed for subgroups using HDA definitions based on high relapse activity (HRA; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not) or HRA plus disease activity on treatment (HRA + DAT; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not, PLUS patients with ⩾1 relapse during the year prior to s...
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effect of Cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis
Multiple sclerosis and related disorders, 2019Co-Authors: Giancarlo Comi, P Vermersch, Gavin Giovannoni, Andrew Galazka, Stuart D. Cook, Axel Nolting, Christine Hicking, P Rieckmann, Per Soelberg Sorensen, Fernando DangondAbstract:Abstract Background Immune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19+ B cells and T cells, followed by reconstitution of adaptive immune function. Objective To characterize long-term lymphocyte count changes in pooled data from the 2-year CLARITY and subsequent 2-year CLARITY Extension studies, and the PREMIERE registry (Long-term CLARITY cohort). Methods Data from patients randomized to placebo (n = 435) or Cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as Cladribine tablets 3.5 mg/kg; n = 685) in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry were pooled to provide long-term follow-up data. The study investigated absolute lymphocyte counts (ALC) up to 312 weeks and B and T cell subsets up to 240 weeks after the first dose, in patients receiving placebo or Cladribine tablets 3.5 mg/kg administered as two short (4 or 5 days) weekly treatments at the start of months 1 and 2 in each treatment year, followed by no further active treatment. Results Treatment with Cladribine tablets 3.5 mg/kg resulted in selective reductions in B and T lymphocytes. Lymphocyte recovery began soon after treatment in each of years 1 and 2. Median ALC recovered to the normal range and CD19+ B cells recovered to threshold values by week 84, approximately 30 weeks after the last dose of Cladribine tablets in year 2. Median CD4+ T cell counts recovered to threshold values by week 96 (approximately 43 weeks after the last dose of Cladribine tablets in year 2). Median CD8+ cell counts never dropped below the threshold value. Conclusion These results show the dynamics of lymphocyte count changes following treatment with Cladribine tablets 3.5 mg/kg. The immune cell repopulation results provide further evidence that Cladribine tablets may represent a form of IRT.
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Safety of Cladribine tablets in the treatment of patients with multiple sclerosis: An integrated analysis
Multiple sclerosis and related disorders, 2018Co-Authors: Stuart D. Cook, Thomas Leist, Giancarlo Comi, Gavin Giovannoni, Andrew Galazka, Xavier Montalban, Axel Nolting, Christine Hicking, Elke SylvesterAbstract:Abstract Background Treating patients with relapsing multiple sclerosis (MS) with Cladribine tablets (two times 4 or 5 days of treatment each year for 2 years) results in long-lasting efficacy, with continued stability in many patients for 4 or more years. Safety and tolerability outcomes from individual clinical studies with Cladribine tablets have been reported previously. Objective Report safety data from an integrated analysis of clinical trials and follow-up in patients with MS to further characterize the safety profile of Cladribine tablets. Methods Data for patients treated with Cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as Cladribine tablets 3.5 mg/kg) as monotherapy (n = 923) or placebo (n = 641) in Phase III clinical trials (CLARITY, CLARITY Extension and ORACLE-MS) and followed up in the PREMIERE registry were aggregated (Monotherapy Oral cohort). To better characterize rare events, additional data from earlier studies which involved the use of parenteral Cladribine in patients with MS, and the ONWARD study, in which patients were given Cladribine tablets in addition to interferon (IFN)-β or placebo plus IFN-β were included in an All Exposed cohort (Cladribine, n = 1926; placebo, n = 802). Adjusted adverse events incidences per 100 patient-years (Adj-AE per 100 PY) were calculated for the integrated analyses. Results The incidence rate of treatment-emergent adverse events (TEAEs) in the Monotherapy Oral cohort was 103.29 vs. 94.26 Adj-AEs per 100 PY for placebo. TEAEs that occurred more frequently with Cladribine tablets were mainly driven by the TEAEs of lymphopenia (Adj-AE per 100 PY 7.94 vs. 1.06 for placebo) and lymphocyte count decreased (Adj-AE per 100 PY 0.78 vs. 0.10 for placebo) as anticipated due to the mode of action of Cladribine. An increase in TEAE incidence rate was also observed in the Cladribine tablets 3.5 mg/kg group vs. placebo for herpes zoster (Adj-AE per 100 PY 0.83 vs. 0.20, respectively). There were no cases of systemic, serious disseminated herpes zoster attributed to treatment with Cladribine tablets. In general there was no increase in the risk of infections including opportunistic infections with Cladribine tablets versus placebo, except for herpes zoster. Periods of severe lymphopenia ( Conclusion The AE profile for Cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterized in a pooled population of patients from early to more advanced relapsing MS. There was no increased risk for infections in general except for a higher incidence of herpes zoster. Lymphopenia was amongst the most frequently observed TEAEs that occurred at a higher incidence with Cladribine relative to placebo. There was also no increase in malignancy rates for Cladribine relative to placebo.
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clinical efficacy of Cladribine tablets in patients with relapsing remitting multiple sclerosis rrms final results from the 120 week phase iiib extension trial to the clarity study p3 028
Neurology, 2016Co-Authors: Gavin Giovannoni, Giancarlo Comi, P Vermersch, Stuart D. Cook, Kottil Rammohan, Peter Rieckmann, Per Soelbergsoerensenn, Emily Martin, Fernando DangondAbstract:Objective: To assess efficacy of Cladribine tablets in RRMS patients treated for 2 additional years beyond an initial 2-year regimen (CLARITY). Background: Cladribine, given annually for 2years in short-duration courses in CLARITY, significantly improved clinical (relapses and disability progression) and MRI outcomes. After a variable treatment gap (median 40 weeks), 2 additional years of Cladribine treatment vs. placebo were assessed in CLARITY-Extension (EXT). Methods: In CLARITY, patients were randomized to treatment with placebo or Cladribine (3.5 or 5.25mg/kg bodyweight). In CLARITY-EXT, placebo recipients in CLARITY received Cladribine 3.5mg/kg; Cladribine recipients were re-randomized 2:1 to Cladribine 3.5mg/kg or placebo (5 groups total). This allowed comparison of 2 years-only treatment plus ≥2 years follow up vs. 4 years’ treatment. Clinical assessments included annualized relapse rate (ARR) and disability score. Results: Baseline characteristics were similar across groups, although placebo-recipients in CLARITY showed evidence of greater clinical and MRI-disease activity. In groups treated with Cladribine in CLARITY, efficacy was maintained in CLARITY-EXT; 2 years’ additional-Cladribine treatment was associated with a slight incremental benefit. The ARR in patients treated with Cladribine 3.5mg/kg in CLARITY and placebo in CLARITY-EXT was 0.15 (97.5[percnt]CI 0.09-0.21; n=98); in patients treated with Cladribine 3.5mg/kg in both CLARITY and CLARITY-EXT, ARR was 0.10 (97.5[percnt]CI 0.06-0.13; n=186, P=0.059). Both groups showed comparable proportions of relapse-free patients (75.6[percnt] and 81.2[percnt], respectively) and times to first relapse (relative to first dose in CLARITY). Median EDSS scores were comparable across all groups; no significant between-group differences were seen in time to confirmed 3-month EDSS progression in CLARITY-EXT. Conclusions: CLARITY-EXT demonstrated that in a majority of patients, the clinical benefits (relapse and disability) of Cladribine 3.5mg/kg given in Years 1 and 2 may be maintained for at least 4years, with decisions on further treatment based upon monitoring during this period. Study supported by: Merck KGaA, Germany. Disclosure: Dr. Giovannoni has received personal compensation for activities with AbbVie Biotherapeutics Inc., Biogen, Bayer HealthCare, Genzyme, Merck Serono, Sanofi-Aventis, Teva, Ironwood, and Novartis. Dr. Comi has received personal compensation for activities with Teva, Novartis, Genzyme, Merck Serono, Biogen, Bayer, Actelion, Almirall, and Serono Symposia International Foundation. Dr. Cook has received personal compensation for activities with Merck Serono, Bayer HealthCare, Sanofi-Aventis, Neurology Reviews, Biogen Idec, Teva Pharmaceuticals, and Actinobac Biomed Inc. Dr. Rammohan has received personal compensation for activities with EMD Serono, Biogen Idec, Sanofi-Aventis, Genzyme Corporation, Novartis, Teva Neurosciences, Acorda and Roche/Genentech Inc. as a speaker and committee member. Dr. Soelberg-Sorensen has received personal compensation for activities with Biogen Idec, Merck Serono, Novartis, Genmab, Teva, Elan, and GlaxoSmithKline, Inc. Dr. Vermersch has received personal compensation for activities with Biogen Idec, Sanofi, Bayer, Novartis, Merck Serono, GlaxoSmithKline, and Almirall. Dr. Vermersch has received research support from Biogen Idec, Sanofi, Bayer, and Merck Serono. Dr. Martin has received personal compensation for activities with EMD Serono, Inc. as an employee. Dr. Dangond has received personal compensation for activities with EMD Serono, Inc. as an employee. Dr. Dangond received personal compensation for activities from EMD Serono, Inc., a subsidiary of Merck KGaA, Massachusetts, USA as an employee.
Alan Saven - One of the best experts on this subject based on the ideXlab platform.
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very long term eradication of minimal residual disease in patients with hairy cell leukemia after a single course of Cladribine
Blood, 2010Co-Authors: Darren Sigal, Carol Burian, Robert W Sharpe, Alan SavenAbstract:Cladribine induces protracted remissions in patients with hairy cell leukemia (HCL). However, many long-term responders ultimately relapse. We sought to determine whether long-term complete responders subsequent to a single 7-day course of Cladribine were without minimal residual disease (MRD) and potentially cured of HCL. From the 358-person Scripps Clinic Cladribine database, we identified 19 patients in continuous and complete hematologic response (median age, 75 years; median time from diagnosis, 18 years; and median time from Cladribine, 16 years). Nine of 19 (47%) patient samples had no evidence of residual disease; 7 of 19 (37%) samples had MRD; and 3 of 19 (16%) had morphologic evidence of HCL in hematoxylin and eosin-stained bone marrow sections. These results indicate that HCL is potentially curable after Cladribine treatment. In addition, patients with MRD and even gross morphologic disease can live many years without manifesting hematologic relapses.
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Cladribine in the treatment of hairy cell leukemia: initial and subsequent results.
Leukemia & Lymphoma, 2009Co-Authors: Edward Huynh, Darren Sigal, Alan SavenAbstract:Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder associated with pancytopenia, splenomegaly, and recurrent infections. Although interferon α and pentostatin were initially found to be effective in this disease, Cladribine has emerged as the preferred initial therapy. Cladribine given as a single continuous intravenous seven-day infusion is the dosing schedule with the most durable complete remissions and evaluated in the greatest number of patients with HCL. Patients who relapse after purine analogue therapy, whether it be Cladribine or pentostatin, can be successfully retreated with Cladribine. Patients with HCL may develop complications of recurrent infection and second malignancies. Although both complications are postulated to be related to therapy, they may also be due to the duration and burden of the disease. Minimal residual disease detected on bone marrow biopsy is thought to predict for future relapse. We will review the initial and subsequent results of Cladribine in t...
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Cladribine in the treatment of hairy cell leukemia: initial and subsequent results.
Leukemia & lymphoma, 2009Co-Authors: Edward Huynh, Darren Sigal, Alan SavenAbstract:Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder associated with pancytopenia, splenomegaly, and recurrent infections. Although interferon alpha and pentostatin were initially found to be effective in this disease, Cladribine has emerged as the preferred initial therapy. Cladribine given as a single continuous intravenous seven-day infusion is the dosing schedule with the most durable complete remissions and evaluated in the greatest number of patients with HCL. Patients who relapse after purine analogue therapy, whether it be Cladribine or pentostatin, can be successfully retreated with Cladribine. Patients with HCL may develop complications of recurrent infection and second malignancies. Although both complications are postulated to be related to therapy, they may also be due to the duration and burden of the disease. Minimal residual disease detected on bone marrow biopsy is thought to predict for future relapse. We will review the initial and subsequent results of Cladribine in the management of HCL.
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Cladribine in indolent non-Hodgkin’s lymphoma
Expert review of anticancer therapy, 2008Co-Authors: Darren Sigal, Alan SavenAbstract:Before the advent of rationally designed targeted antineoplastic therapies, Cladribine was identified as a lymphocyte-specific cytotoxic agent. Cladribine is a purine nucleoside analogue that is resistant to cellular catabolism. Through diverse mechanisms, Cladribine is equally toxic to dividing and nondividing cells, making it highly active in indolent lymphoproliferative diseases. In clinical practice, Cladribine is mostly used in the treatment of hairy cell leukemia and Waldenstrom's macroglobulinemia. However, its remarkable activity in follicular lymphoma and other indolent non-Hodgkin's lymphoma subtypes has not been more widely appreciated. Cladribine compares favorably to other standard treatments for these conditions. Future Phase III clinical studies should incorporate Cladribine into multiagent chemotherapy programs to more fully evaluate its potential in indolent non-Hodgkin's lymphoma.
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Cladribine in Hairy Cell Leukemia
Hematology oncology clinics of North America, 2006Co-Authors: Rajesh Belani, Alan SavenAbstract:Cladribine results in prolonged complete remissions in most patients wo have HCL. Several studies have indicated that patients who are in complete remission have survivals that are comparable to those of normal age-matched controls. HCL-related mortality is distinctly uncommon. Nevertheless, it is unlikely that Cladribine treatment of HCL is curative because MRD is common in the bone marrows of complete responders. Response criteria for HCL include clinical, hematologic, and morphologic criteria, but do not include flow cytometry, immunohistochemical analysis, or molecular studies. More sensitive techniques have been used by Filleul and colleagues to detect MRD. The used clonoegenic probes from the hypervariable regions of the immunoglobulin heavy-chain gene and performed polymerase chain reactions (PCRs) on bone marrow biopsy specimens, All seven patients who were in morphologic complete remission after a single Cladribine infusion were PCR positive. These data indicate that Cladribine induces protracted remissions but is not necessarily curative. MRD can be detected in most patients when sensitive techniques are used. Persistence of immunohistochemical MRD may predict detected MRD remains to be studied in a large number of patients. Investigators from the University of Pisa in Italy have used a combination of Cladribine and rituximab to eradicate MRD in patients who have HCL. Ten patients received treatment with a standard infusion of Cladribine. Two patients achieved a complete remission, 6 patients achieved a partial remission, and 2 patients failed to respond. All were PCR positive for the immunoglobulin heavy-chain (IgH) gene product at the completion of Cladribine treatment. All 10 patients had achieved a complete hematologic response 2 months after the completion of ritximab therapy. The curative nature of this treatment will require long-term follow-up. Cladribine represents a major therapeutic advance in the treatment of HCL. The prognosis of patients who have HCL has improved greatly with Cladribine therapy. Future strategies should address combination therapy with purine analogs and monclonal antibodies. These strategies should address eradication of MRD in an attempt to develop a potentially curative combination treatment program.
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Assessing the Long-Term Effectiveness of Cladribine vs. Placebo in the Relapsing-Remitting Multiple Sclerosis CLARITY Randomized Controlled Trial and CLARITY Extension Using Treatment Switching Adjustment Methods
Advances in Therapy, 2019Co-Authors: Helen Bell Gorrod, Nicholas R. Latimer, Doris Damian, Robert Hettle, Gerard T. Harty, Schiffon L. WongAbstract:ObjectivesTreatment switching adjustment methods are often used to adjust for switching in oncology randomized controlled trials (RCTs). In this exploratory analysis, we apply these methods to adjust for treatment changes in the setting of an RCT followed by an extension study in relapsing–remitting multiple sclerosis.MethodsThe CLARITY trial evaluated Cladribine tablets versus placebo over 96 weeks. In the 96-week CLARITY Extension, patients who received placebo in CLARITY received Cladribine tablets; patients who received Cladribine tablets in CLARITY were re-randomized to placebo or Cladribine tablets. End points were time to first qualifying relapse (FQR) and time to 3- and 6-month confirmed disability progression (3mCDP, 6mCDP). We aimed to compare the effectiveness of Cladribine tablets with placebo over CLARITY and the extension. The rank-preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE) were used to estimate what would have happened if patients had received placebo in CLARITY and the extension versus patients that received Cladribine tablets and switched to placebo. To gauge whether treatment effect waned after the 96 weeks of CLARITY, we compared hazard ratios (HRs) from the adjustment analysis with HRs from CLARITY.ResultsThe RPSFTM resulted in an HR of 0.48 [95% confidence interval (CI) 0.36–0.62] for FQR, 0.62 (95% CI 0.46–0.84) for 3mCDP and 0.62 (95% CI 0.44–0.88) for 6mCDP. IPE algorithm results were similar. CLARITY HRs were 0.44 (95% CI 0.34–0.58), 0.60 (95% CI 0.41–0.87) and 0.58 (95% CI 0.40–0.83) for FQR, 3mCDP and 6mCDP, respectively.ConclusionsTreatment switching adjustment methods are applicable in non-oncology settings. Adjusted CLARITY plus CLARITY Extension HRs were similar to the CLARITY HRs, demonstrating significant treatment benefits associated with Cladribine tablets versus placebo.FundingEMD Serono, Inc. (a business of Merck KGaA, Darmstadt, Germany).