Ofatumumab

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Tadeusz Robak - One of the best experts on this subject based on the ideXlab platform.

  • improvement in parameters of hematologic and immunologic function and patient well being in the phase iii resonate study of ibrutinib versus Ofatumumab in patients with previously treated chronic lymphocytic leukemia small lymphocytic lymphoma
    Clinical Lymphoma Myeloma & Leukemia, 2018
    Co-Authors: Jacqueline C Barrientos, Christopher Pocock, Steven Coutre, Ulrich Jaeger, Susan Obrien, Nishitha Reddy, Stephen P. Mulligan, Stephen Devereux, Jennifer R Brown, Tadeusz Robak
    Abstract:

    Abstract Background Ibrutinib compared with Ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients and Methods Measures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or Ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization. Results With up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on Ofatumumab (P  Conclusion Ibrutinib led to significant improvements in hematologic function and disease symptomatology versus Ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL.

  • efficacy and safety of idelalisib in combination with Ofatumumab for previously treated chronic lymphocytic leukaemia an open label randomised phase 3 trial
    The Lancet Haematology, 2017
    Co-Authors: Jeffrey A. Jones, Steven Coutre, Tadeusz Robak, Jennifer R Brown, Farrukh T Awan, Xavier Badoux, Javier Loscertales, Kerry Taylor, Elisabeth Vandenberghe, Malgorzata Wach
    Abstract:

    Summary Background Idelalisib, a selective inhibitor of PI3Kδ, is approved for the treatment of patients with relapsed chronic lymphocytic leukaemia (CLL) in combination with rituximab. We aimed to assess the efficacy and safety of idelalisib in combination with a second-generation anti-CD20 antibody, Ofatumumab, in a similar patient population. Methods In this global, open-label, randomised, controlled phase 3 trial, we enrolled patients with relapsed CLL progressing less than 24 months from last therapy. Patients refractory to Ofatumumab were excluded. Patients were stratified by relapsed versus refractory disease, presence or absence of del(17p) or TP53 mutation, or both, and IGHV mutated versus unmutated. We randomised patients in a 2:1 ratio using a web-based interactive system that generated a unique treatment code, and assigned patients to receive either idelalisib plus Ofatumumab (oral idelalisib 150 mg twice daily continuously plus Ofatumumab 300 mg intravenously in week 1, then 1000 mg intravenously weekly for 7 weeks, and every 4 weeks for 16 weeks) or Ofatumumab alone (Ofatumumab dosing as per the combination group, except 2000 mg was substituted for the 1000 mg dose). An independent review committee assessed response, including progressive disease, based on imaging using modified International Workshop on Chronic Lymphocytic Leukaemia 2008 criteria. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. We did a primary analysis (data cutoff Jan 15, 2015) and an updated analysis (data cutoff Sept 1, 2015). This trial is registered with Clinicaltrials.gov, number NCT01659021. Findings Between Dec 17, 2012, and March 31, 2014, we enrolled 261 patients (median age 68 years [IQR 61–74], median previous therapies three [IQR 2–4]). At the primary analysis, median progression-free survival was 16·3 months (95% CI 13·6–17·8) in the idelalisib plus Ofatumumab group and 8·0 months (5·7–8·2) in the Ofatumumab group (adjusted hazard ratio [HR] 0·27, 95% CI 0·19–0·39, p vs 14 [16%] in the Ofatumumab group), diarrhoea (34 [20%] vs one [1%]), and pneumonia (25 [14%] vs seven [8%]). The most frequent grade 3 or worse adverse events in the Ofatumumab group were neutropenia (14 [16%]), pneumonia (seven [8%]), and thrombocytopenia (six [7%] vs 19 [11%] in the idelalisib plus Ofatumumab group). Serious infections were more common in the idelalisib plus Ofatumumab group and included pneumonia (23 [13%] patients in the idelalisib plus Ofatumumab group vs nine [10%] in the Ofatumumab group), sepsis (11 [6%] vs one [1%]), and Pneumocystis jirovecii pneumonia (eight [5%] vs one [1%]). 22 treatment-related deaths occurred in the idelalisib plus Ofatumumab group (the most common being sepsis, septic shock, viral sepsis, and pneumonia). Six treatment-related deaths occurred in the Ofatumumab group (the most common being progressive multifocal leukoencephalopathy and pneumonia). Interpretation The idelalisib plus Ofatumumab combination resulted in better progression-free survival compared with Ofatumumab alone in patients with relapsed CLL, including in those with high-risk disease, and thus might represent a new treatment alternative for this patient population. Funding Gilead Sciences, Inc.

  • updated results of a phase iii randomized controlled study of idelalisib in combination with Ofatumumab for previously treated chronic lymphocytic leukemia cll
    Journal of Clinical Oncology, 2016
    Co-Authors: Jeffrey A. Jones, Tadeusz Robak, Jennifer R Brown, Malgorzata Wach, Nina D Wagnerjohnston, Alexander R Menter, Elizabeth Vandenberghe, Loic Ysebaert, Jonathan Polikoff, Farrukh T Awan
    Abstract:

    7515Background: Idelalisib (IDELA) is an oral PI3Kd inhibitor approved for use with rituximab in pts with relapsed CLL. This open-label study (NCT01659021) compared IDELA + Ofatumumab (OFA) v OFA i...

  • chlorambucil plus Ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia complement 1 a randomised multicentre open label phase 3 trial
    The Lancet, 2015
    Co-Authors: Peter Hillmen, Tadeusz Robak, Ann Janssens, Govind K Babu, Janusz Kloczko, Sebastian Grosicki, Michael Doubek, Panagiotis Panagiotidis, Eva Kimby, Anna Schuh
    Abstract:

    Summary Background Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of Ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options. Methods We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m 2 ) on days 1–7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous Ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189. Findings We enrolled 447 patients, median age 69 years (range 35–92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus Ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0–25·2) in the group assigned to chlorambucil plus Ofatumumab compared with 13·1 months (10·6–13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45–0·72; p vs 98 [43%] given chlorambucil alone), with neutropenia being the most common event (56 [26%] vs 32 [14%]). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus Ofatumumab. Five (2%) patients died during treatment in each group. Interpretation Addition of Ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus Ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy. Funding GlaxoSmithKline, Genmab A/S.

  • Ofatumumab monotherapy in fludarabine refractory chronic lymphocytic leukemia final results from a pivotal study
    Haematologica, 2015
    Co-Authors: Anders Osterborg, Roxanne C Jewell, Stephan Stilgenbauer, Thomas J Kipps, Jiři Mayer, Andrzej Hellmann, Cathy D Williams, Richard R Furman, Swami Padmanabhaniyer, Tadeusz Robak
    Abstract:

    While fludarabine-based regimens are a standard for treatment of chronic lymphocytic leukemia (CLL), patients who become refractory to fludarabine have had low response rates with salvage therapy and poor survival outcomes.1–3 We reported that Ofatumumab, a human monoclonal antibody that binds to a distinct epitope of the CD20 molecule on B cells,4 was effective as monotherapy for fludarabine-refractory CLL at the interim analysis.5 Here we report the final analysis of the study, including a landmark analysis demonstrating the clinical benefits in patients who responded, and the results of both pharmacokinetic and exploratory analyses to identify factors associated with Ofatumumab pharmacokinetics and clinical outcomes.

Thomas J Kipps - One of the best experts on this subject based on the ideXlab platform.

  • associations of Ofatumumab exposure and treatment outcomes in patients with untreated cll receiving chemoimmunotherapy
    Leukemia & Lymphoma, 2017
    Co-Authors: Roxanne C Jewell, Francisco J Hernandezilizaliturri, Stephan Stilgenbauer, Thomas J Kipps, Jan Durig, Laimonas Griskevicius, Lukas Smolej, Jiři Mayer, Georg Hess, Swaminathan Padmanabhaniyer
    Abstract:

    AbstractRelationships between patient characteristics, Ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of Ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg Ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median Cmax and Ctrough values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients. Higher Cmax and Ctrough values at Cycles 3 and 6 were significantly associated with an increased likelihood of CR, whereas Ofatumumab pharmacokinetics were not associated with an objective response (OR) on the basis of univariate analyses. Multivariate analyses indicated that baseline patient/disease factors were predominantly associated with CR (17p status) or OR (bulky lymphadenopathy, gender, and serum thymidine kinase), rather than ofat...

  • Ofatumumab monotherapy in fludarabine refractory chronic lymphocytic leukemia final results from a pivotal study
    Haematologica, 2015
    Co-Authors: Anders Osterborg, Roxanne C Jewell, Stephan Stilgenbauer, Thomas J Kipps, Jiři Mayer, Andrzej Hellmann, Cathy D Williams, Richard R Furman, Swami Padmanabhaniyer, Tadeusz Robak
    Abstract:

    While fludarabine-based regimens are a standard for treatment of chronic lymphocytic leukemia (CLL), patients who become refractory to fludarabine have had low response rates with salvage therapy and poor survival outcomes.1–3 We reported that Ofatumumab, a human monoclonal antibody that binds to a distinct epitope of the CD20 molecule on B cells,4 was effective as monotherapy for fludarabine-refractory CLL at the interim analysis.5 Here we report the final analysis of the study, including a landmark analysis demonstrating the clinical benefits in patients who responded, and the results of both pharmacokinetic and exploratory analyses to identify factors associated with Ofatumumab pharmacokinetics and clinical outcomes.

  • Ofatumumab and high dose methylprednisolone for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia
    Blood Cancer Journal, 2014
    Co-Authors: Januario E Castro, Michael Y Choi, T Carvajal, E Almahasnah, J Chang, Danelle F James, Thomas J Kipps
    Abstract:

    Ofatumumab is a humanized anti-CD20 monoclonal antibody that has been approved by the FDA for the treatment of patients with chronic lymphocytic leukemia. We conducted a phase II single-arm study at a single center. Patients received Ofatumumab (300 mg then 1000 mg weekly for 12 weeks) and methylprednisolone (1000 mg/m2 for 3 days of each 28-day cycle). Twenty-one patients enrolled, including 29% with unfavorable cytogenetics (del17p or del11q). Ninety percent of patients received the full course without dose reductions or delays. The overall response rate was 81% (17/21) with 5% complete response, 10% nodular partial response, 67% partial response, 14% stable disease and 5% progressive disease. After a median follow-up of 31 months, the median progression-free survival was 9.9 months and the median time to next treatment was 12.1 months. The median overall survival has not yet been reached. The combination of high-dose methylprednisolone and Ofatumumab is an effective and tolerable treatment regimen. This regimen may be useful for patients who are unable to tolerate more aggressive therapies, or have not responded to other treatments.

  • chemoimmunotherapy with o fc in previously untreated patients with chronic lymphocytic leukemia
    Blood, 2011
    Co-Authors: William G Wierda, Stephan Stilgenbauer, Thomas J Kipps, Jan Durig, Laimonas Griskevicius, Lukas Smolej, Jiři Mayer, Georg Hess, Rasa Griniute, Francisco J Hernandezilizaliturri
    Abstract:

    We conducted an international phase 2 trial to evaluate 2 dose levels of Ofatumumab, a human CD20 mAb, combined with fludarabine and cyclophosphamide (O-FC) as frontline therapy for chronic lymphocytic leukemia (CLL). Patients with active CLL were randomized to Ofatumumab 500 mg (n = 31) or 1000 mg (n = 30) day 1, with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 days 2-4, course 1; days 1-3, courses 2-6; every 4 weeks for 6 courses. The first Ofatumumab dose was 300 mg for both cohorts. The median age was 56 years; 13% of patients had a 17p deletion; 64% had β2-microglobulin > 3.5 mg/L. Based on the 1996 National Cancer Institute Working Group (NCI-WG) guidelines, the complete response (CR) rate as assessed by an independent review committee was 32% for the 500-mg and 50% for the 1000-mg cohort; the overall response (OR) rate was 77% and 73%, respectively. Based on univariable regression analyses, β2-microglobulin and the number of O-FC courses were significantly correlated ( P < .05) with CR and OR rates and progression-free survival (PFS). The most frequent Common Terminology Criteria (CTC) grade 3-4 investigator-reported adverse events were neutropenia (48%), thrombocytopenia (15%), anemia (13%), and infection (8%). O-FC is active and safe in treatment-naive patients with CLL, including high-risk patients. This trial was registered at [www.clinicaltrials.gov][1] as [NCT00410163][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00410163&atom=%2Fbloodjournal%2F117%2F24%2F6450.atom

  • Ofatumumab combined with fludarabine and cyclophosphamide o fc shows high activity in patients with previously untreated chronic lymphocytic leukemia results from a randomized multicenter international two dose parallel group phase ii trial
    Clinical Lymphoma Myeloma & Leukemia, 2010
    Co-Authors: William G Wierda, Stephan Stilgenbauer, Thomas J Kipps, Jan Durig, Laimonas Griskevicius, Lukas Smolej, Georg Hess, Jiri Mayer, Rasa Griniute, Francisco J Hernandezilizaliturri
    Abstract:

    Abstract 207 Introduction: Chemoimmunotherapy regimens have become the treatment standard for patients with CLL. Ofatumumab is a human monoclonal antibody that targets a unique small-loop epitope on CD20 and elicits rapid and efficient in vitro complement-dependent cytotoxicity, as well as antibody-dependent cellular cytotoxicity. Recent studies demonstrated single-agent Ofatumumab activity, with high overall response rates (ORR) in patients with refractory CLL. We conducted an international, randomized, parallel group, Phase II trial with two doses of Ofatumumab combined with fludarabine and cyclophosphamide (FC) in previously untreated patients with CLL to evaluate the efficacy and tolerability of this chemoimmunotherapy regimen. Methods: Previously untreated patients (N=61) with active CLL (by NCI-WG guidelines) were randomized to receive Ofatumumab 500 mg (Group A) or 1000 mg (Group B) on day 1, combined with fludarabine (25 mg/m 2 IV daily; days 1–3) and cyclophosphamide (250 mg/m 2 IV daily; days 1–3) every 4 weeks for a total of 6 courses. In both Groups, the first dose of Ofatumumab was 300 mg. Dose reduction of FC, but not Ofatumumab, was allowed. Premedication for Ofatumumab was paracetamol and antihistamine prior to each infusion, and glucocorticoid prior to infusions 1 and 2. Neutrophil growth factor and anti-infective prophylaxis were not mandated. The primary endpoint was complete response (CR) rate (1996 NCI-WG criteria) assessed by an Independent Review Committee (IRC), measured from the start of treatment until 3 months after the last infusion. Safety evaluations included investigator-reported adverse events (AEs) and deaths. Follow-up continues for collection of time-to-event endpoints. Results: Data from all 61 patients were available for response assessment (primary endpoint). Pretreatment characteristics are shown in the Table. 71% and 57% of patients in Groups A and B, respectively, completed all 6 courses of O-FC treatment. The CR rate (95% CI) by IRC evaluation was 32% (17, 51%) for Group A and 50% (31, 69%) for Group B; the ORR (95% CI) was 77% (59, 90%) and 73% (54, 88%), respectively (Table). The median progression-free survival has not been reached with the short median follow up of 8 months. No CTC grade 3–4 infusion-related reactions on the day of Ofatumumab infusion were reported. During treatment and up to 30 days following the last dose, the most common (>10% of patients) grade 3–4 AEs reported by investigators were infections in 11 patients (Group A, n=4; Group B, n=7) including febrile neutropenia in 3 patients in each Group, and hematologic AEs including neutropenia in 29 patients (Group A, n=11; Group B, n=18), anemia in 8 patients (Group A, n=2; Group B, n=6) and thrombocytopenia in 9 patients (Group A, n=2; Group B, n=7); grade 3–4 hemolytic anemia occurred in 2 patients in Group A and 1 in Group B; one patient in Group B died (19 days from last dose) with dyspnea (etiology unknown). Beyond the AE reporting period mentioned above, one patient in Group A died (50 days from last dose) due to febrile neutropenia during the follow up period. Results from additional analysis of data will be presented at the meeting. Conclusions: The O-FC regimen is highly active in previously untreated patients with CLL at both Ofatumumab doses investigated and may offer a new chemoimmunotherapy treatment option in these patients. AEs with the O-FC regimen were manageable with no unexpected toxicities. The 1000 mg dose of Ofatumumab is currently being evaluated in combination with chemotherapy in other studies for patients with CLL. Disclosures: Wierda: Genmab, GlaxoSmithKline: Honoraria, Research Funding. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Kipps: Physicians9 Education Resource, Educational Concepts: Speakers Bureau; Genmab, Abbott Industries, Celgene, Biogen Idec, Cephalon, sanofi-aventis, Medimmune, Memgem, Genentech: Research Funding. Durig: GlaxoSmithKline: Honoraria. Griskevicius: GlaxoSmithKline, Genmab: Research Funding. Stilgenbauer: GlaxoSmithKline, Genmab: Consultancy, Honoraria, Research Funding. Mayer: GlaxoSmtihKline: Consultancy. Smolej: Bayer Schering: Honoraria. Padmanabhan: GlaxoSmithKline: Consultancy, Honoraria; Celgene, Genentech: Consultancy. Gorczyca: GlaxoSmithKline: Employment. Chan: GlaxoSmithKline: Employment. Gupta: GlaxoSmithKline: Employment. Andersen: H. Lundbeck A/S: Shares ownership; Novo Nordisk A/S, H. Lundbeck A/S and Genmab A/S: Consultancy. Strange: Genmab: Employment. Nielsen: Genmab: Employment. Russell: Genmab: Employment, Equity Ownership.

Stephan Stilgenbauer - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of duvelisib following disease progression on Ofatumumab in patients with relapsed refractory cll or sll in the duo crossover extension study
    Clinical Cancer Research, 2020
    Co-Authors: Matthew S. Davids, Peter Hillmen, Constantine S Tam, Bryone J Kuss, Marco Montillo, Carol Moreno, James Essell, Nicole Lamanna, Zsolt Nagy, Stephan Stilgenbauer
    Abstract:

    Purpose: In the phase 3 DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy vs Ofatumumab (median [m]PFS, 13.3 vs 9.9 months [HR, 0.52; P < .0001]; ORR, 74% vs 45% [P < .0001]), with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after Ofatumumab who crossed over to duvelisib in the DUO trial. Experimental Design: Patients with radiographically confirmed PD after Ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety. Results: As of December 14, 2018, 90 Ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or TP53 mutations had similar outcomes (ORR, 77% [20/26]; mPFS, 14.7 months). Notably, 73% of patients (47/64) with disease previously refractory to Ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%). Conclusions: Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on Ofatumumab, including patients with high-risk disease and disease previously refractory to Ofatumumab.

  • associations of Ofatumumab exposure and treatment outcomes in patients with untreated cll receiving chemoimmunotherapy
    Leukemia & Lymphoma, 2017
    Co-Authors: Roxanne C Jewell, Francisco J Hernandezilizaliturri, Stephan Stilgenbauer, Thomas J Kipps, Jan Durig, Laimonas Griskevicius, Lukas Smolej, Jiři Mayer, Georg Hess, Swaminathan Padmanabhaniyer
    Abstract:

    AbstractRelationships between patient characteristics, Ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of Ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg Ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median Cmax and Ctrough values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients. Higher Cmax and Ctrough values at Cycles 3 and 6 were significantly associated with an increased likelihood of CR, whereas Ofatumumab pharmacokinetics were not associated with an objective response (OR) on the basis of univariate analyses. Multivariate analyses indicated that baseline patient/disease factors were predominantly associated with CR (17p status) or OR (bulky lymphadenopathy, gender, and serum thymidine kinase), rather than ofat...

  • Ofatumumab monotherapy in fludarabine refractory chronic lymphocytic leukemia final results from a pivotal study
    Haematologica, 2015
    Co-Authors: Anders Osterborg, Roxanne C Jewell, Stephan Stilgenbauer, Thomas J Kipps, Jiři Mayer, Andrzej Hellmann, Cathy D Williams, Richard R Furman, Swami Padmanabhaniyer, Tadeusz Robak
    Abstract:

    While fludarabine-based regimens are a standard for treatment of chronic lymphocytic leukemia (CLL), patients who become refractory to fludarabine have had low response rates with salvage therapy and poor survival outcomes.1–3 We reported that Ofatumumab, a human monoclonal antibody that binds to a distinct epitope of the CD20 molecule on B cells,4 was effective as monotherapy for fludarabine-refractory CLL at the interim analysis.5 Here we report the final analysis of the study, including a landmark analysis demonstrating the clinical benefits in patients who responded, and the results of both pharmacokinetic and exploratory analyses to identify factors associated with Ofatumumab pharmacokinetics and clinical outcomes.

  • chemoimmunotherapy with o fc in previously untreated patients with chronic lymphocytic leukemia
    Blood, 2011
    Co-Authors: William G Wierda, Stephan Stilgenbauer, Thomas J Kipps, Jan Durig, Laimonas Griskevicius, Lukas Smolej, Jiři Mayer, Georg Hess, Rasa Griniute, Francisco J Hernandezilizaliturri
    Abstract:

    We conducted an international phase 2 trial to evaluate 2 dose levels of Ofatumumab, a human CD20 mAb, combined with fludarabine and cyclophosphamide (O-FC) as frontline therapy for chronic lymphocytic leukemia (CLL). Patients with active CLL were randomized to Ofatumumab 500 mg (n = 31) or 1000 mg (n = 30) day 1, with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 days 2-4, course 1; days 1-3, courses 2-6; every 4 weeks for 6 courses. The first Ofatumumab dose was 300 mg for both cohorts. The median age was 56 years; 13% of patients had a 17p deletion; 64% had β2-microglobulin > 3.5 mg/L. Based on the 1996 National Cancer Institute Working Group (NCI-WG) guidelines, the complete response (CR) rate as assessed by an independent review committee was 32% for the 500-mg and 50% for the 1000-mg cohort; the overall response (OR) rate was 77% and 73%, respectively. Based on univariable regression analyses, β2-microglobulin and the number of O-FC courses were significantly correlated ( P < .05) with CR and OR rates and progression-free survival (PFS). The most frequent Common Terminology Criteria (CTC) grade 3-4 investigator-reported adverse events were neutropenia (48%), thrombocytopenia (15%), anemia (13%), and infection (8%). O-FC is active and safe in treatment-naive patients with CLL, including high-risk patients. This trial was registered at [www.clinicaltrials.gov][1] as [NCT00410163][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00410163&atom=%2Fbloodjournal%2F117%2F24%2F6450.atom

  • Ofatumumab combined with fludarabine and cyclophosphamide o fc shows high activity in patients with previously untreated chronic lymphocytic leukemia results from a randomized multicenter international two dose parallel group phase ii trial
    Clinical Lymphoma Myeloma & Leukemia, 2010
    Co-Authors: William G Wierda, Stephan Stilgenbauer, Thomas J Kipps, Jan Durig, Laimonas Griskevicius, Lukas Smolej, Georg Hess, Jiri Mayer, Rasa Griniute, Francisco J Hernandezilizaliturri
    Abstract:

    Abstract 207 Introduction: Chemoimmunotherapy regimens have become the treatment standard for patients with CLL. Ofatumumab is a human monoclonal antibody that targets a unique small-loop epitope on CD20 and elicits rapid and efficient in vitro complement-dependent cytotoxicity, as well as antibody-dependent cellular cytotoxicity. Recent studies demonstrated single-agent Ofatumumab activity, with high overall response rates (ORR) in patients with refractory CLL. We conducted an international, randomized, parallel group, Phase II trial with two doses of Ofatumumab combined with fludarabine and cyclophosphamide (FC) in previously untreated patients with CLL to evaluate the efficacy and tolerability of this chemoimmunotherapy regimen. Methods: Previously untreated patients (N=61) with active CLL (by NCI-WG guidelines) were randomized to receive Ofatumumab 500 mg (Group A) or 1000 mg (Group B) on day 1, combined with fludarabine (25 mg/m 2 IV daily; days 1–3) and cyclophosphamide (250 mg/m 2 IV daily; days 1–3) every 4 weeks for a total of 6 courses. In both Groups, the first dose of Ofatumumab was 300 mg. Dose reduction of FC, but not Ofatumumab, was allowed. Premedication for Ofatumumab was paracetamol and antihistamine prior to each infusion, and glucocorticoid prior to infusions 1 and 2. Neutrophil growth factor and anti-infective prophylaxis were not mandated. The primary endpoint was complete response (CR) rate (1996 NCI-WG criteria) assessed by an Independent Review Committee (IRC), measured from the start of treatment until 3 months after the last infusion. Safety evaluations included investigator-reported adverse events (AEs) and deaths. Follow-up continues for collection of time-to-event endpoints. Results: Data from all 61 patients were available for response assessment (primary endpoint). Pretreatment characteristics are shown in the Table. 71% and 57% of patients in Groups A and B, respectively, completed all 6 courses of O-FC treatment. The CR rate (95% CI) by IRC evaluation was 32% (17, 51%) for Group A and 50% (31, 69%) for Group B; the ORR (95% CI) was 77% (59, 90%) and 73% (54, 88%), respectively (Table). The median progression-free survival has not been reached with the short median follow up of 8 months. No CTC grade 3–4 infusion-related reactions on the day of Ofatumumab infusion were reported. During treatment and up to 30 days following the last dose, the most common (>10% of patients) grade 3–4 AEs reported by investigators were infections in 11 patients (Group A, n=4; Group B, n=7) including febrile neutropenia in 3 patients in each Group, and hematologic AEs including neutropenia in 29 patients (Group A, n=11; Group B, n=18), anemia in 8 patients (Group A, n=2; Group B, n=6) and thrombocytopenia in 9 patients (Group A, n=2; Group B, n=7); grade 3–4 hemolytic anemia occurred in 2 patients in Group A and 1 in Group B; one patient in Group B died (19 days from last dose) with dyspnea (etiology unknown). Beyond the AE reporting period mentioned above, one patient in Group A died (50 days from last dose) due to febrile neutropenia during the follow up period. Results from additional analysis of data will be presented at the meeting. Conclusions: The O-FC regimen is highly active in previously untreated patients with CLL at both Ofatumumab doses investigated and may offer a new chemoimmunotherapy treatment option in these patients. AEs with the O-FC regimen were manageable with no unexpected toxicities. The 1000 mg dose of Ofatumumab is currently being evaluated in combination with chemotherapy in other studies for patients with CLL. Disclosures: Wierda: Genmab, GlaxoSmithKline: Honoraria, Research Funding. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Kipps: Physicians9 Education Resource, Educational Concepts: Speakers Bureau; Genmab, Abbott Industries, Celgene, Biogen Idec, Cephalon, sanofi-aventis, Medimmune, Memgem, Genentech: Research Funding. Durig: GlaxoSmithKline: Honoraria. Griskevicius: GlaxoSmithKline, Genmab: Research Funding. Stilgenbauer: GlaxoSmithKline, Genmab: Consultancy, Honoraria, Research Funding. Mayer: GlaxoSmtihKline: Consultancy. Smolej: Bayer Schering: Honoraria. Padmanabhan: GlaxoSmithKline: Consultancy, Honoraria; Celgene, Genentech: Consultancy. Gorczyca: GlaxoSmithKline: Employment. Chan: GlaxoSmithKline: Employment. Gupta: GlaxoSmithKline: Employment. Andersen: H. Lundbeck A/S: Shares ownership; Novo Nordisk A/S, H. Lundbeck A/S and Genmab A/S: Consultancy. Strange: Genmab: Employment. Nielsen: Genmab: Employment. Russell: Genmab: Employment, Equity Ownership.

Jennifer R Brown - One of the best experts on this subject based on the ideXlab platform.

  • improvement in parameters of hematologic and immunologic function and patient well being in the phase iii resonate study of ibrutinib versus Ofatumumab in patients with previously treated chronic lymphocytic leukemia small lymphocytic lymphoma
    Clinical Lymphoma Myeloma & Leukemia, 2018
    Co-Authors: Jacqueline C Barrientos, Christopher Pocock, Steven Coutre, Ulrich Jaeger, Susan Obrien, Nishitha Reddy, Stephen P. Mulligan, Stephen Devereux, Jennifer R Brown, Tadeusz Robak
    Abstract:

    Abstract Background Ibrutinib compared with Ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients and Methods Measures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or Ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization. Results With up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on Ofatumumab (P  Conclusion Ibrutinib led to significant improvements in hematologic function and disease symptomatology versus Ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL.

  • efficacy and safety of idelalisib in combination with Ofatumumab for previously treated chronic lymphocytic leukaemia an open label randomised phase 3 trial
    The Lancet Haematology, 2017
    Co-Authors: Jeffrey A. Jones, Steven Coutre, Tadeusz Robak, Jennifer R Brown, Farrukh T Awan, Xavier Badoux, Javier Loscertales, Kerry Taylor, Elisabeth Vandenberghe, Malgorzata Wach
    Abstract:

    Summary Background Idelalisib, a selective inhibitor of PI3Kδ, is approved for the treatment of patients with relapsed chronic lymphocytic leukaemia (CLL) in combination with rituximab. We aimed to assess the efficacy and safety of idelalisib in combination with a second-generation anti-CD20 antibody, Ofatumumab, in a similar patient population. Methods In this global, open-label, randomised, controlled phase 3 trial, we enrolled patients with relapsed CLL progressing less than 24 months from last therapy. Patients refractory to Ofatumumab were excluded. Patients were stratified by relapsed versus refractory disease, presence or absence of del(17p) or TP53 mutation, or both, and IGHV mutated versus unmutated. We randomised patients in a 2:1 ratio using a web-based interactive system that generated a unique treatment code, and assigned patients to receive either idelalisib plus Ofatumumab (oral idelalisib 150 mg twice daily continuously plus Ofatumumab 300 mg intravenously in week 1, then 1000 mg intravenously weekly for 7 weeks, and every 4 weeks for 16 weeks) or Ofatumumab alone (Ofatumumab dosing as per the combination group, except 2000 mg was substituted for the 1000 mg dose). An independent review committee assessed response, including progressive disease, based on imaging using modified International Workshop on Chronic Lymphocytic Leukaemia 2008 criteria. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. We did a primary analysis (data cutoff Jan 15, 2015) and an updated analysis (data cutoff Sept 1, 2015). This trial is registered with Clinicaltrials.gov, number NCT01659021. Findings Between Dec 17, 2012, and March 31, 2014, we enrolled 261 patients (median age 68 years [IQR 61–74], median previous therapies three [IQR 2–4]). At the primary analysis, median progression-free survival was 16·3 months (95% CI 13·6–17·8) in the idelalisib plus Ofatumumab group and 8·0 months (5·7–8·2) in the Ofatumumab group (adjusted hazard ratio [HR] 0·27, 95% CI 0·19–0·39, p vs 14 [16%] in the Ofatumumab group), diarrhoea (34 [20%] vs one [1%]), and pneumonia (25 [14%] vs seven [8%]). The most frequent grade 3 or worse adverse events in the Ofatumumab group were neutropenia (14 [16%]), pneumonia (seven [8%]), and thrombocytopenia (six [7%] vs 19 [11%] in the idelalisib plus Ofatumumab group). Serious infections were more common in the idelalisib plus Ofatumumab group and included pneumonia (23 [13%] patients in the idelalisib plus Ofatumumab group vs nine [10%] in the Ofatumumab group), sepsis (11 [6%] vs one [1%]), and Pneumocystis jirovecii pneumonia (eight [5%] vs one [1%]). 22 treatment-related deaths occurred in the idelalisib plus Ofatumumab group (the most common being sepsis, septic shock, viral sepsis, and pneumonia). Six treatment-related deaths occurred in the Ofatumumab group (the most common being progressive multifocal leukoencephalopathy and pneumonia). Interpretation The idelalisib plus Ofatumumab combination resulted in better progression-free survival compared with Ofatumumab alone in patients with relapsed CLL, including in those with high-risk disease, and thus might represent a new treatment alternative for this patient population. Funding Gilead Sciences, Inc.

  • updated results of a phase iii randomized controlled study of idelalisib in combination with Ofatumumab for previously treated chronic lymphocytic leukemia cll
    Journal of Clinical Oncology, 2016
    Co-Authors: Jeffrey A. Jones, Tadeusz Robak, Jennifer R Brown, Malgorzata Wach, Nina D Wagnerjohnston, Alexander R Menter, Elizabeth Vandenberghe, Loic Ysebaert, Jonathan Polikoff, Farrukh T Awan
    Abstract:

    7515Background: Idelalisib (IDELA) is an oral PI3Kd inhibitor approved for use with rituximab in pts with relapsed CLL. This open-label study (NCT01659021) compared IDELA + Ofatumumab (OFA) v OFA i...

  • ibrutinib versus Ofatumumab in previously treated chronic lymphocytic leukemia small lymphocytic lymphoma cll sll results from the randomized phase iii resonate pcyc 1112 trial
    Clinical Lymphoma Myeloma & Leukemia, 2015
    Co-Authors: Jennifer R Brown, Jacqueline C Barrientos, Steven Coutre, Susan Obrien, Nishitha Reddy, Stephen P. Mulligan, John C Byrd, Neil E Kay, Constantine S Tam, Ulrich Jaeger
    Abstract:

    304 Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Results From the Randomized Phase III RESONATETM (PCYC-1112) Trial J Jennifer R. Brown, MD, PhD1, John C. Byrd, MD2, Susan O’Brien, MD3, Jacqueline C. Barrientos, MD4, Neil E. Kay, MD5, Nishitha M. Reddy, MBBS, MD6, Steven Coutre, MD7, Constantine S. Tam, MBBS, MD8, Stephen Mulligan, MBBS, PhD, FRACP, FRCPA9, Ulrich Jaeger, MD10, Stephen Devereux, PhD, FRCP, FRCPath11, Paul M. Barr, MD12, Richard Furman, MD13, Thomas Kipps, MD, PhD14, Florence Cymbalista, MD, PhD15, Maria Fardis, PhD, MBA16, Jesse McGreivy, MD16, Fong Clow, DSc16, Danelle F. James, MD, MAS16, Peter Hillmen, MD, PhD, FRCP, FRCPath17 1Dana-Farber Cancer Institute, Boston, MA, USA; 2The Ohio State University Medical Center, Columbus, OH, USA; 3University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4North Shore Long Island Jewish Health System, Manhasset, NY, USA; 5Mayo Clinic, Rochester, MN, USA; 6Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 7Stanford University School of Medicine, Stanford, CA, USA; 8Peter MacCallum Cancer Centre and St. Vincent’s Hospital, Melbourne, Australia; 9Royal North Shore Hospital, Sydney, Australia; 10Medical University of Vienna, Vienna, Austria; 11Kings College Hospital, NHS Foundation Trust Denmark Hill, London, UK; 12University of Rochester Cancer Center, Rochester, NY, USA; 13Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY, USA; 14Moores UCSD Cancer Center, San Diego, CA, USA; 15Hopital Avicenne, Paris, France; 16Pharmacyclics, Inc., Sunnyvale, CA, USA; 17The Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds, UK Context: Ibrutinib, a first-in-class, once-daily oral, covalent inhibitor of Bruton’s tyrosine kinase, demonstrated single-agent activity and an acceptable safety profile in a phase II relapsed/refractory (R/R) CLL/SLL study (Byrd et al. NEJM 2013). Ibrutinib is FDA approved for CLL patients who have received ≥1 prior therapy, and for patients with del(17p) CLL. Objective: Interim safety and efficacy results from an international, multicenter, open-label, randomized phase III study of single-agent ibrutinib vs Ofatumumab in R/R CLL/SLL Patients: Patients with R/R CLL/SLL who received ≥1 previous therapy considered inappropriate for purine analogs Main Outcome Measures: Independent Review Committee-assessed PFS (primary); overall survival (OS), ORR, safety (secondary) Intervention: 420 mg oral ibrutinib daily or IV Ofatumumab 300/2000 mg (12 doses) Results: 391 patients (median age 67 years, 40% ≥70 years, 30% del17p); 195 randomized to ibrutinib, 196 to Ofatumumab. Ibrutinib patients had median 3 prior therapies vs 2 for Ofatumumab. Ibrutinib significantly improved PFS (median not reached vs 8.1 months; HR 0.215, 95% CI 0.146-0.317, P<0.0001; 78.5% risk reduction), and OS (median not reached; HR 0.434, 95% CI 0.238-0.789, P=0.0049; 57% risk reduction) vs Ofatumumab. Ofatumumab patients (n=57) with confirmed progressive disease crossed over to the ibrutinib arm. ORR by IRC, including partial response with lymphocytosis: 62.6% for ibrutinib vs 4.1% for Ofatumumab. Similar effects were seen in del(17p) and purine analog-refractory subsets. Most frequent adverse events (AEs) for ibrutinib vs Ofatumumab: diarrhea (47.7% vs 17.8%), fatigue (27.7% vs 29.8%), and nausea (26.2% vs 18.3%). Any-grade atrial fibrillation was observed more frequently with ibrutinib (5.1% vs 0.5%). Major hemorrhage rates: 1% for ibrutinib vs 1.6% for Ofatumumab. Drug discontinuation due to AEs: 4.1% for ibrutinib vs 3.6% for Ofatumumab. At median time on study of 9.6 months, 86% of ibrutinib patients were continuing treatment. Conclusions: Single-agent ibrutinib significantly improved PFS, OS, and ORR in patients with previously treated CLL/SLL compared with Ofatumumab. The effect of ibrutinib on PFS was observed irrespective of baseline features, including del(17p) or purine analog-refractory disease. The safety profile was comparable with that reported previously. These results support ibrutinib as an effective therapy for patients with previously treated CLL.

  • ibrutinib versus Ofatumumab in previously treated chronic lymphoid leukemia
    The New England Journal of Medicine, 2014
    Co-Authors: John C Byrd, Jacqueline C Barrientos, Steven Coutre, Susan Obrien, Nishitha Reddy, Stephen P. Mulligan, Jennifer R Brown, Neil E Kay, Constantine S Tam, Ulrich Jaeger
    Abstract:

    Background In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton’s tyrosine kinase, in patients at risk for a poor outcome. Methods In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody Ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points. Results At a median follow-up of 9.4 months, ibrutinib significantly improved progressionfree survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the Ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P = 0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the Ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the Ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the Ofatumumab group. Conclusions Ibrutinib, as compared with Ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.)

Koji Sasaki - One of the best experts on this subject based on the ideXlab platform.

  • hyper cvad plus Ofatumumab versus hyper cvad plus rituximab as frontline therapy in adults with philadelphia chromosome negative acute lymphoblastic leukemia a propensity score analysis
    Cancer, 2021
    Co-Authors: Koji Sasaki, Hagop M Kantarjian, Kiyomi Morita, Nicholas J Short, Marina Konopleva, Nitin Jain, Farhad Ravandi, Guillermo Garciamanero, Sa Wang, Joseph D Khoury
    Abstract:

    Background The outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus Ofatumumab hyper-CVAD + Ofatumumab (hyper-CVAD + Ofatumumab) has not been compared with the outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus Ofatumumab hyper-CVAD plus rituximab (hyper-CVAD + Rituximab) in Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) in a randomized clinical trial. Methods The authors compared the outcomes of 69 patients treated with hyper-CVAD + Ofatumumab and 95 historical-control patients treated with hyper-CVAD + Rituximab. Historical-control patients were treated with hyper-CVAD + Rituximab if they had CD20 expression ≥ 20%. Ofatumumab (day 1 of course 1, 300 mg intravenously; subsequent doses, 2000 mg intravenously) was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of 8 doses. A propensity score analysis with inverse probability of treatment weighting (IPTW) was performed to adjust for baseline covariates between groups. Results The median event-free survival with stem cell transplantation (SCT) censoring was 33 and 65 months with hyper-CVAD + Rituximab and hyper-CVAD + Ofatumumab, respectively (crude P = .064; IPTW P = .054). The median overall survival with SCT censoring was 52 months and not reached, respectively (crude P = .087; IPTW P = .097). Conclusions Hyper-CVAD + Ofatumumab was associated with better outcomes than hyper-CVAD + Rituximab among patients with newly diagnosed Philadelphia chromosome-negative ALL.

  • hyper cvad regimen in combination with Ofatumumab as frontline therapy for adults with philadelphia chromosome negative b cell acute lymphoblastic leukaemia a single arm phase 2 trial
    The Lancet Haematology, 2020
    Co-Authors: Elias Jabbour, Marina Konopleva, Guillaume Richardcarpentier, Yuya Sasaki, Keyur P Patel, Kathryn G Roberts, Zhaohui Gu, Feng Wang, Xuelin Huang, Koji Sasaki
    Abstract:

    Summary Background The addition of rituximab to intensive chemotherapy improves outcomes in patients with B-cell acute lymphoblastic leukaemia. Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small extracellular loop of CD20 and has greater in vitro complement-mediated cytotoxicity than rituximab. In this study, we assessed the activity and safety of Ofatumumab in combination with chemotherapy in patients with Philadelphia chromosome (Ph)-negative CD20-positive B-cell acute lymphoblastic leukaemia. Methods This was a single-arm, phase 2 trial done at the MD Anderson Cancer Center (Houston, TX, USA). Patients with newly diagnosed, Ph-negative B-cell acute lymphoblastic leukaemia or lymphoblastic lymphoma with CD20 expression of at least 1% were eligible. Patients were treated with up to eight courses of the hyper-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) on courses 1, 3, 5, and 7 alternating with high-dose methotrexate and cytarabine on courses 2, 4, 6, and 8. Ofatumumab was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of eight doses. The first dose of Ofatumumab was 300 mg intravenously and all subsequent doses were 2000 mg intravenously. Patients received 30 courses of maintenance therapy with 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP), with four intensification courses (high-dose methotrexate plus L-asparaginase and hyper-CVAD plus Ofatumumab on courses 6–7 and 18–19). The primary endpoints were event-free survival, overall response, and overall survival. All enrolled patients were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, NCT01363128. Findings Between Aug 26, 2011, and May 18, 2017, 69 patients (67 patients had B-cell acute lymphoblastic leukaemia and two had B-cell lymphoblastic lymphoma; median age 41 years [IQR 32-50]) were enrolled and treated, including 33 (48%) aged between 18 and 39 years. Nine (27%) of 33 patients had Ph-like acute lymphoblastic leukaemia. With a median follow-up of 44 months (26–53), 4-year event-free survival was 59% (95% CI 48–73); 69% (54–87) in adolescents and young adults aged 18–39 years. 4-year overall survival was 68% (58–81); 74% (60–91) in adolescents and young adults. The overall response rate was 98% (64 of 65 patients). The most common non-haematological grade 3 or 4 adverse events were infections (35 [54%] of 65 patients during induction and 53 [78%] of 68 patients during consolidation). Ten (14%) of 69 patients died in complete remission from sepsis (two [3%]), cardiac arrest (one [1%]), therapy-related acute myeloid leukaemia (two [3%]), and haematopoietic stem-cell transplantation complications (five [7%]). None of these deaths were considered related to Ofatumumab treatment by the study investigators. Interpretation The combination of hyper-CVAD plus Ofatumumab is safe and active in adults with Ph-negative CD20-positive B-cell acute lymphoblastic leukaemia. Modifications of this regimen with the addition of novel monoclonal and bispecific antibody constructs targeting CD19 and CD22 might further improve outcomes and allow reduction in the intensity and duration of chemotherapy. Funding Novartis.

  • a phase 2 study of hyper cvad plus Ofatumumab as frontline therapy in cd20 acute lymphoblastic leukemia all updated results
    Journal of Clinical Oncology, 2018
    Co-Authors: Abdul Hamid Bazarbachi, Nicholas J Short, Farhad Ravandi, Guillermo Garciamanero, Musa Yilmaz, Deborah A Thomas, Maria Khouri, Rebecca Garris, Jorge E Cortes, Koji Sasaki
    Abstract:

    7041Background: In vitro studies showed that Ofatumumab (O), a type I human antibody that targets a different CD20 epitope compared to rituximab, induces more potent antibody-dependent and compleme...

  • updated results of frontline Ofatumumab hyper cvad in adults with cd20 acute lymphoblastic leukemia
    Journal of Clinical Oncology, 2017
    Co-Authors: Abhishek Maiti, Hagop M Kantarjian, Nicholas J Short, Farhad Ravandi, Guillermo Garciamanero, Deborah A Thomas, Maria Khouri, Rebecca Garris, Jorge E Cortes, Koji Sasaki
    Abstract:

    7033Background: Chemoimmunotherapy is an effective frontline therapy for acute lymphoblastic leukemia (ALL). Ofatumumab (O) binds to a proximal small-loop epitope on CD20 and is more potent in vitr...

  • updated results from the phase ii study of hyper cvad in combination with Ofatumumab as frontline therapy for adults with cd20 positive cd20 acute lymphoblastic leukemia all
    Journal of Clinical Oncology, 2016
    Co-Authors: Ghayas C Issa, Hagop M Kantarjian, Nicholas J Short, Farhad Ravandi, Guillermo Garciamanero, Deborah A Thomas, Maria Khouri, Rebecca Garris, Jorge E Cortes, Koji Sasaki
    Abstract:

    7042Background: Chemoimmunotherapy is standard of care for patients (pts) with CD20+ ALL. Ofatumumab targets a unique small-loop epitope on CD20 and is more potent in vitro than rituximab. The comb...

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