scholarly journals Outcomes of Reduced Frequency Dosing of Ibrutinib in Chronic Lymphocytic Leukemia Patients Following Complete or Partial Remission: A Pilot Study

2020 ◽  
Vol 9 (3) ◽  
pp. 55-61
Author(s):  
William Alexander ◽  
Sarah Davis ◽  
Raj Ramakrishna ◽  
Arumugam Manoharan
Keyword(s):  
Pilot Study ◽  
Chronic Lymphocytic Leukemia ◽  
Partial Remission ◽  
Lymphocytic Leukemia ◽  
Reduced Frequency

scholarly journals A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia

Blood ◽  
2018 ◽  
Vol 132 (21) ◽  
pp. 2249-2259 ◽  
Author(s):  
Lisa S. Chen ◽  
Prithviraj Bose ◽  
Nichole D. Cruz ◽  
Yongying Jiang ◽  
Qi Wu ◽  
...  
Keyword(s):  
Pilot Study ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Downstream Signaling ◽  
Protein Levels ◽  
Lower Drug ◽  
Dose Dependent ◽  
Initial Cycle ◽  
Different Doses ◽  
Dose Reductions

Abstract Ibrutinib is highly efficacious and used at 420 mg/d for treatment of chronic lymphocytic leukemia (CLL). We previously demonstrated a decline in Bruton’s tyrosine kinase (BTK) protein levels in CLL cells after 1 cycle of ibrutinib, suggesting ibrutinib dose could be lowered after the first cycle without loss of biological effect. To test this postulate, a pilot study (NCT02801578) was designed to systematically reduce ibrutinib dosing within the same patient with CLL over the course of three 28-day cycles. After an initial cycle of 420 mg/d, the dose was reduced to 280 mg/d in cycle 2, and then to 140 mg/d in cycle 3. Eleven patients began study treatment, and 9 completed the 3 cycles. Plasma and intracellular pharmacokinetics (PK), BTK occupancy, and pharmacodynamic (PD) response at different doses of ibrutinib were compared. Plasma and intracellular levels of ibrutinib were dose-dependent, and even the lowest dose was sufficient to occupy, on average, more than 95% of BTK protein. In concert, BTK downstream signaling inhibition was maintained with 140 mg/d ibrutinib in cycle 3, and there were comparable reductions in total and phospho-BTK (Tyr223) protein levels across 3 cycles. Reductions of plasma chemokine CCL3 and CCL4 levels, considered to be biomarkers of ibrutinib response, were similar during the 3 cycles. These PK/PD data demonstrate that after 1 cycle of ibrutinib at the standard 420 mg/d dose, the dose can be reduced without losing biological activity. Clinical efficacy of lower doses needs to be systematically evaluated. Such dose reductions would lower drug cost, lessen untoward toxicity, and facilitate rationale-based combinations. This trial was registered at www.clinicaltrials.gov as #NCT02801578.

scholarly journals Retreatment with obinutuzumab: An addition to the therapeutic landscape of chronic lymphocytic leukemia

2019 ◽  
Vol 7 ◽  
pp. 2050313X1882391 ◽  
Author(s):  
Sharad Khurana ◽  
Salman Ahmed ◽  
Victoria R Alegria ◽  
Sonikpreet Aulakh ◽  
Meghna Ailawadhi ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Partial Remission ◽  
Single Agent ◽  
Chronic Lymphocytic Leukemia Patient ◽  
Lymphocytic Leukemia ◽  
Viable Option ◽  
Leukemia Patient ◽  
Therapeutic Landscape ◽  
Response Status ◽  
Anti Cd20

Obinutuzumab is used for the treatment of chronic lymphocytic leukemia. So far there are no data of using this for retreatment in patients who have received it previously. We introduced obinutuzumab for the retreatment in a chronic lymphocytic leukemia patient, who had first achieved partial remission with it and eventually relapsed over a course of 2.5 years. After retreatment with single-agent obinutuzumab, the patient achieved a partial remission again within one cycle and continues to maintain the response status. This case is a platform for considering obinutuzumab as a viable option for retreatment of chronic lymphocytic leukemia patients who have received it before, similar to the pattern of use for other anti-CD20 monoclonal antibodies in this disease, including rituximab.

A pilot study of epirubicin and chlorambucil in the treatment of chronic lymphocytic leukemia (CLL)

2006 ◽  
Vol 9 (6) ◽  
pp. 315-321 ◽  
Author(s):  
G. M. Smith ◽  
J. A. Child ◽  
D. W. Milligan ◽  
M. A. McEvoy ◽  
J. A. Murray
Keyword(s):  
Pilot Study ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia

Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1094-1100 ◽  
Author(s):  
Bertrand Coiffier ◽  
Stéphane Lepretre ◽  
Lars Møller Pedersen ◽  
Ole Gadeberg ◽  
Henrik Fredriksen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Partial Remission ◽  
Phase 1 ◽  
Objective Response ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Safety And Efficacy ◽  
Anti Cd20

Abstract Safety and efficacy of the fully human anti-CD20 monoclonal antibody, ofatumumab, was analyzed in a multicenter dose-escalating study including 33 patients with relapsed or refractory chronic lymphocytic leukemia. Three cohorts of 3 (A), 3 (B), and 27 (C) patients received 4, once weekly, infusions of ofatumumab at the following doses: (A) one 100 mg and three 500 mg; (B) one 300 mg and three 1000 mg; (C) one 500 mg and three 2000 mg. Sixty-seven percent of the patients were Binet stage B, and the median number of previous treatments was 3. The maximum tolerated dose was not reached. The majority of related adverse events occurred at first infusion, and the number of adverse events decreased at each subsequent infusion. Seventeen (51%) of 33 patients experienced infections, 88% of them of grade 1-2. One event of interstitial pneumonia was fatal; all other cases resolved within one month. The response rate of cohort C was 50% (13/26), one patient having a nodular partial remission and 12 patients partial remission. In conclusion, ofatumumab was found to be well tolerated in patients with chronic lymphocytic leukemia (CLL) in doses up to 2000 mg. Preliminary data on safety and objective response are encouraging and support further studies on the role of ofatumumab in CLL patients. This trial was registered at www.clinicaltrials.gov as no. NCT00093314.

The Combination of 2-CDA and Rituximab in Patients with Chronic Lymphocytic Leukemia (CLL): A Prospective Multicenter Phase II Trial (SAKK 34/02).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2057-2057 ◽  
Author(s):  
Nicolas Leupin ◽  
Jan C. Schuller ◽  
Max Solenthaler ◽  
Andre Tichelli ◽  
Alois Gratwohl ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Partial Remission ◽  
Alkylating Agents ◽  
Lymphocytic Leukemia ◽  
Stem Cell Mobilization ◽  
Remission Induction ◽  
Bone Marrow Biopsies ◽  
Cell Mobilization ◽  
Grade 3

Abstract Introduction: This trial aimed to determine the efficacy and toxicity of an induction immunochemotherapy consisting of rituximab and cladribine (2-chlorodeoxyadenosine, 2-CDA) in patients (pts) suffering from chronic lymphocytic leukemia (CLL). Methods: Inclusion criteria were CLL at first diagnosis or after one treatment with alkylating agents. The regimen consisted of four remission induction cycles. In cycle 1, 2-CDA (0.1 mg/kg/day) was administered for 5 days. In cycles 2-4, Rituximab (375 mg/m^2) was given on day 1 followed by 2-CDA (0.1 mg/kg body weight), in intervals of 28 days. Responding pts (complete remission (CR), very good partial remission (VGPR) or nodular partial remission (NPR)) underwent stem cell mobilization chemotherapy with Cyclophosphamide (4g/m^2 on day 2) G-CSF (10 microgram/kg s.c. daily, from day 4 on), and Rituximab (375 mg/m^2) on day 1 and 8 as in vivo purging. If no CR, VGPR or NPR was achieved, up to 4 cycles CHOP were administered. Primary endpoint was CR, secondary endpoints were VGPR, NPR and toxicity after induction and feasibility of stem cell mobilization. For response evaluation, staging procedures included clinical examination as well as bone marrow biopsies and CT-scans. A total of 41 pts was planned using Simon’s two-stage design with 5% significance and 80% power for the null hypothesis of CR rate < 25% and the alternative hypothesis of CR rate > 45%. Results: 42 pts were included, median age 53.8 y (range 38 – 65), WHO performance status 0 in 33 pts and 1 in 9 pts, stage Binet B in 20 pts, Binet C in 8 pts and progressive A in 14 pts. 2 pts were not evaluable for response. 9 pts reached CR (22.5%, 95% CI: 11–38%). Overall response rate including 15 VGPR and 2 NPR was 65% (CI: 48–79%). Of the 14 non-responders, 8 underwent CHOP treatment of which 2 achieved VGPR. 20 patients underwent mobilization and 8 pts refused further protocol treatment. 14 pts had leucapheresis. Stem cell harvest was feasible in 7 pts, all with ≥ 2×10^6 cells/kg. Fever and infection were reported respectively in 13 and 9 pts. Infusion related adverse events of Rituximab were moderate and occurred mainly after the first infusion. 42 of 158 cycles (27%) were associated with grade 3 or 4 neutropenia and 6 of 158 cycles (4%) with grade 3 thrombocytopenia. Conclusions: Although the expected CR rate was not achieved, a combination of Rituximab and 2-CDA is an effective and well tolerated treatment.

Validation of CLL FISH Panel Scoring by Members of the Chronic Lymphocytic Leukemia Research Consortium.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1067-1067
Author(s):  
Stephanie A. Smoley ◽  
Daniel L. Van Dyke ◽  
Neil E. Kay ◽  
Nyla A. Heerema ◽  
Marie L. dell’ Aquila ◽  
...  
Keyword(s):  
Pilot Study ◽  
Chronic Lymphocytic Leukemia ◽  
Proficiency Test ◽  
Collaborative Study ◽  
Lymphocytic Leukemia ◽  
International Standards ◽  
Pilot Studies ◽  
Trisomy 12 ◽  
Research Consortium ◽  
Local Protocol

Abstract Fluorescence in situ hybridization (FISH) probes and analysis methods for B-cell Chronic Lymphocytic Leukemia (CLL) vary extensively among cytogenetic laboratories. This is not unexpected, as neither national nor international standards have been established for most FISH studies. Lack of standardization is problematic when data collected at multiple institutions are used for clinical correlative studies. To circumvent such problems, the five participating laboratories in the CLL Research Consortium (CRC) designed and executed a joint CLL FISH validation study. Methods: Initially a survey was sent to assess equipment, methods and experience with FISH for CLL. In a pilot study to compare laboratory performance in scoring patient samples, slides from ten patients were prepared and sent to each participating lab to be hybridized with five probe sets (= 50 hybridizations) and analyzed according to their local protocol. In a second pilot study, slides from two patient samples and identical probe sets were sent to the participating labs where hybridization and analysis were carried out according to their local protocol. Next, technologists and directors from all participating labs attended a workshop where technologists working in pairs scored nuclei together, techniques and scoring criteria were established, and consensus reached on other concerns. In a proficiency test nine months after the workshop, slides from two patient samples (10 hybridizations) were hybridized and scored according to each lab’s protocol and results shared using a common reporting form. Results: Survey results indicated that four labs used the same commercially available CLL FISH panel, and one used a combination of probes from the same vendor plus several home-brew probes. Each lab scored between 100 and 200 nuclei per hybridization site, and each independently set normal cutoff values. The FISH panel included probes to detect 11q, 13q, and 17p deletions, trisomy 12, and IGH gene rearrangement. One lab included probes to detect 6q deletion. In the first pilot study each lab used their hybridization methods, probe sets, and scoring criteria. Differences among labs were observed due to variations in probe strategy, reporting of anomalies, and perhaps most important, scoring criteria. Probe strategy differences resulted in variable reporting of 11q- vs monosomy 11 and 12q duplication vs trisomy 12. Some participants reported 13q-x1 and 13q-x2 as subclones and some reported only 13q-. One lab reported an IGH rearrangement whereas the others scored IGH as normal. In the second pilot study each lab used the same methods and probe sets to facilitate comparison of scoring by the technologists. All labs correctly identified the abnormalities, and there were no false positive results. Minor scoring differences were attributed to variation in scoring criteria or inexperience with an unfamiliar FISH probe strategy. The proficiency test that followed the workshop demonstrated 100% concordance in identification of abnormalities. Inter-lab scoring was much improved compared to the first pilot study. The only exceptions were a 13q- range of 72–90% in one case, and a 17p- range of 38–67% in another case. Conclusion: The pilot studies identified a need to develop common scoring criteria. The subsequent workshop and proficiency test demonstrated that the collaborative effort resulted in more standardized scoring among the CRC laboratories. Our collaborative study emphasizes the need to establish rigorous standards and guidelines for FISH procedures and scoring criteria. Standardization of FISH methods among participating laboratories will enhance the confidence in FISH studies for both clinical applications and cooperative intergroup clinical research.

Ibrutinib-Based Therapy in the Treatment of Relapsed and Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5599-5599 ◽  
Author(s):  
Alexey Kuvshinov ◽  
Sergei Voloshin ◽  
Irina Martynkevich ◽  
Ludmila Martynenko ◽  
Andrei Garifullin ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Partial Remission ◽  
Response Rate ◽  
Remission Rate ◽  
Treatment Protocol ◽  
Lymphocytic Leukemia ◽  
Prognostic Indicators ◽  
Major Advance ◽  
Group 2 ◽  
Group 1

Abstract Introduction . The development of Bruton's tyrosine kinase inhibitors and their introduction into clinical practice represent a major advance in the treatment of chronic lymphocytic leukemia (CLL). Several studies in CLL have determined the achievement of minimal residual disease (MRD) negativity as an independent favorable prognostic factor, associated with superior progression-free survival (PFS) and overall survival. MRD status is the single best posttreatment predictor of long-term outcomes after treatment, regardless of the treatment protocol or the presence of other pre-existing prognostic indicators. Aim.To estimate of response rate, PFS and MRD after ibrutinib-based therapy in the treatment patients with relapsed/refractory CLL. M ethods.21 pts with relapsed/refractory CLL were included in the analysis. Stratification of patients into groups based on therapy. Group 1 (n = 14): 2nd and subsequent lines of rituximab-based chemotherapy (RB - 10, FCR - 4) and Group 2 (n = 12): ibrutinib-based therapy (420 mg daily oral Ibrutinib ± Chemoimmunotherapy). We have used NCI-IWCLL revised guidelines for treatment initiation and assessment of response. MRD was detected by multicolor flow cytometry of bone marrow in patients achieved a complete or partial remission: Group 1 - 7 pts, Group 2 - 5 pts. Results. The median age was 60.5 years (45-83) in Group 1 and 62.5 years (49-82) in Group 2 and median previous lines of therapy was 1 (1-4) and 2 (1-4), respectively. Patients with unfavorable chromosomal abnormalities were detected in each group: Group 1 - 2 pts (combination del(11q) with del(13q)); Group 2 - 1 pts (del(17p)). Overall response rate (ORR) in Group 1 was 71.4% (complete remission (CR) - 1 pt, partial remission (PR) - 9 pts, stable disease (SD) - 3 pts, progression disease - 1 pt). Group 2: ORR 91.7% (CR - 3 pts, PR - 8 pts; SD - 1 pt). Statistically significant differences in the frequency of ORR between groups were not detected (p>0.05). MRD-negative remission rate was 40% (2/5, CR - 1 pt) in Group 2 compared to 14.3% (1/7 pts, CR) in Group 1 (p>0.05). Statistically significant differences in PFS were detected between Group 1 vs. Group 2 (p=0.0006). Median PFS in Group 2 has not been reached. Median PFS in Group 1 was 16.9 month. Conclusion. Ibrutinib is highly effective at controlling disease, but best responses are typically partial remission, and patients must remain on treatment to maintain disease control. Evaluation of response and MRD after ibrutinib-containing therapy in the treatment of patients with relapsed/refractory chronic lymphocytic leukemia require further research. Disclosures Shuvaev: Pfizer: Honoraria; BMS: Honoraria; Novartis pharma: Honoraria.

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