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Retrospective Study: Efficacy and Safety of Chlorambucil + Rituximab in CLL Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01862445
Recruitment Status : Unknown
Verified March 2018 by Gruppo Italiano Malattie EMatologiche dell'Adulto.
Recruitment status was:  Active, not recruiting
First Posted : May 24, 2013
Last Update Posted : March 22, 2018
Information provided by (Responsible Party):
Gruppo Italiano Malattie EMatologiche dell'Adulto

Brief Summary:
This is a non interventional study to evaluate the efficacy and safety of Chlorambucil plus Rituximab as firstline therapy in elderly and/or unfit patients affected by B-cell Chronic Lymphocytic Leukemia (B-CLL).

Condition or disease
CLL B-cell Small Lymphocytic Lymphoma Untreated B-CLL Elderly Patients

Detailed Description:

Illness: treatment overview Chronic lymphocytic leukemia (B-CLL) is the most prevalent adult leukemia among western countries (6.7% Non-Hodgkin Lymphomas- NHL). The incidence rate is 2-6 cases per 100.000 person per year increasing with age and reaching an incidence rate of about 13/100.000 at 65 years, median age of onset of the disease. There are two clinical staging systems currently in use for CLL (Rai and Binet staging systems) allowing a rough division of patients into three prognostic groups: good, intermediate and poor prognosis. The clinical course ranges from an indolent behaviour (Rai 0, Binet A) with a long term survival to an aggressive disease with a median survival of 2 years (Rai III and IV, Binet C). There is non survival benefit associated with an early therapy (Binet stage A and B). Treatment usually is initiated when patient progress to the advanced stage (Binet stage C) and/or become symptomatic (fever, night sweats, weight loss). Purine-analogues based chemo-immunotherapy regimens are now considered the standard of care for fit patient with B-CLL (Fludarabine-Cyclophosphamyde-Rituximab, FCR regimen). But aging of the host and biological features of the disease are critical issues in the choice of therapy. The FCR regimen can result in significant myelosuppression and a high rate of early and late infections, especially in elderly patients with B-CLL, suggesting that it may be too toxic and therefore unsuitable for the large subpopulation of elderly and comorbid patients affected by B-CLL/SLL.

Rationale Chlorambucil, an alkylating agent, was the standard first line treatment for B-CLL/SLL before the development of the purine analogues and monoclonal antibodies. Later, phase III trials showed an improved ORR and a prolongation of PFS with fludarabine alone. A further improvement was obtained with the addition of Cyclophosphamide to Fludarabine. Eventually, Fludarabine in combination with Cyclophosphamide and the monoclonal anti-CD20 antibody Rituximab became the standard first line therapy for CLL patients 18 to 65 years old. At the same time, the FCR regimen showed a significant rate of early toxicity consisting of myelosuppression and infection and also a high rate of late infection. Data showed by Hallek et al reported a rate of grade 3-4 hematological toxicity and total infections of 56% and 25%, respectively. They reported 8 treatment-related deaths (2%), five of these due to infections and 4 deaths occurring before the 3th cycle. Also has been reported by Tam et al a risk of 10% of late infection for the first year of remission after FCR treatment. Low-dose FCR was evaluated as an alternative option showing a lower rate of neutropenia, without reduction of response rate. Nevertheless, it was demonstrated to reduce the PFS and it has not been evaluated in the elderly or medically unfit population. Alternative treatments (i.e., low-dose fludarabine, low-dose fludarabine plus cyclophosphamide, rituximab alone) have been explored in phase II trials in elderly and/or medically unfit patients with CLL. Since the cohort sizes were small, however, no definitive recommendations could be made for clinical practice. About three-quarters of CLL patients are more than 65 years old. Data from the CLL 5 phase III trial of GCLLSG (German CLL study group) comparing fludarabine vs Chlorambucil in this setting of patients (median age 70 years, range 65-80 years) displayed no differences in OS and PFR between Fludarabine and Chl, despite a greater percentage of CR and ORR with Fludarabine. This suggests that in elderly B-CLL patients, Fludarabine alone does not represent a major benefit in respect of Chl as front-line therapy. However, rates of complete response (CR) with front-line Chlorambucil single agent are relatively low (up to 7%) as are overall responses (approximately 65%). Phase II trials are ongoing to investigate the efficacy and safety of Rituximab in combination with Chl in previously untreated patients affected by B-CLL.

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Study Type : Observational
Estimated Enrollment : 100 participants
Observational Model: Case-Only
Time Perspective: Retrospective
Official Title: A Retrospective Study to Assess the Efficacy and Safety of Chlorambucil Plus Rituximab as Front-line Therapy in Elderly and/or Unfit Patients Affected by B-cell Chronic Lymphocytic Leukemia
Study Start Date : October 2013
Estimated Primary Completion Date : May 2018
Estimated Study Completion Date : May 2018

Study group
Patients receiving Chlorambucil plus Rituximab

Primary Outcome Measures :
  1. Number of responding patients. [ Time Frame: 10 months from study entry ]
    Overall response rate.

Secondary Outcome Measures :
  1. Number of adverse events. [ Time Frame: 24 months from study entry ]
    Safety of Rituximab and Chlorambucil regimen (type, frequency and severity).

  2. Number of days from the first dose of treatment to re-treatment. [ Time Frame: 24 months from study entry. ]
    Time to Re-Treatment (TTR) estimation starting from the date of the first dose of the study drug

  3. Number of patients surviving. [ Time Frame: 24 months from study entry. ]

    Progression Free Survival (PFS) estimation starting from the date of the first dose of the study drug.

    Overall Survival (OS) estimation starting from the date of the first dose of the study drug

  4. Number of patients in which the response and the biological and clinical characteristics of the disease at baseline are associated. [ Time Frame: After 10 months from study entry. ]
    Fitness status, FISH, IgVH, Zap70 and CD38.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
The GIMEMA Chronic Lymphocytic Leukemia Working Party promotes an observational, retrospective, multicenter study on safety and efficacy of Chl-R administered front-line to treat elderly and/or unfit pts affected by B-CLL.

Inclusion Criteria:

  • Have a diagnosis of B-CLL or Small Lymphocytic Lymphoma (SLL) according to the World Health Organisation (WHO) classification 2008;
  • Previously untreated B-CLL requiring therapy according to the NCI criteria (Hallek M et al, Blood 2008 (Appendix G) undergone to first line of therapy with Chl-R;
  • All patients included in the study must have started treatment by December 2011;
  • Age ≥ 65 years or unfit pts ≥ 18 years old with a CIRS score ≥7 (Appendix E);
  • Eastern Cooperative Oncology Group Performance Status Grade of 0-2 (Appendix B) ;
  • Life expectancy > 6 months;
  • Signed written informed consent according to ICH/EU/GCP and national local law.

Exclusion Criteria:

  • Patients who have received prior therapy: chemotherapy and/or immunotherapy, stem cell transplantation, investigational drugs administered to treat B-CLL before Chl-R;
  • Transformation of B-CLL to aggressive lymphomas (Richter's Syndrome);
  • One or more individual organ/system impairment score of 4 as assessed by CIRS definition;
  • HIV infection;
  • Active, uncontrolled HCV and/or HBV infections or liver cirrhosis;
  • Patients who started Chl-R after December 2011.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01862445

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Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
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Study Chair: Luca Laurenti, Dr. Istituto di Ematologia, Università Cattolica del Sacro Cuore di Roma
Additional Information:
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Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto Identifier: NCT01862445    
Other Study ID Numbers: LLC1013
First Posted: May 24, 2013    Key Record Dates
Last Update Posted: March 22, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:
Chronic Lymphoid Leukemia, Chlorambucil, Rituximab
Additional relevant MeSH terms:
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Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, B-Cell
Leukemia, Lymphoid
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases