Rituximab and Alemtuzumab in Treating Older Patients With Progressive Chronic Lymphocytic Leukemia

A Phase II Randomized Trial Comparing Standard and Low Dose Rituximab: Initial Treatment of Progressive Chronic Lymphocytic Leukemia in Elderly Patients Using Alemtuzumab and Rituximab

RATIONALE: Monoclonal antibodies, such as rituximab and alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer killing substances to them. Giving rituximab together with alemtuzumab may kill more cancer cells.

PURPOSE: This randomized phase II trial is studying two different doses of rituximab to compare how well they work when given together with alemtuzumab in treating older patients with progressive chronic lymphocytic leukemia.

Study Overview

• Status: Terminated
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Biological: rituximab; Biological: alemtuzumab

Detailed Description

OBJECTIVES:

Primary

• To compare the rate of complete and overall response in elderly patients with progressive chronic lymphocytic leukemia (CLL) treated with one of two doses of rituximab combined with alemtuzumab to determine if the use of modified-dose rituximab significantly affects outcome.

Secondary

• To monitor and assess toxicity of these regimens.
• To determine the overall and progression-free survival, time to clinical response, time to next treatment, and duration of response in patients treated with these regimens
• To assess the correlation between risk stratification prognostic markers (i.e., CD38, ZAP-70, fluorescent in situ hybridization (FISH), and IgVH mutation) and clinical outcome.
• To assess response to these regimens using both the 1996 National Cancer Institute Working Group (NCI-WG 96) criteria and an expanded definition of response for patients in complete remission, including immunohistochemical examination of the bone marrow and sensitive flow cytometry (4-6 color) of blood for minimal residual disease and computed tomography (CT) scans for residual adenopathy.
• To determine the mechanism of action of rituximab and alemtuzumab and to determine mechanisms of resistance of a subpopulation of CLL cells to these drugs.

OUTLINE: This is a multicenter study. Patients are stratified according to FISH risk (low [13q14-] vs intermediate [12+, no abnormality, all other abnormalities] vs high [17p13-,11q22-]). Patients are randomized to 1 of 2 treatment arms.

• Arm A: Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles.
• Arm B: Patients receive alemtuzumab as in arm A. Patients also receive low-dose rituximab IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 and on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 in cycless 2 and 3. Treatment repeats every 28 days for up to 3 cycles.

Blood and bone marrow samples are collected periodically for cytogenetic and biomarker analysis.

Alemtuzumab dose for Cycle 1 Week 1 of both Arms A and B requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1).

After completion of study therapy, patients are followed up periodically for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259-5499
      • Mayo Clinic Scottsdale
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital
    • Jupiter, Florida, United States, 33458
      • Ella Milbank Foshay Cancer Center at Jupiter Medical Center
    • Miami Beach, Florida, United States, 33140
      • CCOP - Mount Sinai Medical Center
  • Georgia
    • Savannah, Georgia, United States, 31405
      • Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler
  • Illinois
    • Aurora, Illinois, United States, 60504
      • Rush-Copley Cancer Care Center
    • Bloomington, Illinois, United States, 61701
      • Illinois CancerCare - Bloomington
    • Bloomington, Illinois, United States, 61701
      • St. Joseph Medical Center
    • Canton, Illinois, United States, 61520
      • Illinois CancerCare - Canton
    • Canton, Illinois, United States, 61520
      • Graham Hospital
    • Carthage, Illinois, United States, 62321
      • Memorial Hospital
    • Carthage, Illinois, United States, 62321
      • Illinois CancerCare - Carthage
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Eureka, Illinois, United States, 61530
      • Illinois CancerCare - Eureka
    • Eureka, Illinois, United States, 61530
      • Eureka Community Hospital
    • Galesburg, Illinois, United States, 61401
      • Galesburg Clinic, PC
    • Havana, Illinois, United States, 62644
      • Illinois CancerCare - Havana
    • Kewanee, Illinois, United States, 61443
      • Illinois CancerCare - Kewanee Clinic
    • Macomb, Illinois, United States, 61455
      • Illinois CancerCare - Macomb
    • Macomb, Illinois, United States, 61455
      • Mcdonough District Hospital
    • Monmouth, Illinois, United States, 61462
      • Illinois CancerCare - Monmouth
    • Monmouth, Illinois, United States, 61462
      • OSF Holy Family Medical Center
    • Normal, Illinois, United States, 61761
      • Bromenn Regional Medical Center
    • Normal, Illinois, United States, 61761
      • Community Cancer Center
    • Normal, Illinois, United States, 61761
      • Illinois CancerCare - Community Cancer Center
    • Ottawa, Illinois, United States, 61350
      • Community Hospital of Ottawa
    • Ottawa, Illinois, United States, 61350
      • Oncology Hematology Associates of Central Illinois, PC - Ottawa
    • Pekin, Illinois, United States, 61554
      • Cancer Treatment Center at Pekin Hospital
    • Pekin, Illinois, United States, 61603
      • Illinois CancerCare - Pekin
    • Peoria, Illinois, United States, 61636
      • Methodist Medical Center of Illinois
    • Peoria, Illinois, United States, 61614
      • Proctor Hospital
    • Peoria, Illinois, United States, 61637
      • OSF St. Francis Medical Center
    • Peoria, Illinois, United States, 61615
      • CCOP - Illinois Oncology Research Association
    • Peoria, Illinois, United States, 61615
      • Oncology Hematology Associates of Central Illinois, PC - Peoria
    • Peru, Illinois, United States, 61354
      • Illinois CancerCare - Peru
    • Peru, Illinois, United States, 61354
      • Illinois Valley Community Hospital
    • Princeton, Illinois, United States, 61356
      • Illinois CancerCare - Princeton
    • Rockford, Illinois, United States, 61104-2315
      • Swedish-American Regional Cancer Center
    • Spring Valley, Illinois, United States, 61362
      • Illinois CancerCare - Spring Valley
    • Urbana, Illinois, United States, 61801
      • CCOP - Carle Cancer Center
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • St. Francis Hospital and Health Centers - Beech Grove Campus
    • Richmond, Indiana, United States, 47374
      • Reid Hospital & Health Care Services
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic, PC
    • Cedar Rapids, Iowa, United States, 52403
      • Cedar Rapids Oncology Associates
    • Cedar Rapids, Iowa, United States, 52403
      • Mercy Regional Cancer Center at Mercy Medical Center
    • Mason City, Iowa, United States, 50401
      • Mercy Cancer Center at Mercy Medical Center - North Iowa
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology-Oncology Associates, LLP
    • Sioux City, Iowa, United States, 51102
      • Mercy Medical Center - Sioux City
    • Sioux City, Iowa, United States, 51104
      • St. Luke's Regional Medical Center
  • Louisiana
    • Alexandria, Louisiana, United States, 71315-3198
      • Tulane Cancer Center Office of Clinical Research
    • Baton Rouge, Louisiana, United States, 70809
      • Hematology-Oncology Clinic
    • Shreveport, Louisiana, United States, 71130-3932
      • Feist-Weiller Cancer Center at Louisiana State University Health Sciences
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49001
      • Borgess Medical Center
    • Kalamazoo, Michigan, United States, 49007-3731
      • West Michigan Cancer Center
    • Marquette, Michigan, United States, 49855
      • Upper Michigan Cancer Center at Marquette General Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Missouri
    • Bolivar, Missouri, United States, 65613
      • Central Care Cancer Center at Carrie J. Babb Cancer Center
    • Branson, Missouri, United States, 65616
      • Skaggs Cancer Center at Skaggs Regional Medical Center
    • Cape Girardeau, Missouri, United States, 63703
      • Southeast Cancer Center
    • Jefferson City, Missouri, United States, 65109
      • Goldschmidt Cancer Center
    • Rolla, Missouri, United States, 65401
      • Phelps County Regional Medical Center
    • Rolla, Missouri, United States, 65401
      • Mercy Clinic Cancer and Hematology - Rolla
    • Saint Louis, Missouri, United States, 63131
      • Missouri Baptist Cancer Center
    • Springfield, Missouri, United States, 65802
      • CCOP - Cancer Research for the Ozarks
    • Springfield, Missouri, United States, 65804
      • St. John's Regional Health Center
    • Springfield, Missouri, United States, 65807
      • Hulston Cancer Center at Cox Medical Center South
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • CCOP - Nevada Cancer Research Foundation
  • North Carolina
    • Asheboro, North Carolina, United States, 27203-5400
      • Randolph Hospital
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital, Incorporated
    • Greensboro, North Carolina, United States, 27403-1198
      • Moses Cone Regional Cancer Center at Wesley Long Community Hospital
    • Hendersonville, North Carolina, United States, 28791
      • Pardee Memorial Hospital
    • Kinston, North Carolina, United States, 28501
      • Kinston Medical Specialists
    • Reidsville, North Carolina, United States, 27320
      • Annie Penn Cancer Center
    • Statesville, North Carolina, United States, 28677
      • Iredell Memorial Hospital
  • North Dakota
    • Bismarck, North Dakota, United States, 58501
      • Medcenter One Hospital Cancer Care Center
    • Bismarck, North Dakota, United States, 58501
      • Mid Dakota Clinic, PC
    • Bismarck, North Dakota, United States, 58502
      • St. Alexius Medical Center Cancer Center
  • Ohio
    • Canton, Ohio, United States, 44710-1799
      • Aultman Cancer Center at Aultman Hospital
    • Dayton, Ohio, United States, 45405
      • Grandview Hospital
    • Dayton, Ohio, United States, 45406
      • Good Samaritan Hospital
    • Dayton, Ohio, United States, 45409
      • David L. Rike Cancer Center at Miami Valley Hospital
    • Dayton, Ohio, United States, 45415
      • Samaritan North Cancer Care Center
    • Dayton, Ohio, United States, 45420
      • CCOP - Dayton
    • Findlay, Ohio, United States, 45840
      • Blanchard Valley Medical Associates
    • Franklin, Ohio, United States, 45005-1066
      • Middletown Regional Hospital
    • Greenville, Ohio, United States, 45331
      • Wayne Hospital
    • Kettering, Ohio, United States, 45429
      • Charles F. Kettering Memorial Hospital
    • Lima, Ohio, United States, 45801
      • St. Rita's Medical Center
    • Troy, Ohio, United States, 45373-1300
      • UVMC Cancer Care Center at Upper Valley Medical Center
    • Xenia, Ohio, United States, 45385
      • Ruth G. McMillan Cancer Center at Greene Memorial Hospital
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center
    • Lewistown, Pennsylvania, United States, 17044
      • Lewistown Hospital
    • Scranton, Pennsylvania, United States, 18501
      • Mercy Hospital Cancer Center - Scranton
    • Scranton, Pennsylvania, United States, 18510
      • Hematology and Oncology Associates of Northeastern Pennsylvania
    • State College, Pennsylvania, United States, 16803
      • Mount Nittany Medical Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37920-6999
      • U.T. Medical Center Cancer Institute
  • Virginia
    • Danville, Virginia, United States, 24541
      • Danville Regional Medical Center
  • Wisconsin
    • Johnson Creek, Wisconsin, United States, 53038
      • UW Cancer Center Johnson Creek
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Center for Cancer and Blood
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
    • Wisconsin Rapids, Wisconsin, United States, 54494
      • Riverview UW Cancer Center at Riverview Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of chronic lymphocytic leukemia (CLL) meeting the following criteria:

  • Minimum threshold peripheral lymphocyte count of 5 x 10^9/L (CLL variant) OR palpable adenopathy > 1 cm or palpable splenomegaly 9small lymphocytic lymphoma [SLL] variant)

  • Immunophenotypic demonstrations of a population of B-lymphocytes (as defined by CD19+) that are monoclonal (by light-chain exclusion) AND have ≥ 3 of the following characteristics:

    • CD5+
    • CD23+
    • Dim surface light chain expression
    • Dim surface CD20 expression
  • FISH analysis is negative for immunoglobulin heavy chain/cyclin D1 gene (IGH/CCND1) and/or immunostaining is negative for cyclin D1 expression (to exclude mantle cell lymphoma)

• Progressive, symptomatic CLL, defined by at least one of the following:

  • Weight loss > 10% within the past 6 months attributable to progressive CLL (grade 2 or higher)
  • Extreme fatigue attributable to progressive CLL (grade 3 or higher)
  • Fevers > 100.5° F for 2 weeks without evidence of infection (grade 1 or higher)
  • Night sweats without evidence of infection (drenching)
  • Evidence of progressive bone marrow failure with hemoglobin < 11 g/dL or platelet count < 100 x 10^9/L

  • Rapidly progressive lymphadenopathy for which the largest node is ≤ 5 cm in any dimension

    • Largest lymph nodes involved in the neck, axilla, and groin need to be measured and followed for response

Exclusion Criteria:

• Prior treatment for CLL
• Massive splenomegaly > 6 cm below left costal margin, at rest, on clinical examination
• Lymphadenopathy > 5 cm in any diameter
• New York Heart Association class III or IV heart disease
• Recent myocardial infarction (within the past month)
• Uncontrolled infection
• Infection with the human immunodeficiency virus (HIV/AIDS)
• Serological evidence of active hepatitis B infection (HBsAg or HBeAg positive)
• Positive hepatitis C serology
• Evidence of active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia
• Other active primary malignancy requiring treatment or that limits survival to ≤ 2 years, except for in situ carcinoma of the cervix or breast or non-metastatic basal cell or squamous cell carcinoma of the skin
• Major surgery within 4 weeks prior to pre-registration

• Concomitant use of continuous systemic corticosteroids

  • Prior corticosteroids are allowed but not at time of pre-registration to the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A (standard dose); Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Biological: rituximab; Given IV; Biological: alemtuzumab; Given IV
Experimental: Arm B (low dose); Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.	Biological: rituximab; Given IV; Biological: alemtuzumab; Given IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients With Complete Response (CR)	Response was evaluated using NCI-WG96 criteria. A CR requires all of the following for >= 2 months: Absence of lymphadenopathy > 1 cm in diameter by physical examination; No hepatomegaly or splenomegaly on physical exam; No constitutional symptoms; Normal complete blood count (CBC); Patients achieving a clinical CR with negative CT scan after 2 cycles of therapy are re-evaluated using immunohistochemical examination of bone marrow biopsy for residual CLL cells. Patients with no evidence of residual disease and no radiological evidence of residual CLL on CT scan of chest-abdomen-pelvis and no clinical evidence of CLL on clinical evaluation after completion of 2 cycles of therapy will be considered to have a CR with no evidence of residual disease	Assessed after 2 cycles of treatment and 2 months after completion of therapy
Proportion of Patients With Overall Response (OR)	OR is defined as either CR, clinical CR, or partial response (PR) evaluated by NCI-WG96 criteria. CR has been defined in the other primary endpoint. A clinical CR requires all of the following: Absence of lymphadenopathy by physical examination; No hepatomegaly or splenomegaly. Spleen and/or liver, if considered enlarged at baseline, should not be palpable, due to disease, on physical exam; Absence of constitutional symptoms; Normal CBC as exhibited by: A PR requires all the following for ≥2 months: ≥50% decrease in peripheral blood lymphocyte count from baseline; ≥50% reduction in lymphadenopathy; ≥50% reduction in size of liver and/or spleen; Polymorphonuclear leukocytes ≥1.5x10^9/L or 50% improvement over baseline; Platelets >100x10^9/L or 50% improvement over baseline; Hemoglobin >11.0 gm/dl or 50% improvement over baseline without transfusions; Any constitutional symptoms	Assessed after 2 cycles of treatment and 2 months after completion of therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS is defined to be time from randomization to death from any cause. Those still alive are censored at the date of last contact.	Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years
Progression-free Survival (PFS)	PFS is defined to be time from randomization to progression (PD) or to death without documentation of progression. For patients without PD, follow-up is censored at the date of last disease assessment without PD, unless death occurs within three months following the date last known progression free. PD is characterized by at least one of the following: ≥50% increase in the sum of the products of at least 2 lymph nodes on 2 consecutive examinations 2 weeks apart (at least 1 node must be >2 cm). Appearance of new palpable lymph nodes (>1 cm in diameter).; ≥50% increase in the size of liver and/or spleen as determined by measurement below the respective costal margin; appearance of palpable hepatomegaly or splenomegaly which was not previously present.; Absolute number of circulating lymphocytes with a count of >5x10^9/L; Transformation to a more aggressive histology	Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years
Time to Response	Time to response is defined to be time from randomization to first confirmed CR, PR or clinical CR. Those without confirmed CR, PR or clinical CR are censored at the date of last disease assessment.	Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years
Duration of Response	Duration of response is defined to be time from first confirmed CR, PR or clinical CR to progression or to death without documentation of progression. Patients without confirmed CR, PR or clinical CR are censored at time 0. Those without documentation of progression are censored at the date of last disease assessment without progression, unless death occurs within three months following the date last known progression free.	Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years

Collaborators and Investigators

• Sponsor: ECOG-ACRIN Cancer Research Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Clive S. Zent, MD, University of Rochester

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2011
• Primary Completion (Actual): April 14, 2015
• Study Completion (Actual): April 14, 2015

Study Registration Dates

• First Submitted: November 13, 2009
• First Submitted That Met QC Criteria: November 13, 2009
• First Posted (Estimated): November 16, 2009

Study Record Updates

• Last Update Posted (Actual): June 28, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: elderly; monoclonal antibodies; CLL; chronic lymphocytic leukemia; alemtuzumab; small lymphocytic lymphoma; low dose rituximab
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab; Alemtuzumab
• Other Study ID Numbers: E1908 (Other Identifier: ECOG-ACRIN Cancer Research Group); U10CA180794 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.