Rituximab, Alemtuzumab, and GM-CSF As First-Line Therapy in Treating Patients With Early-Stage Chronic Lymphocytic Leukemia

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00562328
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 33
• Locations: 2
• Arm: 1
• Actual Duration (Months): 83.5
• Patients Per Site: 16.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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. Colony-stimulating factors, such as GM-CSF, may increase the number of immune cells found in bone marrow or peripheral blood. Giving monoclonal antibody therapy together with GM-CSF may be an effective treatment for early-stage chronic lymphocytic leukemia.

PURPOSE: This phase II trial is studying the side effects of giving rituximab and alemtuzumab together with GM-CSF and to see how well it works in treating patients with early-stage chronic lymphocytic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Biological: Alemtuzumab; Biological: Rituximab; Biological: Sargramostim	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To assess the rate of complete and overall response in patients with high-risk, early-stage, chronic lymphocytic leukemia (CLL) treated with alemtuzumab, rituximab, and sargramostim (GM-CSF).

• To monitor and assess toxicity of this regimen in these patients through clinical evaluation and serial monitoring of cytomegalovirus antigenemia by polymerase chain reaction (PCR).

Secondary

• To determine the overall and progression-free survival, time to response, time to next treatment, and duration of response in patients treated with this regimen.

• To assess the correlation between individual prognostic markers (i.e., 17p-, 11q-, unmutated VH gene, use of VH3-21, ZAP70+, CD38+) and clinical outcome.

Correlative Studies

• To assess response in these patients using an expanded definition of response, including minimal residual disease (MRD) by sensitive flow cytometry in patients in complete clinical remission.

• To assess MRD status of responding patients using sensitive flow cytometry and molecular assays (i.e., spectral karyotype analysis of CLL cells) before treatment and at relapse to identify subpopulations that could contribute to disease resistance and relapse.

• To detail the in vivo effect of this regimen on critical aspects of the immune system in CLL.

• To determine if GM-CSF, β-glucan, and CpG7909 can increase antibody dependent cellular cytotoxicity to improve efficacy against CLL cells and clinical response to treatment.

OUTLINE: Patients receive rituximab IV over 30 minutes on day 3 of weeks 2-5, alemtuzumab subcutaneously (SC) on days 3, 4, and 5 in week 1 and on days 1, 3, and 5 in weeks 2-5, and sargramostim SC on days 1, 3, and 5 in weeks 1-6. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection for measurement of serum cytomegalovirus DNA copy number by polymerase chain reaction at baseline, weekly during treatment, and monthly for the 6 months after completion of treatment. Patients also undergo bone marrow biopsy and aspirate at two months and then again at 12 months (if in complete remission). Blood samples are collected periodically during study for evaluation of prognostic biomarkers (i.e., 11q-, 17p-, unmutated IgVH gene, VH3-21 gene segment use, and CD38 and ZAP-70 expression) by fluorescent in situ hybridization (FISH) and for immunophenotyping by flow cytometry. Blood samples are collected from patients at the Mayo Clinic Rochester site at baseline and periodically during study for immunological and other correlative studies, including minimal residual disease (in responding patients only).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Antibody Therapy With Alemtuzumab, Rituximab and GM-CSF for Initial Treatment of High Risk Chronic Lymphocytic Leukemia
• Actual Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Feb 5, 2010
• Actual Study Completion Date: Dec 18, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alemtuzumab + Rituximab + GM-CSF Alemtuzumab + Rituximab + GM-CSF	Biological: Alemtuzumab; Week 1 (dose escalation): Day 3: 3mg subcutaneously; Day 4: 10mg subcutaneously; Day 5 30mg subcutaneously Weeks 2-5: 30mg subcutaneously three times a week.; Biological: Rituximab; Weeks 2-5: 375 mg/m^2 by IV once weekly; Biological: Sargramostim; Week 1-6: 250 mcg subcutaneously three time as week; Other Names: GM-CSF

Outcome Measures

Primary Outcome Measures

1. Number of Confirmed Responses (Complete or Partial Response Noted as the Objective Status for a Duration of at Least 2 Months) at 6 Months [6 months]

   Response, as defined by the National Cancer Institute Working Group (NCIWG), requires the following for a period of at least 2 months: CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, >100,000/μL platelets, >11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions

Secondary Outcome Measures

1. Progression Free Survival [Time from registration to progression (up to 5 years)]

   Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to the standard NCI-WG96 criteria. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

2. Duration of Response [time from start of response to progression (up to 5 years)]

   Duration of response (DOR) is defined as the time from documentation of response (CR or PR) to disease progression. The median DOR with 95% CI was estimated using the Kaplan Meier method.Response, as defined by the National Cancer Institute Working Group (NCIWG), requires the following for a period of at least 2 months: CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, >100,000/μL platelets, >11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions

3. Time to Next Treatment [time from end of protocol treatment to subsequent treatment (up to 5 years)]

   Time to next treatment was defined as the time from end of active (protocol) treatment to the start of subsequent treatment. The median and 95% CI was estimated using the Kaplan Meier method.

4. Overall Survival [Time from registration to death (up to 5 years)]

   Overall Survival (OS) was defined as the time from registration to death of any cause. Participants were followed for a maximum of 5 years from registration. The median OS with 95% CI was estimated using the Kaplan Meier method.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

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

• Minimum threshold peripheral blood lymphocyte count 5 x 10^9/L

• Monoclonality (light chain exclusion) of B lymphocytes detected by immunophenotyping (CD19-positive), demonstrating ≥ 3 of the following characteristics:

• CD5-positive

• CD23-positive

• Dim surface light chain expression

• Dim surface CD20 expression

• Negative for IGH/CCND1 translocation AND/OR immunostaining is negative for cyclin D1 expression by fluorescent in-situ hybridization (FISH) analysis

• Rai stage 0, I, or II disease that does not meet standard NCI-Working Group criteria for treatment of CLL

• Poor prognosis as defined by ≥ 1 of the following factors:

• Unmutated IgVH mutation status AND CD38 expression (i.e., ≥ 30% cells positive on flow cytometry)

• Unmutated IgVH mutation status AND ZAP-70 expression (i.e., ≥ 20% cells positive on flow cytometry)

• VH3-21 gene segment use irrespective of mutation status AND CD38 expression (≥ 30% cells positive on flow cytometry)

• VH3-21 gene segment use irrespective of mutation status AND ZAP-70 expression (≥ 20% cells positive on flow cytometry)

• 11q-negative*

• 17p-negative* NOTE: *Determination of IgVH mutation status is not required in patients whose eligibility is based on 17p13- or 11q22- deletions

PATIENT CHARACTERISTICS:

• ECOG performance status 0- 2

• Creatinine ≤ 1.5 times upper limit of normal (ULN)

• Total bilirubin ≤ 3.0 times ULN OR direct bilirubin ≤ 1.5 ULN

• AST ≤ 3.0 times ULN (unless due to hemolysis or CLL)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must practice effective contraception

• Willing to provide mandatory blood samples (for patients at the Mayo Clinic in Rochester only) for research studies as required by the protocol

• No comorbid conditions, including any of the following:

• New York Heart Association Class III or IV heart disease

• Myocardial infarction within the past month

• Uncontrolled infection

• HIV infection or AIDS

• Serological evidence of active hepatitis B infection (i.e., serum antigen or e-antigen positivity) or positive hepatitis C serology

• No other active primary malignancy requiring treatment or limiting survival to ≤ 2 years

• No active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia

PRIOR CONCURRENT THERAPY:

• More than 4 weeks since prior major surgery

• No prior chemotherapy or monoclonal antibody treatment for CLL

• No concurrent corticosteroids

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259-5499
2	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Clive S. Zent, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00562328
• Other Study ID Numbers: CDR0000574754; P30CA015083; MC0785; U4449s; 001.0888; 07-002087
• First Posted: Nov 22, 2007
• Last Update Posted: Apr 8, 2020
• Last Verified: May 1, 2017

• Keywords provided by Mayo Clinic: stage 0 chronic lymphocytic leukemia; stage I chronic lymphocytic leukemia; stage II chronic lymphocytic leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Alemtuzumab; Sargramostim

Study Results

Participant Flow

Recruitment Details	Thirty-three (33) participants were recruited at Mayo Clinic (Rochester and Arizona) between January 2008 and February 2010.
Pre-assignment Detail	All patients were deemed eligible.

Arm/Group Title	Alemtuzumab + Rituximab + GM-CSF
Arm/Group Description	Alemtuzumab + Rituximab + GM-CSF
Period Title: Overall Study
STARTED	33
COMPLETED	33
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Alemtuzumab + Rituximab + GM-CSF
Arm/Group Description	Alemtuzumab + Rituximab + GM-CSF
Overall Participants	33
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	10 30.3%
Male	23 69.7%
Region of Enrollment (participants) [Number]
United States	33 100%
Rai Stage (participants) [Number]
Stage 0	2 6.1%
Stage 1	27 81.8%
Stage 2	4 12.1%
CD38 Expression Status (participants) [Number]
Positive (>=30%)	15 45.5%
Negative (<30%)	18 54.5%
Immunoglobulin Variable Heavy Chain (IGVH) Mutation Status (participants) [Number]
Mutated	3 9.1%
Unmutated	30 90.9%
ZAP-70 Expression (participants) [Number]
Positive (>=20%)	25 75.8%
Negative (<20%)	7 21.2%
Unknown	1 3%

Outcome Measures

1. Primary Outcome

Title	Number of Confirmed Responses (Complete or Partial Response Noted as the Objective Status for a Duration of at Least 2 Months) at 6 Months
Description	Response, as defined by the National Cancer Institute Working Group (NCIWG), requires the following for a period of at least 2 months: CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, >100,000/μL platelets, >11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab + Rituximab + GM-CSF
Arm/Group Description	Patients received Alemtuzumab + Rituximab + GM-CSF.
Measure Participants	33
Count of Participants [Participants]	31 93.9%

2. Secondary Outcome

Title	Progression Free Survival
Description	Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to the standard NCI-WG96 criteria. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
Time Frame	Time from registration to progression (up to 5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab + Rituximab + GM-CSF
Arm/Group Description	Patients received Alemtuzumab + Rituximab + GM-CSF.
Measure Participants	33
Median (95% Confidence Interval) [months]	13.0

3. Secondary Outcome

Title	Duration of Response
Description	Duration of response (DOR) is defined as the time from documentation of response (CR or PR) to disease progression. The median DOR with 95% CI was estimated using the Kaplan Meier method.Response, as defined by the National Cancer Institute Working Group (NCIWG), requires the following for a period of at least 2 months: CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, >100,000/μL platelets, >11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions
Time Frame	time from start of response to progression (up to 5 years)

Outcome Measure Data

Analysis Population Description

Only patients who responded to treatment are included in this analysis.

Arm/Group Title	Alemtuzumab + Rituximab + GM-CSF
Arm/Group Description	Patients received Alemtuzumab + Rituximab + GM-CSF.
Measure Participants	31
Median (95% Confidence Interval) [months]	14.9

4. Secondary Outcome

Title	Time to Next Treatment
Description	Time to next treatment was defined as the time from end of active (protocol) treatment to the start of subsequent treatment. The median and 95% CI was estimated using the Kaplan Meier method.
Time Frame	time from end of protocol treatment to subsequent treatment (up to 5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab + Rituximab + GM-CSF
Arm/Group Description	Patients received Alemtuzumab + Rituximab + GM-CSF.
Measure Participants	33
Median (95% Confidence Interval) [months]	33.5

5. Secondary Outcome

Title	Overall Survival
Description	Overall Survival (OS) was defined as the time from registration to death of any cause. Participants were followed for a maximum of 5 years from registration. The median OS with 95% CI was estimated using the Kaplan Meier method.
Time Frame	Time from registration to death (up to 5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab + Rituximab + GM-CSF
Arm/Group Description	Patients received Alemtuzumab + Rituximab + GM-CSF.
Measure Participants	33
Median (95% Confidence Interval) [months]	NA

Adverse Events

Arm/Group Title	Alemtuzumab + Rituximab + GM-CSF
Arm/Group Description	Alemtuzumab + Rituximab + GM-CSF
All Cause Mortality
	Alemtuzumab + Rituximab + GM-CSF
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Alemtuzumab + Rituximab + GM-CSF
	Affected / at Risk (%)	# Events
Total	1/33 (3%)
Infections and infestations
Pneumonia	1/33 (3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/33 (3%)	1
Other (Not Including Serious) Adverse Events
	Alemtuzumab + Rituximab + GM-CSF
	Affected / at Risk (%)	# Events
Total	33/33 (100%)
Blood and lymphatic system disorders
Anemia	2/33 (6.1%)	2
Febrile neutropenia	1/33 (3%)	1
Eye disorders
Vitreous hemorrhage	1/33 (3%)	1
Gastrointestinal disorders
Constipation	1/33 (3%)	1
Mucositis oral	1/33 (3%)	1
Nausea	1/33 (3%)	1
General disorders
Chills	3/33 (9.1%)	4
Fatigue	4/33 (12.1%)	5
Fever	24/33 (72.7%)	43
Injection site reaction	1/33 (3%)	1
Immune system disorders
Hypersensitivity	1/33 (3%)	1
Infections and infestations
Blood Infection	3/33 (9.1%)	5
Bronchial infection	1/33 (3%)	1
Infection without neutropenia	2/33 (6.1%)	5
Lip infection	1/33 (3%)	1
Opportunisitic infection	3/33 (9.1%)	6
Pharyngitis	2/33 (6.1%)	2
Pneumonia	1/33 (3%)	1
Respiratory tract infection	6/33 (18.2%)	9
Investigations
Bilirubin	1/33 (3%)	3
Leukopenia	16/33 (48.5%)	39
Lymphocyte count decreased	1/33 (3%)	2
Neutrophil count decreased	7/33 (21.2%)	17
Platelet count decreased	1/33 (3%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/33 (3%)	1
Myalgia	1/33 (3%)	1
Pain in extremity	1/33 (3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/33 (3%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/33 (3%)	1
Skin and subcutaneous tissue disorders
Dermatology	1/33 (3%)	1
Rash	25/33 (75.8%)	59
Sweating	2/33 (6.1%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.