Methotrexate With or Without Cyclophosphamide in Treating Patients With Lymphocytic Leukemia

• Sponsor: Eastern Cooperative Oncology Group (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00003910
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 59
• Locations: 68
• Arm: 1
• Actual Duration (Months): 151.5
• Patients Per Site: 0.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die.

PURPOSE: Phase II trial to study the effectiveness of methotrexate with or without cyclophosphamide in treating patients who have lymphocytic leukemia with neutropenia or anemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Cyclophosphamide; Drug: Methotrexate; Drug: Prednisone	Phase 2

Detailed Description

LGL leukemia is characterized by clonal expansion of cytotoxic T cells. Prominent clinical features include neutropenia, anemia, and rheumatoid arthritis. The terminal effector memory phenotype (CD3+/CD8+/CD57+/CD45RA+/CD62L-) of leukemic LGL suggest a pivotal chronic antigen driven immune response. LGL survival is then promoted by PDGF and IL-15, resulting in global dysregulation of apoptosis and resistance to normal pathways of activation-induced death. These pathogenic features explain why treatment of LGL leukemia is based on immunosuppression therapy. However, no standard therapy has been established due to the absence of large prospective trials.

Oral low dose MTX has been shown to be efficacious in the treatment of neutropenia. However, response to MTX is slow, requiring several months for the neutrophil count to increase above 500/mm3. Also, complete clinical remission may not be achieved until after one year of MTX therapy. Oral Cy has been the primary drug used for the treatment of severe transfusion-dependent anemia. Beneficial clinical effects are seen despite this treatment having no apparent effect on the abnormal LGL clone. Normal hematocrits are maintained after cessation of Cy and these results contrast the effects seen with MTX, in which clinical remissions are often associated with the disappearance of the clone.

This phase II trial undertaken by the Eastern Cooperative Group (ECOG) was initiated to investigate the mechanism of treatment response in patients with LGL leukemia, who need treatment for anemia or neutropenia.

Study Design

• Study Type: Interventional
• Actual Enrollment: 59 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Initial Treatment With Methotrexate in Large Granular Lymphocytic (LGL) Leukemia
• Actual Study Start Date: Jul 16, 1999
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Methotrexate (Cy if no response to MTX) MTX given orally at 10 mg/m2 in divided doses once weekly. Prednisone was given orally at 1 mg/kg per day for 30 days and then tapered off in the subsequent 24 days. Patients not responding to MTX after 4 months received Cy orally at 100 mg daily in step two with the same prednisone schedule.

Drug: Cyclophosphamide; Patients not responding to MTX after 4 months received Cy orally at 100 mg daily in step two with the same prednisone schedule. In patients showing a partial response, but not a CR, the maximum period of therapy was 1 year.; Drug: Methotrexate; Initial treatment consisted of MTX given orally at 10 mg/m2 in divided doses once weekly.; Drug: Prednisone; Prednisone was given orally at 1 mg/kg per day for 30 days and then tapered off in the subsequent 24 days.

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients With Complete or Partial Response to Treatment With MTX [Assessed during the first 4 months, then at least every three months for two years. Then every six months until five years after study entry, and every 12 months thereafter until full study stop date.]

   We will report the overall response rate below. Complete remission requires that all of the following be present for at least four weeks: The patient must have a normal CBC including neutrophil count > 1500/mm3, lymphocyte count< 4000/mm3, hemoglobin > 11 g/dl, and platelet count > 100,000/mm3. In addition, the patient must have a normal LGL count. A complete response will be attained if CD8+ cells were less than 760/mm³. A partial response will be defined as achievement of any one of the following in the absence of CR. The response must last for at least four weeks:In patients being treated for severe neutropenia (less than 500 neutrophils/mm3) an improvement to over 500 neutrophils/mm3 will be considered a partial response, as long as that improvement represents at least a 50% improvement.

Secondary Outcome Measures

1. Proportion of Patients With Complete or Partial Response to Treatment of CY Among Patients Failing to Respond to MTX [Assessed during the first 4 months of treatment and followed until reaching full study stop date]

   We will report the overall response rate below. Complete remission requires that all of the following be present for at least four weeks: The patient must have a normal CBC including neutrophil count > 1500/mm3, lymphocyte count< 4000/mm3, hemoglobin > 11 g/dl, and platelet count > 100,000/mm3. In addition, the patient must have a normal LGL count. A complete response will be attained if CD8+ cells were less than 760/mm³. A partial response will be defined as achievement of any one of the following in the absence of CR. The response must last for at least four weeks:In patients being treated for severe neutropenia (less than 500 neutrophils/mm3) an improvement to over 500 neutrophils/mm3 will be considered a partial response, as long as that improvement represents at least a 50% improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion:

• Phenotypic studies from peripheral blood showing CD3+, CD57+ cells greater than 400/mm3 or CD8+ cells greater than 650/mm3 within eight weeks prior to registration

• Evidence for clonal T-cell receptor gene rearrangement within one year prior to registration

• At least one of the following: Severe neutropenia less than 500/mm3, neutropenia associated with recurrent infections, symptomatic anemia, or transfusion-dependent anemia

• Bilirubin ≤ 2.0 mg/dl, SGOT(AST) ≤ 1.5 times normal, and Creatinine ≤ 2.0 mg/dl within 4 weeks prior to registration

• ECOG performance status of 0-2

• At least 18 years of age

• Written informed consent

Exclusion:

• Prior therapy with oral MTX or oral Cy

• Previous or concurrent malignancies except inactive non-melanoma skin cancer, in situ carcinoma of the cervix, or other cancer if the patient has been disease free for over 5 years

• Pregnant or breast-feeding for female patients

• Serious medical illness, other than that treated by the study, which would limit survival to less than 2 years, or psychiatric condition which would prevent informed consent

Note: to be eligible for step 2 of this study, patients were required to have no response after at least 4 months of methotrexate treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Aurora Presbyterian Hospital	Aurora	Colorado	United States	80012
2	Boulder Community Hospital	Boulder	Colorado	United States	80301-9019
3	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado	United States	80933
4	St. Anthony Central Hospital	Denver	Colorado	United States	80204
5	Porter Adventist Hospital	Denver	Colorado	United States	80210
6	Presbyterian - St. Luke's Medical Center	Denver	Colorado	United States	80218
7	St. Joseph Hospital	Denver	Colorado	United States	80218
8	Rose Medical Center	Denver	Colorado	United States	80220
9	CCOP - Colorado Cancer Research Program	Denver	Colorado	United States	80224-2522
10	Swedish Medical Center	Englewood	Colorado	United States	80110
11	St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center	Grand Junction	Colorado	United States	81502
12	North Colorado Medical Center	Greeley	Colorado	United States	80631
13	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
14	Hope Cancer Care Center at Longmont United Hospital	Longmont	Colorado	United States	80501
15	McKee Medical Center	Loveland	Colorado	United States	80539
16	St. Mary - Corwin Regional Medical Center	Pueblo	Colorado	United States	81004
17	North Suburban Medical Center	Thornton	Colorado	United States	80229
18	Exempla Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
19	Medical Center of Central Georgia	Macon	Georgia	United States	31208
20	Rush-Copley Cancer Care Center	Aurora	Illinois	United States	60504
21	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois	United States	60611-3013
22	Evanston Northwestern Healthcare - Evanston Hospital	Evanston	Illinois	United States	60201-1781
23	Joliet Oncology-Hematology Associates, Limited - West	Joliet	Illinois	United States	60435
24	North Shore Oncology and Hematology Associates, Limited - Libertyville	Libertyville	Illinois	United States	60048
25	Carle Cancer Center at Carle Foundation Hospital	Urbana	Illinois	United States	61801
26	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
27	Methodist Cancer Center at Methodist Hospital	Indianapolis	Indiana	United States	46202
28	Saint Anthony Memorial Health Centers	Michigan City	Indiana	United States	46360
29	McFarland Clinic, PC	Ames	Iowa	United States	50010
30	Mercy Cancer Center at Mercy Medical Center - North Iowa	Mason City	Iowa	United States	50401
31	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa	United States	51101
32	Mercy Medical Center - Sioux City	Sioux City	Iowa	United States	51104
33	St. Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
34	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
35	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
36	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
37	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
38	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
39	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
40	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
41	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
42	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
43	Meeker County Memorial Hospital	Litchfield	Minnesota	United States	55355
44	HealthEast Cancer Care at St. John's Hospital	Maplewood	Minnesota	United States	55109
45	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota	United States	55109
46	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
47	Hennepin County Medical Center - Minneapolis	Minneapolis	Minnesota	United States	55415
48	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
49	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
50	Park Nicollet Cancer Center	Saint Louis Park	Minnesota	United States	55416
51	Regions Hospital Cancer Care Center	Saint Paul	Minnesota	United States	55101
52	HealthEast Cancer Care at St. Joseph's Hospital	Saint Paul	Minnesota	United States	55102
53	United Hospital	Saint Paul	Minnesota	United States	55102
54	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota	United States	55379
55	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
56	HealthEast Cancer Care at Woodwinds Health Campus	Woodbury	Minnesota	United States	55125
57	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota	United States	55125
58	Aultman Cancer Center at Aultman Hospital	Canton	Ohio	United States	44710-1799
59	St. Rita's Medical Center	Lima	Ohio	United States	45801
60	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
61	Central Pennsylvania Hematology and Medical Oncology Associates, PC	Lemoyne	Pennsylvania	United States	17043
62	Lewistown Hospital	Lewistown	Pennsylvania	United States	17044
63	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania	United States	19111-2497
64	McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center	Reading	Pennsylvania	United States	19612-6052
65	Mount Nittany Medical Center	State College	Pennsylvania	United States	16803
66	Gundersen Lutheran Center for Cancer and Blood	La Crosse	Wisconsin	United States	54601
67	Froedtert Hospital and Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
68	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Eastern Cooperative Oncology Group
• National Cancer Institute (NCI)

Investigators

• Study Chair: Thomas P. Loughran, MD, Milton S. Hershey Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eastern Cooperative Oncology Group
• ClinicalTrials.gov Identifier: NCT00003910
• Other Study ID Numbers: CDR0000067089; U10CA021115; E5998
• First Posted: Jan 27, 2003
• Last Update Posted: Jan 23, 2019
• Last Verified: Dec 1, 2018

• Keywords provided by Eastern Cooperative Oncology Group: stage I chronic lymphocytic leukemia; stage II chronic lymphocytic leukemia; stage III chronic lymphocytic leukemia; stage IV chronic lymphocytic leukemia; T-cell large granular lymphocyte leukemia; LGL clone
• Additional relevant MeSH terms: Leukemia; Prednisone; Cyclophosphamide; Methotrexate

Study Results

Participant Flow

Recruitment Details	This study accrued 59 patients between July 16, 1999 and March 24, 2009. The study terminated with 59 patients on March 24, 2009 due to slower than expected accrual.

Arm/Group Title	Methotrexate	Cyclophosphomide
Arm/Group Description	MTX given orally at 10 mg/m2 in divided doses once weekly. Prednisone was given orally at 1 mg/kg per day for 30 days and then tapered off in the subsequent 24 days. If patient had a partial response, MTX was continued for up to 1 year. If patient had CR, MTX was continued for 1 month. If no response, then pt went onto step 2 and received CY.	Patients not responding to MTX after 4 months received Cy orally at 100 mg daily in step two with the same prednisone schedule.
Period Title: Step 1
STARTED	55	0
COMPLETED	55	0
NOT COMPLETED	0	0
Period Title: Step 1
STARTED	0	16
COMPLETED	0	16
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Methotrexate
Arm/Group Description	MTX given orally at 10 mg/m2 in divided doses once weekly. Prednisone was given orally at 1 mg/kg per day for 30 days and then tapered off in the subsequent 24 days. Patients not responding to MTX after 4 months received Cy orally at 100 mg daily in step two with the same prednisone schedule.
Overall Participants	55
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	20 36.4%
>=65 years	35 63.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.4 (17.8)
Sex: Female, Male (Count of Participants)
Female	25 45.5%
Male	30 54.5%
Region of Enrollment (participants) [Number]
United States	55 100%

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients With Complete or Partial Response to Treatment With MTX
Description	We will report the overall response rate below. Complete remission requires that all of the following be present for at least four weeks: The patient must have a normal CBC including neutrophil count > 1500/mm3, lymphocyte count< 4000/mm3, hemoglobin > 11 g/dl, and platelet count > 100,000/mm3. In addition, the patient must have a normal LGL count. A complete response will be attained if CD8+ cells were less than 760/mm³. A partial response will be defined as achievement of any one of the following in the absence of CR. The response must last for at least four weeks:In patients being treated for severe neutropenia (less than 500 neutrophils/mm3) an improvement to over 500 neutrophils/mm3 will be considered a partial response, as long as that improvement represents at least a 50% improvement.
Time Frame	Assessed during the first 4 months, then at least every three months for two years. Then every six months until five years after study entry, and every 12 months thereafter until full study stop date.

Outcome Measure Data

Analysis Population Description

Of the 59 pts, 4 were ineligible and excluded from the analysis.

Arm/Group Title	Methotrexate
Arm/Group Description	MTX given orally at 10 mg/m2 in divided doses once weekly. Prednisone was given orally at 1 mg/kg per day for 30 days and then tapered off in the subsequent 24 days. Patients not responding to MTX after 4 months received Cy orally at 100 mg daily in step two with the same prednisone schedule.
Measure Participants	55
Number (95% Confidence Interval) [proportion of participants]	0.39 0.7%

2. Secondary Outcome

Title	Proportion of Patients With Complete or Partial Response to Treatment of CY Among Patients Failing to Respond to MTX
Description	We will report the overall response rate below. Complete remission requires that all of the following be present for at least four weeks: The patient must have a normal CBC including neutrophil count > 1500/mm3, lymphocyte count< 4000/mm3, hemoglobin > 11 g/dl, and platelet count > 100,000/mm3. In addition, the patient must have a normal LGL count. A complete response will be attained if CD8+ cells were less than 760/mm³. A partial response will be defined as achievement of any one of the following in the absence of CR. The response must last for at least four weeks:In patients being treated for severe neutropenia (less than 500 neutrophils/mm3) an improvement to over 500 neutrophils/mm3 will be considered a partial response, as long as that improvement represents at least a 50% improvement.
Time Frame	Assessed during the first 4 months of treatment and followed until reaching full study stop date

Outcome Measure Data

Analysis Population Description

Eligible patients who received Cy after failing to respond to MTX are included in this analysis.

Arm/Group Title	Cyclophosphamide (Cy)
Arm/Group Description	Patients not responding to MTX after 4 months received Cy orally at 100 mg daily in step two with the same prednisone schedule. In patients showing a partial response, but not a CR, the maximum period of therapy was 1 year.
Measure Participants	14
Number (95% Confidence Interval) [proportion of participants]	0.64 1.2%

Adverse Events

Time Frame	Assessed every 30 days while on treatment and for 30 days after the end of treatment.
Adverse Event Reporting Description	Here we look at all patients, all 59, whereas we excluded the ineligible patients from the baseline tables etc (n=55) as is standard to do in our final reports for ECOG.
Arm/Group Title	Methotrexate		Cyclophosphamide
Arm/Group Description	MTX given orally at 10 mg/m2 in divided doses once weekly. Prednisone was given orally at 1 mg/kg per day for 30 days and then tapered off in the subsequent 24 days. Patients not responding to MTX after 4 months received Cy orally at 100 mg daily in step two with the same prednisone schedule.		step 2 patients who received CY
All Cause Mortality
	Methotrexate		Cyclophosphamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Methotrexate		Cyclophosphamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	56/59 (94.9%)		8/16 (50%)
Blood and lymphatic system disorders
Anemia	13/59 (22%)		5/16 (31.3%)
Creatinine	1/59 (1.7%)		0/16 (0%)
Hemmorhage	1/59 (1.7%)		0/16 (0%)
Hyperglycemia	6/59 (10.2%)		2/16 (12.5%)
Leukopenia	10/59 (16.9%)		6/16 (37.5%)
Lymphopenia	5/59 (8.5%)		7/16 (43.8%)
Neutropenia	30/59 (50.8%)		6/16 (37.5%)
Thrombocytopenia	6/59 (10.2%)		1/16 (6.3%)
Cardiac disorders
Hypertension	1/59 (1.7%)		0/16 (0%)
Cardiac-left ventricular function	0/59 (0%)		1/16 (6.3%)
Gastrointestinal disorders
Nausea	1/59 (1.7%)		0/16 (0%)
Melena/GI bleeding	0/59 (0%)		1/16 (6.3%)
General disorders
Cough	1/59 (1.7%)		0/16 (0%)
Fatigue	5/59 (8.5%)		0/16 (0%)
Infections and infestations
Infection with grade 3 or 4 neutropenia	6/59 (10.2%)		0/16 (0%)
Infection without neutropenia	3/59 (5.1%)		0/16 (0%)
Metabolism and nutrition disorders
Hyponatremia	2/59 (3.4%)		0/16 (0%)
Hypoxia	2/59 (3.4%)		0/16 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/59 (1.7%)		0/16 (0%)
Muscle weakness	1/59 (1.7%)		0/16 (0%)
Psychiatric disorders
Depressed level of consciousness	0/59 (0%)		1/16 (6.3%)
Renal and urinary disorders
Hematuria	0/59 (0%)		1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/59 (1.7%)		1/16 (6.3%)
Pneumonitis	5/59 (8.5%)		1/16 (6.3%)
Pulmonary fibrosis	0/59 (0%)		1/16 (6.3%)
Skin and subcutaneous tissue disorders
Rash	1/59 (1.7%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Methotrexate		Cyclophosphamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	56/59 (94.9%)		6/16 (37.5%)
Blood and lymphatic system disorders
Anemia	41/59 (69.5%)		5/16 (31.3%)
Leukopenia	37/59 (62.7%)		6/16 (37.5%)
Neutropenia	49/59 (83.1%)		6/16 (37.5%)
Thrombocytopenia	20/59 (33.9%)		1/16 (6.3%)
Cardiac disorders
Cardiac-left ventricular function	0/59 (0%)		1/16 (6.3%)
Gastrointestinal disorders
Constipation	4/59 (6.8%)		0/16 (0%)
Diarrhea	5/59 (8.5%)		0/16 (0%)
Nausea	14/59 (23.7%)		0/16 (0%)
Stomatitis	10/59 (16.9%)		0/16 (0%)
Melena/GI bleeding	0/59 (0%)		1/16 (6.3%)
General disorders
Fatigue	34/59 (57.6%)		0/16 (0%)
Fever	8/59 (13.6%)		0/16 (0%)
Insomnia	10/59 (16.9%)		0/16 (0%)
Infections and infestations
Infection with grade 3 or 4 neutropenia	7/59 (11.9%)		0/16 (0%)
Infection with unknown ANC	0/59 (0%)		1/16 (6.3%)
Metabolism and nutrition disorders
AST increased	21/59 (35.6%)		0/16 (0%)
Alkaline Phosphatase Increased	9/59 (15.3%)		0/16 (0%)
Anorexia	11/59 (18.6%)		0/16 (0%)
Bilirubin Increased	15/59 (25.4%)		0/16 (0%)
Creatinine	11/59 (18.6%)		0/16 (0%)
Edema	5/59 (8.5%)		0/16 (0%)
Hyperglycemia	34/59 (57.6%)		3/16 (18.8%)
Hypoalemia	9/59 (15.3%)		0/16 (0%)
Hypoglycemia	7/59 (11.9%)		0/16 (0%)
Hypokalemia	9/59 (15.3%)		0/16 (0%)
Hyponatremia	14/59 (23.7%)		0/16 (0%)
Psychiatric disorders
Depressed level of consciousness	0/59 (0%)		1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	11/59 (18.6%)		1/16 (6.3%)
Pulmonary fibrosis	0/59 (0%)		1/16 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.