Comparison of Two Combination Chemotherapy Regimens in Treating Adults With Previously Untreated Leukemia or Lymphoma

• Sponsor: Memorial Sloan Kettering Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00002766
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 170
• Locations: 7
• Arms: 2
• Duration (Months): 186
• Patients Per Site: 24.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known which regimen of combination chemotherapy is more effective for acute lymphoblastic leukemia, lymphoblastic lymphoma, or chronic myelogenous leukemia.

PURPOSE: This randomized phase III trial is studying two different chemotherapy regimens and comparing them to see how well they work in treating adults with acute lymphoblastic leukemia, lymphoblastic lymphoma, or chronic myelogenous leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Lymphoma	Biological: dactinomycin; Biological: sargramostim; Drug: carmustine; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: doxorubicin hydrochloride; Drug: etoposide; Drug: mercaptopurine; Drug: methotrexate; Drug: mitoxantrone hydrochloride; Drug: pegaspargase; Drug: prednisone; Drug: vincristine sulfate; Radiation: radiation therapy	Phase 3

Detailed Description

OBJECTIVES:

• Compare the incidence of complete remission (CR) following induction with the ALL-2 regimen (cytarabine and high-dose mitoxantrone) vs the L-20 regimen (vincristine and prednisone) in previously untreated adult patients with acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma, and lymphoid blast crisis chronic myelogenous leukemia.

• Compare the time to CR, length of hospital stay, efficacy of treatment in Philadelphia chromosome-positive ALL, and the proportion of patients achieving durable (greater than 5 years) remission in each treatment regimen.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating institution and antecedent lymphoid blast crisis of chronic myelogenous leukemia (yes vs no). Patients are randomized to one of two treatment arms.

Arm I:

• Patients receive induction therapy consisting of cytarabine IV over 3 hours on days 1-5 with high-dose mitoxantrone IV on day 3 and methotrexate intrathecally on days 2 and 4. Patients receive sargramostim (GM-CSF) subcutaneously or IV over 4 hours beginning on day 7 and continuing until blood counts recover.

• At 7-14 days following induction therapy, patients receive consolidation therapy consisting of vincristine IV on days 1, 8, 15, 22, and 29, oral prednisone 2-3 times daily on days 1-30 and methotrexate intrathecally on days 8, 15, 22, and 29.

• At 2-3 weeks following the last dose of vincristine, patients receive an additional course of consolidation therapy consisting of cyclophosphamide IV on day 1 and GM-CSF subcutaneously beginning on day 3 and continuing until blood counts recover.

• At 3-4 weeks following the second consolidation course, patients receive a third course of consolidation therapy consisting of cytarabine IV bolus on day 1 followed by continuous infusion cytarabine on days 1-4 with etoposide IV over 1 hour on days 1-3 and methotrexate intrathecally on days 2 and 4. Patients receive GM-CSF subcutaneously beginning on day 6 and continuing until blood counts recover.

• Following recovery from the third consolidation course, patients receive a fourth consolidation course consisting of pegaspargase IV or intramuscularly (IM) on day 1.

• Following recovery from consolidation therapy patients receive 2 sequences of maintenance therapy with sequence one consisting of vincristine IV on days 1 and 8, oral prednisone 2-3 times daily on days 1-8, doxorubicin IV on day 15, oral mercaptopurine 2-3 times daily on days 36-64, oral methotrexate on days 39, 46, 53, and 60, dactinomycin IV on day 85, and methotrexate intrathecally on days 36 and 43.

• At 2 weeks following sequence one of maintenance therapy, patients receive sequence two consisting of the same regimen as in the first sequence with the addition of cyclophosphamide IV and carmustine IV on day 15.

• Patients with CNS involvement receive whole brain radiotherapy in addition to chemotherapy regimens.

Arm II:

• Patients receive induction therapy consisting of vincristine IV on days 1, 8, 15, 22, and 29, oral prednisone 2-3 times daily on days 1-29, cyclophosphamide IV on day 5, doxorubicin IV on days 23-25 and 42, methotrexate intrathecally on days 3, 5, 13, 16, 32, and 34 and GM-CSF subcutaneously or IV over 4 hours beginning from days 7 and 27 and continuing until blood counts recover.

• At approximately 3 weeks following induction therapy, patients receive consolidation therapy consisting of cytarabine IV bolus on day 1 followed by continuous infusion cytarabine on days 1-5, with daunorubicin IV on days 1-3 and methotrexate intrathecally on days 2 and 4. Patients receive GM-CSF subcutaneously beginning on day 7 and continuing until blood counts recover.

• At 6-8 weeks following the first course of consolidation therapy, patients receive a second consolidation course consisting of cytarabine IV bolus on day 1 followed by continuous infusion cytarabine on days 1-4 with methotrexate IV on days 1-4 and methotrexate intrathecally on days 2 and 4. Patients receive GM-CSF subcutaneously beginning on day 6 and continuing until blood counts recover.

• At 6-8 weeks following the second course of consolidation therapy, patients receive a third consolidation course consisting of pegaspargase IV or IM on day 1.

• At 3-4 weeks following the third course of consolidation therapy, patients receive a fourth consolidation course consisting of cyclophosphamide IV on day 1.

• At 3 weeks following the completion of consolidation therapy, patients receive the same maintenance regimen as in Arm I.

Treatment continues in patients achieving complete response. Patients in both arms receive alternating sequences of maintenance therapy over 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 170 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Trial Comparing ARA-C/High-Dose Mitoxantrone ("ALL-2') to A Standard Vincristine/Prednisone Based Regimen ('L-20') as Induction Therapy For Adult Patients With Acute Lymphoblastic Leukemia (ALL): The ALL-4 Protocol
• Study Start Date: Mar 1, 1996
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ARA-C/High-Dose Mitoxantrone("All-2") See detail description	Biological: dactinomycin; Biological: sargramostim; Drug: carmustine; Drug: cyclophosphamide; Drug: cytarabine; Drug: doxorubicin hydrochloride; Drug: etoposide; Drug: mercaptopurine; Drug: methotrexate; Drug: mitoxantrone hydrochloride; Drug: pegaspargase; Drug: prednisone; Drug: vincristine sulfate; Radiation: radiation therapy
Active Comparator: Standard Vincristine/Prednisone ("L-20") See detail description	Biological: sargramostim; Drug: carmustine; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: doxorubicin hydrochloride; Drug: methotrexate; Drug: pegaspargase; Drug: prednisone; Drug: vincristine sulfate

Outcome Measures

Primary Outcome Measures

1. Complete Remission (CR) [2 years]

   complete remission (CR) Disappearance of all clinical evidence of leukemia for a minimum of four weeks. The patient should have a neutrophil count > 1,000 x 10^6/1, a platelet count > 100,000 x 10^9/1, no circulating blasts, and < than or = to blasts on bone marrow differential in a qualitatively normal or hypercellular marrow. Progressive disease or failure: Increasing bone marrow infiltrate or development of organ failure or extramedullary infiltrates due to leukemia.

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 one of the following malignancies:

• Acute lymphoblastic leukemia (ALL) of B- or T-cell lineage

• Philadelphia chromosome-positive ALL eligible

• Lymphoblastic lymphoma

• Chronic myelogenous leukemia in lymphoid blast crisis

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 20-100%

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Bilirubin no greater than 2.0 mg/dL

• Glucocorticoids for higher bilirubin allowed prior to entry, at principal investigator's discretion

Renal:

• Creatinine no greater than 2.0 mg/dL

• Glucocorticoids or renal radiotherapy for higher creatinine allowed prior to entry, at principal investigator's discretion

Cardiovascular:

• Left ventricular ejection fraction at least 50%

Other:

• Not pregnant

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior biologic therapy

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• No prior endocrine therapy

Radiotherapy

• No prior radiotherapy

Surgery

• No prior surgery

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Jonsson Comprehensive Cancer Center, UCLA	Los Angeles	California	United States	90095-1678
2	Stanford Cancer Center at Stanford University Medical Center	Stanford	California	United States	94305-5750
3	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
4	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
5	New York Medical College	Valhalla	New York	United States	10595
6	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
7	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• Memorial Sloan Kettering Cancer Center
• National Cancer Institute (NCI)

Investigators

• Study Chair: Nicole Lamanna, MD, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT00002766
• Other Study ID Numbers: 96-015; P30CA008748; MSKCC-96015A1; NCI-V96-0881
• First Posted: Jan 27, 2003
• Last Update Posted: Feb 22, 2016
• Last Verified: Jan 1, 2016

• Keywords provided by Memorial Sloan Kettering Cancer Center: blastic phase chronic myelogenous leukemia; untreated adult acute lymphoblastic leukemia; chronic myelogenous leukemia, BCR-ABL1 positive; T-cell adult acute lymphoblastic leukemia; B-cell adult acute lymphoblastic leukemia; stage I adult lymphoblastic lymphoma; stage II adult lymphoblastic lymphoma; stage III adult lymphoblastic lymphoma; stage IV adult lymphoblastic lymphoma; contiguous stage II adult lymphoblastic lymphoma; noncontiguous stage II adult lymphoblastic lymphoma
• Additional relevant MeSH terms: Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Cytarabine; Dactinomycin; Prednisone; Cyclophosphamide; Carmustine; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Vincristine; Daunorubicin; Mitoxantrone; Mercaptopurine; Pegaspargase; Sargramostim

Study Results

Participant Flow

Arm/Group Title	All-2	L-20
Arm/Group Description	ARA-C/High-Dose Mitoxantrone("All-2") Patients receive induction therapy consisting of cytarabine IV over 3 hours on days 1-5 with high-dose mitoxantrone IV on day 3 and methotrexate intrathecally on days 2 and 4. Patients receive sargramostim (GM-CSF) subcutaneously or IV over 4 hours beginning on day 7 and continuing until blood counts recover.	Standard Vincristine/Prednisone ("L-20") Patients receive induction therapy consisting of vincristine IV on days 1, 8, 15, 22, and 29, oral prednisone 2-3 times daily on days 1-29, cyclophosphamide IV on day 5, doxorubicin IV on days 23-25 and 42, methotrexate intrathecally on days 3, 5, 13, 16, 32, and 34 and GM-CSF subcutaneously or IV over 4 hours beginning from days 7 and 27 and continuing until blood counts recover.
Period Title: Overall Study
STARTED	81	89
COMPLETED	78	85
NOT COMPLETED	3	4

Baseline Characteristics

Arm/Group Title	All-2	L-20	Total
Arm/Group Description	ARA-C/High-Dose Mitoxantrone("All-2")	Standard Vincristine/Prednisone ("L-20")	Total of all reporting groups
Overall Participants	81	89	170
Age (Count of Participants)
<=18 years	3 3.7%	4 4.5%	7 4.1%
Between 18 and 65 years	76 93.8%	77 86.5%	153 90%
>=65 years	2 2.5%	8 9%	10 5.9%
Sex: Female, Male (Count of Participants)
Female	31 38.3%	36 40.4%	67 39.4%
Male	50 61.7%	53 59.6%	103 60.6%

Outcome Measures

1. Primary Outcome

Title	Complete Remission (CR)
Description	complete remission (CR) Disappearance of all clinical evidence of leukemia for a minimum of four weeks. The patient should have a neutrophil count > 1,000 x 10^6/1, a platelet count > 100,000 x 10^9/1, no circulating blasts, and < than or = to blasts on bone marrow differential in a qualitatively normal or hypercellular marrow. Progressive disease or failure: Increasing bone marrow infiltrate or development of organ failure or extramedullary infiltrates due to leukemia.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All-2	L-20
Arm/Group Description	ARA-C/High-Dose Mitoxantrone("All-2")	Standard Vincristine/Prednisone ("L-20")
Measure Participants	78	85
Complete Remission	50 61.7%	50 56.2%
Complete Response (CR)	14 17.3%	11 12.4%
Failure	5 6.2%	14 15.7%
Failure-Progression	8 9.9%	10 11.2%
Relapse	1 1.2%	0 0%

Adverse Events

Arm/Group Title	All-2		L-20
Arm/Group Description	ARA-C/High-Dose Mitoxantrone("All-2")		Standard Vincristine/Prednisone ("L-20")
All Cause Mortality
	All-2		L-20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	All-2		L-20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/81 (48.1%)		33/89 (37.1%)
Blood and lymphatic system disorders
Amylase	1/81 (1.2%)	1	0/89 (0%)	0
Blood,Bone marrow,other	1/81 (1.2%)	1	0/89 (0%)	0
Fibrinogen	1/81 (1.2%)	1	0/89 (0%)	0
Hematuria	1/81 (1.2%)	1	0/89 (0%)	0
Hemoglobin (Hgb)	2/81 (2.5%)	2	0/89 (0%)	0
Leukocytes	2/81 (2.5%)	2	1/89 (1.1%)	1
Neutrophils (Leukemia)	1/81 (1.2%)	1	1/89 (1.1%)	1
Platelets	3/81 (3.7%)	4	2/89 (2.2%)	2
SGOT (AST)	1/81 (1.2%)	1	0/89 (0%)	0
SGPT (ALT)	1/81 (1.2%)	1	0/89 (0%)	0
Neutrophils	0/81 (0%)	0	1/89 (1.1%)	1
disseminated intravascular coagulation	0/81 (0%)	0	1/89 (1.1%)	1
ALT, SGPT	0/81 (0%)	0	1/89 (1.1%)	1
Cardiac disorders
Cardiac left ventricle	1/81 (1.2%)	1	0/89 (0%)	0
Cardiovascular, other	1/81 (1.2%)	1	0/89 (0%)	0
Hypotension	2/81 (2.5%)	2	0/89 (0%)	0
Sinus tachycardia	1/81 (1.2%)	1	0/89 (0%)	0
Ventricular arrhythmia	1/81 (1.2%)	1	0/89 (0%)	0
Supraventricular tachycardia	0/81 (0%)	0	1/89 (1.1%)	1
Supravent arrhythmia	0/81 (0%)	0	1/89 (1.1%)	1
Cardiovascular, Arrhythmia other	0/81 (0%)	0	1/89 (1.1%)	1
Eye disorders
Vision-blurred vision	1/81 (1.2%)	1	0/89 (0%)	0
Gastrointestinal disorders
Abdominal pain/cramping	3/81 (3.7%)	3	0/89 (0%)	0
Acidosis	1/81 (1.2%)	1	0/89 (0%)	0
Colitits	2/81 (2.5%)	2	0/89 (0%)	0
Constipation	3/81 (3.7%)	3	1/89 (1.1%)	1
Diarrhea	1/81 (1.2%)	1	1/89 (1.1%)	1
Dysphagia, esophagitis	1/81 (1.2%)	1	0/89 (0%)	0
Ileus (or neuroconstipation)	1/81 (1.2%)	1	5/89 (5.6%)	5
Nausea	1/81 (1.2%)	1	0/89 (0%)	0
Pancreatitis	3/81 (3.7%)	3	1/89 (1.1%)	1
Vomiting	1/81 (1.2%)	1	0/89 (0%)	0
Stomatitis/pharyngitis	0/81 (0%)	0	1/89 (1.1%)	1
Gastrointestinal, other	0/81 (0%)	0	1/89 (1.1%)	1
General disorders
Bone pain	1/81 (1.2%)	1	0/89 (0%)	0
Febrile neutropenia	11/81 (13.6%)	13	13/89 (14.6%)	17
Fever	2/81 (2.5%)	2	0/89 (0%)	0
Headache	1/81 (1.2%)	1	1/89 (1.1%)	1
Hemorrhage, other	1/81 (1.2%)	1	3/89 (3.4%)	3
Pain, other	1/81 (1.2%)	1	2/89 (2.2%)	2
Syncope	2/81 (2.5%)	2	1/89 (1.1%)	1
Epistaxis	0/81 (0%)	0	1/89 (1.1%)	1
Dehydration	0/81 (0%)	0	2/89 (2.2%)	2
Chest pain	0/81 (0%)	0	1/89 (1.1%)	1
Infections and infestations
infection	1/81 (1.2%)	1	2/89 (2.2%)	2
Infection with grade 3/4 neutrophils	1/81 (1.2%)	1	0/89 (0%)	0
Infection/Febrible Neutrophil-Other	10/81 (12.3%)	12	4/89 (4.5%)	4
Metabolism and nutrition disorders
Bilirubin	3/81 (3.7%)	4	1/89 (1.1%)	1
Hyperglycemia	2/81 (2.5%)	2	0/89 (0%)	0
Hypokalemia	1/81 (1.2%)	1	0/89 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle weakness	2/81 (2.5%)	2	0/89 (0%)	0
Nervous system disorders
Neurology, other	2/81 (2.5%)	2	0/89 (0%)	0
Neuropathy-motor	2/81 (2.5%)	2	2/89 (2.2%)	2
Seizure	1/81 (1.2%)	1	0/89 (0%)	0
Dizziness	0/81 (0%)	0	2/89 (2.2%)	2
Renal and urinary disorders
Hepatic enlargement	1/81 (1.2%)	1	0/89 (0%)	0
Hepatic, other	1/81 (1.2%)	1	0/89 (0%)	0
Renal failure	4/81 (4.9%)	4	2/89 (2.2%)	2
Respiratory, thoracic and mediastinal disorders
Adult respiratory disorder	4/81 (4.9%)	4	2/89 (2.2%)	2
Ataxia	2/81 (2.5%)	2	0/89 (0%)	0
Dyspnea	1/81 (1.2%)	1	0/89 (0%)	0
Hypoxia	1/81 (1.2%)	1	0/89 (0%)	0
Pleural effusion	1/81 (1.2%)	1	0/89 (0%)	0
Pulmonary, other	1/81 (1.2%)	1	2/89 (2.2%)	2
Thrombosis	0/81 (0%)	0	1/89 (1.1%)	1
Ascites	0/81 (0%)	0	1/89 (1.1%)	1
Skin and subcutaneous tissue disorders
Hand-Foot Skin reaction	1/81 (1.2%)	1	0/89 (0%)	0
Dermatology, skin other	0/81 (0%)	0	1/89 (1.1%)	1
Other (Not Including Serious) Adverse Events
	All-2		L-20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/81 (60.5%)		42/89 (47.2%)
Blood and lymphatic system disorders
Prothrombin Time	0/81 (0%)	0	5/89 (5.6%)	5
SGPT (ALT)	6/81 (7.4%)	6	5/89 (5.6%)	5
Eye disorders
Vision-blurred vision	0/81 (0%)	0	5/89 (5.6%)	5
Gastrointestinal disorders
Abdominal pain/cramping	11/81 (13.6%)	11	12/89 (13.5%)	12
Stomatitis/pharyngitis	5/81 (6.2%)	5	10/89 (11.2%)	10
General disorders
Anorexia	6/81 (7.4%)	6	5/89 (5.6%)	5
Bone pain	6/81 (7.4%)	6	0/89 (0%)	0
Fatigue	12/81 (14.8%)	12	15/89 (16.9%)	15
Febrile neutropenia	7/81 (8.6%)	7	0/89 (0%)	0
Insomnia	5/81 (6.2%)	5	0/89 (0%)	0
Muscle weakness	6/81 (7.4%)	6	0/89 (0%)	0
Pain, other	12/81 (14.8%)	12	12/89 (13.5%)	12
Rigors, chills	7/81 (8.6%)	7	0/89 (0%)	0
Metabolism and nutrition disorders
Bilirubin	9/81 (11.1%)	9	6/89 (6.7%)	6
Hypokalemia	18/81 (22.2%)	18	14/89 (15.7%)	14
Hypomagnesemia	10/81 (12.3%)	10	7/89 (7.9%)	7
Hyponatremia	0/81 (0%)	0	5/89 (5.6%)	5
Hypophosphatemia	12/81 (14.8%)	12	13/89 (14.6%)	13
Nervous system disorders
Dizziness	7/81 (8.6%)	7	6/89 (6.7%)	6
Syncope	6/81 (7.4%)	6	0/89 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	6/81 (7.4%)	6	7/89 (7.9%)	7
Thrombosis	0/81 (0%)	0	7/89 (7.9%)	7

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.