Study Description

PRIMARY OBJECTIVE:

I. To evaluate the response rate and toxicity of lenalidomide (CC-5013) plus dexamethasone (standard dose) versus CC-5013 plus low dose dexamethasone in patients with newly diagnosed myeloma at any time in the first 4 cycles of treatment and to determine if CC-5013 plus low dose dexamethasone will have similar response rate with lower toxicity (First Phase).

SECONDARY OBJECTIVES:

I. To evaluate the response rate of thalidomide plus dexamethasone (Thal/Dex) in patients with newly diagnosed myeloma who do not achieve a complete or partial response at any time in the first 4 cycles with the CC-5013 and dexamethasone combination in either of the two arms (First Phase).

II. To study the effect of CC-5013 on bone marrow microvessel density and angiogenesis grade, on plasma cell labeling index (PCLI), and on the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in the marrow (First Phase).

III. To study the effect of CC-5013 and dexamethasone on bone marrow mesenchymal progenitor cells (MPCs) (First Phase).

IV. To evaluate in a separate expansion phase the efficacy of aspirin (325 mg/day) versus Coumadin (dose adjusted to maintain a target international normalized ratio [INR] of 2-3) in preventing deep vein thrombosis (DVT) in patients with newly diagnosed myeloma receiving CC-5013 plus standard dose dexamethasone.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, and standard-dose dexamethasone PO QD on days 1-4, 9-12, and 17-20.

Arm II: Patients receive lenalidomide as in Arm I and low-dose dexamethasone PO QD on days 1, 8, 15, and 22.

In both arms, cycles repeat every 28 days in the absence of unacceptable toxicity or disease progression. Patients not responding at any point during the first 4 cycles of lenalidomide and dexamethasone are assigned to 1 of 2 salvage therapy arms. Patients who progress during treatment on Arms I or II have the option to register on salvage therapy Arms III or IV respectively.

Arm III (patients with no response after treatment on Arm I): Patients receive thalidomide PO QD on days 1-28 and standard-dose dexamethasone PO QD on days 1-4, 9-12, and 17-20.

Arm IV (patients with no response after treatment on Arm II): Patients receive thalidomide as in Arm III and low-dose dexamethasone PO QD on days 1, 8, 15, and 22.

In both salvage therapy arms, cycles repeat every 28 days in the absence of unacceptable toxicity or disease progression. After completion of 4 cycles of therapy, patients may undergo stem cell harvest (using growth factors only) for cryopreservation.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 2 years.

Condition or Disease	Intervention/Treatment
DS Stage I Multiple Myeloma DS Stage II Multiple Myeloma DS Stage III Multiple Myeloma	Drug: Dexamethasone Other: Laboratory Biomarker Analysis Drug: Lenalidomide Drug: Thalidomide

Study Design

Study Type	Interventional
Actual Enrollment	452 participants
Design Allocation	Randomized
Interventional Model	Parallel Assignment
Masking	Double
Primary Purpose	Treatment
Official Title	A Randomized Phase III Study of CC-5013 Plus Dexamethasone Versus CC-5013 Plus Low Dose Dexamethasone in Multiple Myeloma With Thalidomide Plus Dexamethasone Salvage Therapy for Non-Responders
Study Start Date	November 3, 2004
Actual Primary Completion Date	November 30, 2008
Anticipated Study Completion Date	October 22, 2025

Groups and Cohorts

Group/ Cohort	Intervention/ Treatment
Arm I (lenalidomide, dexamethasone) Patients receive lenalidomide PO QD on days 1-21 and standard-dose dexamethasone PO QD on days 1-4, 9-12, and 17-20.	Drug: Dexamethasone Given PO Other: Laboratory Biomarker Analysis Drug: Lenalidomide
Arm II (lenalidomide, low-dose dexamethasone) Patients receive lenalidomide and acetylsalicylic acid as in Arm I and low-dose dexamethasone PO QD on days 1, 8, 15, and 22.	Drug: Dexamethasone Given PO Other: Laboratory Biomarker Analysis Drug: Lenalidomide
Arm III (thalidomide, dexamethasone) Patients with no response after treatment on Arm I: Patients receive thalidomide PO QD on days 1-28 and standard-dose dexamethasone PO QD on days 1-4, 9-12, and 17-20	Drug: Dexamethasone Given PO Other: Laboratory Biomarker Analysis Drug: Thalidomide
Arm IV (thalidomide, low-dose dexamethasone) Patients with no response after treatment on Arm II: Patients receive thalidomide as in arm III and low-dose dexamethasone PO QD on days 1, 8, 15, and 22.	Drug: Dexamethasone Given PO Other: Laboratory Biomarker Analysis Drug: Thalidomide

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients With Objective Response (First Phase, Step 1) [Assessed every 4 weeks for 16 weeks during Step 1]
   Objective response is defined as either complete response (CR) or partial response (PR). Patients who have complete disappearance of an M-protein and no evidence of myeloma in the bone marrow are considered to have CR. PR requires all the following: (1) ≥50% reduction in the level of the serum monoclonal paraprotein. (2) Reduction in 24-hour urinary light chain excretion either by ≥90% or to <200 mg. (3)For patients with non-secretory (or oligosecretory) myeloma only, a ≥50% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy must be documented. (4)50% reduction in size of soft tissue plasmacytoma (by radiography or clinical examination). (5) No increase in the number or size of lytic bone lesions (development of a compression fracture does not exclude response).
   
   As the expansion phase was a substudy terminated early with only 7 patients enrolled, the clinical results presented are mainly for the first phase only.

Secondary Outcome Measures

1. Proportion of Patients With Objective Response (First Phase, Step 2) [Assessed every 4 weeks for 16 weeks during Step 2]
   Objective response is defined as either complete response (CR) or partial response (PR). Patients who have complete disappearance of an M-protein and no evidence of myeloma in the bone marrow are considered to have CR. PR requires all the following: (1) ≥50% reduction in the level of the serum monoclonal paraprotein. (2) Reduction in 24-hour urinary light chain excretion either by ≥90% or to <200 mg. (3)For patients with non-secretory (or oligosecretory) myeloma only, a ≥50% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy must be documented. (4)50% reduction in size of soft tissue plasmacytoma (by radiography or clinical examination). (5) No increase in the number or size of lytic bone lesions (development of a compression fracture does not exclude response).
   
   As the expansion phase was a substudy terminated early with only 7 patients enrolled, the clinical results presented are mainly for the first phase only.

Eligibility Criteria

Ages Eligible for Study	18 Years and Older (Adult, Older Adult)
Sexes Eligible for Study	All
Accepts Healthy Volunteers	No
Inclusion Criteria	Patients must be diagnosed with symptomatic multiple myeloma within the past 90 days confirmed by the following: Bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma which must be obtained within 4 weeks prior to randomization Measurable levels of monoclonal protein (M protein): >= 1.0 g/dL on serum protein electrophoresis or >= 200 mg of monoclonal light chain on a 24 hour urine protein electrophoresis which must be obtained within 4 weeks prior to randomization; both serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) are required to be performed within 28 days prior to randomization; please note that if both serum and urine m-components are present, both must be followed in order to evaluate response Hemoglobin > 7 g/dL Platelet count > 75,000 cells/mm^3 Absolute neutrophil count > 1000 cells/mm^3 Creatinine < 2.5 mg/dL and creatinine clearance (measured or calculated) >= 60 mL/min Bilirubin =< 1.5 mg/dL Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 times the upper limit of normal Prior palliative and/or localized radiation therapy is permitted provided at least 4 weeks have passed from date of last radiation therapy to date of registration; patients with prior solitary plasmacytoma treated with radiation therapy with curative intent are eligible if the disease has now progressed to active multiple myeloma meeting all the eligibility criteria for this protocol Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24 hours prior to starting cycle 1 of lenalidomide; further, they must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method (intrauterine device [IUD], birth control pills, tubal ligation or partner's vasectomy) and one additional effective method (condom, diaphragm or cervical cap); FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy starting 4 weeks prior to and while taking CC5013 or thalidomide and for four weeks after discontinuing this therapy; a FCBP is a sexually mature woman who: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure Patients with a history of prior malignancy are eligible provided there is no active malignancy and a low expectation of recurrence within 6 months
Exclusion Criteria	No prior systemic therapy with the exception of bisphosphonates for multiple myeloma Prior glucocorticosteroid therapy for the treatment of multiple myeloma is not permitted; prior systemic glucocorticosteroid use for the treatment of non-malignant disorders is permitted; concurrent use after registration on the study should be restricted to the equivalent of prednisone 10 mg per day; prior or concurrent topical or localized glucocorticosteroid therapy to treat non-malignant comorbid disorders is permitted Patients must not have active, uncontrolled seizure disorder; patients must have had no seizures in the last 6 months Patients must not have uncontrolled intercurrent illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance with the study, or a prior history of Stevens Johnson syndrome Patients with smoldering myeloma or monoclonal gammopathy of undetermined significance are not eligible Patients must not have grade 2 or higher peripheral neuropathy due to other medical conditions at the time of randomization Patients must not have active, uncontrolled infection Patients must not have a history of current or previous deep vein thrombosis or pulmonary embolism regardless of whether or not the patient is receiving anticoagulation therapy For patients registered prior to activation of Addendum # 6; patients must be willing and able to take prophylaxis with either aspirin at 325 mg/day or alternative prophylaxis with either low molecular weight heparin or Coumadin For patients registered after activation of Addendum # 6; patients entering the expansion phase of the protocol, which tests anticoagulant prophylaxis, must be able and willing to be randomized between aspirin at 325 mg/day and Coumadin Female patients MUST NOT be pregnant or breastfeeding; due to the potential teratogenic properties of CC 5013, and the known teratogenicity associated with thalidomide, the use of these drugs in this patient population is ABSOLUTELY CONTRAINDICATED

Contacts and Locations

Sponsors and Collaborators	National Cancer Institute (NCI)
Locations	University of Alabama at Birmingham Cancer Center | Birmingham, Alabama, United States, 35233 Huntsville Hospital | Huntsville, Alabama, United States, 35801 Providence Alaska Medical Center | Anchorage, Alaska, United States, 99508 Mayo Clinic in Arizona | Scottsdale, Arizona, United States, 85259 Providence Saint Joseph Medical Center/Disney Family Cancer Center | Burbank, California, United States, 91505 Saint Jude Medical Center | Fullerton, California, United States, 92835 El Camino Hospital | Mountain View, California, United States, 94040 Kaiser Permanente-San Diego Mission | San Diego, California, United States, 92108 The Medical Center of Aurora | Aurora, Colorado, United States, 80012 Penrose-Saint Francis Healthcare | Colorado Springs, Colorado, United States, 80907 SCL Health Saint Joseph Hospital | Denver, Colorado, United States, 80218 Swedish Medical Center | Englewood, Colorado, United States, 80113 Poudre Valley Hospital | Fort Collins, Colorado, United States, 80524 Banner McKee Medical Center | Loveland, Colorado, United States, 80539 Danbury Hospital | Danbury, Connecticut, United States, 06810 Eastern Connecticut Hematology and Oncology Associates | Norwich, Connecticut, United States, 06360 Holy Cross Hospital | Fort Lauderdale, Florida, United States, 33308 University of Florida Health Science Center - Gainesville | Gainesville, Florida, United States, 32610 Baptist MD Anderson Cancer Center | Jacksonville, Florida, United States, 32207 Mayo Clinic in Florida | Jacksonville, Florida, United States, 32224-9980 Martin Hospital South | Stuart, Florida, United States, 34997 Phoebe Putney Memorial Hospital | Albany, Georgia, United States, 31701 Emory University Hospital/Winship Cancer Institute | Atlanta, Georgia, United States, 30322 Atlanta Regional CCOP | Atlanta, Georgia, United States, 30342 Augusta Oncology Associates PC-D'Antignac | Augusta, Georgia, United States, 30901 Dekalb Medical Center | Decatur, Georgia, United States, 30033 Atrium Health Navicent | Macon, Georgia, United States, 31201 Lewis Cancer and Research Pavilion at Saint Joseph's/Candler | Savannah, Georgia, United States, 31405 University of Hawaii Cancer Center | Honolulu, Hawaii, United States, 96813 Saint Luke's Cancer Institute - Boise | Boise, Idaho, United States, 83712 OSF Saint Anthony's Health Center | Alton, Illinois, United States, 62002 Northwestern University | Chicago, Illinois, United States, 60611 John H Stroger Jr Hospital of Cook County | Chicago, Illinois, United States, 60612 Decatur Memorial Hospital | Decatur, Illinois, United States, 62526 Ascension Alexian Brothers - Elk Grove Village | Elk Grove Village, Illinois, United States, 60007 Edward Hines Jr VA Hospital | Hines, Illinois, United States, 60141 Midwest Center for Hematology Oncology | Joliet, Illinois, United States, 60432 Duly Health and Care Joliet | Joliet, Illinois, United States, 60435 Swedish American Hospital | Rockford, Illinois, United States, 61104 UW Health Carbone Cancer Center Rockford | Rockford, Illinois, United States, 61114 Edward H Kaplan MD and Associates | Skokie, Illinois, United States, 60076 Elkhart General Hospital | Elkhart, Indiana, United States, 46515 Fort Wayne Medical Oncology and Hematology Inc-Parkview | Fort Wayne, Indiana, United States, 46845 Indiana University/Melvin and Bren Simon Cancer Center | Indianapolis, Indiana, United States, 46202 Franciscan Health Indianapolis | Indianapolis, Indiana, United States, 46237 IU Health Arnett Cancer Care | Lafayette, Indiana, United States, 47904 Saint Joseph Regional Medical Center-Mishawaka | Mishawaka, Indiana, United States, 46545 Memorial Hospital of South Bend | South Bend, Indiana, United States, 46601 McFarland Clinic - Ames | Ames, Iowa, United States, 50010 University of Iowa Healthcare Cancer Services Quad Cities | Bettendorf, Iowa, United States, 52722 Iowa Methodist Medical Center | Des Moines, Iowa, United States, 50309 Siouxland Regional Cancer Center | Sioux City, Iowa, United States, 51101 MercyOne Waterloo Cancer Center | Waterloo, Iowa, United States, 50702 Kansas City NCI Community Oncology Research Program | Prairie Village, Kansas, United States, 66208 Harold Alfond Center for Cancer Care | Augusta, Maine, United States, 04330 Greater Baltimore Medical Center | Baltimore, Maryland, United States, 21204 HealthAlliance Hospital - Leominster | Leominster, Massachusetts, United States, 01453 Henry Ford Health Saint John Hospital | Detroit, Michigan, United States, 48236 West Michigan Cancer Center | Kalamazoo, Michigan, United States, 49007 Mercy Hospital | Coon Rapids, Minnesota, United States, 55433 Fairview Southdale Hospital | Edina, Minnesota, United States, 55435 Unity Hospital | Fridley, Minnesota, United States, 55432 Saint John's Hospital - Healtheast | Maplewood, Minnesota, United States, 55109 Mayo Clinic in Rochester | Rochester, Minnesota, United States, 55905 Regions Hospital | Saint Paul, Minnesota, United States, 55101 United Hospital | Saint Paul, Minnesota, United States, 55102 Mercy Hospital Saint Louis | Saint Louis, Missouri, United States, 63141 Saint Louis-Cape Girardeau CCOP | Saint Louis, Missouri, United States, 63141 Montana Cancer Consortium NCORP | Billings, Montana, United States, 59102 Great Falls Clinic | Great Falls, Montana, United States, 59405 Nebraska Cancer Research Center | Lincoln, Nebraska, United States, 68510 Nebraska Methodist Hospital | Omaha, Nebraska, United States, 68114 Alegent Health Immanuel Medical Center | Omaha, Nebraska, United States, 68122 Alegent Health Bergan Mercy Medical Center | Omaha, Nebraska, United States, 68124 Midlands Community Hospital | Papillion, Nebraska, United States, 68046 Hackensack University Medical Center | Hackensack, New Jersey, United States, 07601 The Cancer Institute of New Jersey Hamilton | Hamilton, New Jersey, United States, 08690 Morristown Medical Center | Morristown, New Jersey, United States, 07960 Virtua Memorial | Mount Holly, New Jersey, United States, 08060 Jersey Shore Medical Center | Neptune, New Jersey, United States, 07753 Rutgers Cancer Institute of New Jersey | New Brunswick, New Jersey, United States, 08903 Robert Wood Johnson University Hospital Somerset | Somerville, New Jersey, United States, 08876 Garnet Health Medical Center | Middletown, New York, United States, 10940 NYU Langone Hospital - Long Island | Mineola, New York, United States, 11501 Mount Sinai Union Square | New York, New York, United States, 10003 Stony Brook University Medical Center | Stony Brook, New York, United States, 11794 Mission Hospital | Asheville, North Carolina, United States, 28801 Wayne Memorial Hospital | Goldsboro, North Carolina, United States, 27534 Southeast Clinical Oncology Research Consortium NCORP | Winston-Salem, North Carolina, United States, 27104 Sanford Bismarck Medical Center | Bismarck, North Dakota, United States, 58501 Essentia Health Cancer Center-South University Clinic | Fargo, North Dakota, United States, 58103 Sanford Broadway Medical Center | Fargo, North Dakota, United States, 58122 Summa Health System - Akron Campus | Akron, Ohio, United States, 44304 MetroHealth Medical Center | Cleveland, Ohio, United States, 44109 Miami Valley Hospital | Dayton, Ohio, United States, 45409 Miami Valley Hospital North | Dayton, Ohio, United States, 45415 Atrium Medical Center-Middletown Regional Hospital | Franklin, Ohio, United States, 45005-1066 Kettering Medical Center | Kettering, Ohio, United States, 45429 Saint Charles Hospital | Oregon, Ohio, United States, 43616 Firelands Regional Medical Center | Sandusky, Ohio, United States, 44870 ProMedica Flower Hospital | Sylvania, Ohio, United States, 43560 Mercy Hospital of Tiffin | Tiffin, Ohio, United States, 44883 Toledo Community Hospital Oncology Program CCOP | Toledo, Ohio, United States, 43617 Toledo Clinic Cancer Centers-Toledo | Toledo, Ohio, United States, 43623 Kaiser Permanente Northwest | Portland, Oregon, United States, 97227 Jefferson Abington Hospital | Abington, Pennsylvania, United States, 19001 Penn State Milton S Hershey Medical Center | Hershey, Pennsylvania, United States, 17033-0850 Lancaster General Hospital | Lancaster, Pennsylvania, United States, 17602 Saint Mary Medical and Regional Cancer Center | Langhorne, Pennsylvania, United States, 19047 University of Pennsylvania/Abramson Cancer Center | Philadelphia, Pennsylvania, United States, 19104 Pennsylvania Hospital | Philadelphia, Pennsylvania, United States, 19107 Thomas Jefferson University Hospital | Philadelphia, Pennsylvania, United States, 19107 Fox Chase Cancer Center | Philadelphia, Pennsylvania, United States, 19111 Chestnut Hill Health System | Philadelphia, Pennsylvania, United States, 19118 Einstein Medical Center Philadelphia | Philadelphia, Pennsylvania, United States, 19141 Guthrie Medical Group PC-Robert Packer Hospital | Sayre, Pennsylvania, United States, 18840 Grand View Hospital | Sellersville, Pennsylvania, United States, 18960 Mount Nittany Medical Center | State College, Pennsylvania, United States, 16803 Reading Hospital | West Reading, Pennsylvania, United States, 19611 Lankenau Medical Center | Wynnewood, Pennsylvania, United States, 19096 WellSpan Health-York Hospital | York, Pennsylvania, United States, 17403 McLeod Regional Medical Center | Florence, South Carolina, United States, 29506 Rapid City Regional Hospital | Rapid City, South Dakota, United States, 57701 Sanford Cancer Center Oncology Clinic | Sioux Falls, South Dakota, United States, 57104 Sentara Martha Jefferson Hospital | Charlottesville, Virginia, United States, 22901 University of Virginia Cancer Center | Charlottesville, Virginia, United States, 22908 Centra Alan B Pearson Regional Cancer Center | Lynchburg, Virginia, United States, 24501 Virginia Commonwealth University/Massey Cancer Center | Richmond, Virginia, United States, 23298 Swedish Medical Center-First Hill | Seattle, Washington, United States, 98122 West Virginia University Healthcare | Morgantown, West Virginia, United States, 26506 ThedaCare Regional Cancer Center | Appleton, Wisconsin, United States, 54911 Gundersen Lutheran Medical Center | La Crosse, Wisconsin, United States, 54601 SSM Health Dean Medical Group - South Madison Campus | Madison, Wisconsin, United States, 53715 University of Wisconsin Carbone Cancer Center - University Hospital | Madison, Wisconsin, United States, 53792 Marshfield Medical Center-Marshfield | Marshfield, Wisconsin, United States, 54449 Medical College of Wisconsin | Milwaukee, Wisconsin, United States, 53226 ProHealth Oconomowoc Memorial Hospital | Oconomowoc, Wisconsin, United States, 53066 ProHealth Waukesha Memorial Hospital | Waukesha, Wisconsin, United States, 53188
Investigators	Principal Investigator: S. V Rajkumar, ECOG-ACRIN Cancer Research Group

More Information

Publications

• Baker A, Braggio E, Jacobus S, Jung S, Larson D, Therneau T, Dispenzieri A, Van Wier SA, Ahmann G, Levy J, Perkins L, Kim S, Henderson K, Vesole D, Rajkumar SV, Jelinek DF, Carpten J, Fonseca R. Uncovering the biology of multiple myeloma among African Americans: a comprehensive genomics approach. Blood. 2013 Apr 18;121(16):3147-52. doi: 10.1182/blood-2012-07-443606. Epub 2013 Feb 19.

• Kumar SK, Uno H, Jacobus SJ, Van Wier SA, Ahmann GJ, Henderson KJ, Callander NS, Haug JL, Siegel DS, Greipp PR, Fonseca R, Rajkumar SV. Impact of gene expression profiling-based risk stratification in patients with myeloma receiving initial therapy with lenalidomide and dexamethasone. Blood. 2011 Oct 20;118(16):4359-62. doi: 10.1182/blood-2011-03-342089. Epub 2011 Aug 22.

• Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010 Jan;11(1):29-37. doi: 10.1016/S1470-2045(09)70284-0. Epub 2009 Oct 21. Erratum In: Lancet Oncol. 2010 Jan;11(1):14.

Additional Relevant MeSH Terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Neoplasms by Histologic Type
• Neoplasms
• Hemostatic Disorders
• Vascular Diseases
• Cardiovascular Diseases
• Paraproteinemias
• Blood Protein Disorders
• Hematologic Diseases
• Hemorrhagic Disorders
• Lymphoproliferative Disorders
• Immunoproliferative Disorders
• Immune System Diseases