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Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin's Lymphomas

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01660451
Recruitment Status : Active, not recruiting
First Posted : August 8, 2012
Results First Posted : January 8, 2018
Last Update Posted : January 11, 2022
Sponsor:
Information provided by (Responsible Party):
Bayer

Brief Summary:

The objective of the study (part A) is to evaluate the efficacy and safety of BAY80-6946 in patients with indolent or aggressive Non-Hodgkin's Lymphoma, who have progressed after standard therapy. 30 patients will be enrolled to both indolent and aggressive disease group. The objective of the study part B (CHRONOS-1) is to evaluate the efficacy and safety of BAY80-6946 in patients with relapsed/refractory follicular lymphoma. 120 patients will be enrolled in the part B of the study. Further objectives are to evaluate the pharmacokinetics and biomarkers. Quality of life will be a further objective of part B of the study.

In a cohort of 20 patients (enrolled both in part A and B) an ECG substudy will be performed to assess the potential for cardiac toxicity and QT/QTc interval prolongation of BAY80-6946.

After an up to 28-day screening period, eligible patients will start treatment with BAY80-6946 at a dose of 0.8 mg/kg (Part A) and at a dose of 60 mg (Part B).

Treatment will be continued until disease has progressed or until another criterion is met for withdrawal from study. An end-of-treatment visit will be performed within 7 days after discontinuation of study treatment. Thirty to 35 days after last study drug administration, a safety followup visit will be performed for the collection of adverse events (AEs) and concomitant medication data. Patients will be contacted quarterly to determine overall survival status up to 4 years after last patient first treatment. Patients who discontinue study drug for reasons other than disease progression will enter the Active Assessment Follow-up period. Once the study is analyzed for survival at 4 years after last patient started study treatment, any patient still on treatment may continue to be treated and followed under a separate provision to be determined (e.g. roll-over-study). The end of study notification to Health Authorities will be based on the completion of the collection of survival data.

The efficacy is measured by the decrease in tumor size. Tumor assessments will be done at Screening, every 8 weeks during Year 1, every 12 weeks during Year 2, and every 6 months during Year 3. Blood samples will be collected for pharmacokinetic analysis. Archival tumor tissue and blood samples will be collected for biomarker analysis (mandatory) and for central pathology review (part B), fresh biopsy tissue will also be collected if available.


Condition or disease Intervention/treatment Phase
Lymphoma, Non-Hodgkin Drug: Copanlisib (Aliqopa, BAY80-6946) Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 227 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin's Lymphomas
Actual Study Start Date : November 19, 2012
Actual Primary Completion Date : June 22, 2016
Estimated Study Completion Date : March 8, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Copanlisib

Arm Intervention/treatment
Experimental: Copanlisib (indolent NHL)
Part A: Participants in this arm will be patients with indolent NHL.
Drug: Copanlisib (Aliqopa, BAY80-6946)

BAY 80-6946 is administered in a normal saline solution, 100 mL, intravenously over 1h. No intravenous glucose preparations should be administered on the days of infusion. Dosing is weekly for the first 3 weeks (on Days 1, 8, and 15) of a 28-day cycle, followed by a 1-week break (i.e., no infusion on Day 22).

Part A: The individual dose will be 0.8 mg/kg (max. 65 mg) per infusion from Cycle 1 on. The maximum dose of 65 mg should never be exceeded.

Part B: The individual dose will be 60 mg per infusion from Cycle 1 on.


Experimental: Copanlisib (aggressive NHL)
Part A: Participants in this arm will be patients with aggressive NHL.
Drug: Copanlisib (Aliqopa, BAY80-6946)

BAY 80-6946 is administered in a normal saline solution, 100 mL, intravenously over 1h. No intravenous glucose preparations should be administered on the days of infusion. Dosing is weekly for the first 3 weeks (on Days 1, 8, and 15) of a 28-day cycle, followed by a 1-week break (i.e., no infusion on Day 22).

Part A: The individual dose will be 0.8 mg/kg (max. 65 mg) per infusion from Cycle 1 on. The maximum dose of 65 mg should never be exceeded.

Part B: The individual dose will be 60 mg per infusion from Cycle 1 on.


Experimental: Copanlisib (indolent B-cell NHL)
Part B: Participants in this arm will be patients with indolent B-cell NHL.
Drug: Copanlisib (Aliqopa, BAY80-6946)

BAY 80-6946 is administered in a normal saline solution, 100 mL, intravenously over 1h. No intravenous glucose preparations should be administered on the days of infusion. Dosing is weekly for the first 3 weeks (on Days 1, 8, and 15) of a 28-day cycle, followed by a 1-week break (i.e., no infusion on Day 22).

Part A: The individual dose will be 0.8 mg/kg (max. 65 mg) per infusion from Cycle 1 on. The maximum dose of 65 mg should never be exceeded.

Part B: The individual dose will be 60 mg per infusion from Cycle 1 on.





Primary Outcome Measures :
  1. Objective Response Rate (ORR) Based on Independent Review-Part A [ Time Frame: Baseline up to the last patient has completed the 16 weeks of treatment ]
    Objective response rate was defined as the proportion of participants with a best response rating of complete response (CR), unconfirmed complete response (CRu) or partial response (PR), based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999, as evaluated by the Independent Response Adjudication Committee (IRAC). For chronic lymphocytic leukemia (CLL) patients Hallek criteria (2008) were used and assessed by investigator.

  2. Objective Response Rate (ORR) Based on Independent Review-Part B [ Time Frame: Baseline up to the last patient has completed the 16 weeks of treatment ]
    Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.

  3. ORR Based on Investigator Assessment-Part A [ Time Frame: Baseline up to the last patient has completed the 16 weeks of treatment ]
    Objective response rate was defined as the proportion of participants with a best response rating of CR, CRu or PR, based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999. For CLL patients Hallek criteria (2008) were used and assessed by investigator.

  4. ORR Based on Investigator Assessment-Part B [ Time Frame: Baseline up to the last patient has completed the 16 weeks of treatment ]
    Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.


Secondary Outcome Measures :
  1. Duration of Response (DOR) Based on Independent Review [ Time Frame: Baseline up to the last patient has completed the 16 weeks of treatment ]
    Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason "other" or "AE not related to disease progression.

  2. DOR Based on Investigator Assessment [ Time Frame: Baseline up to the last patient has completed the 16 weeks of treatment ]
    Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason "other" or "AE not related to disease progression.

  3. Progression Free Survival (PFS) Based on Independent Review [ Time Frame: Baseline up to the last patient has completed the 16 weeks of treatment ]
    PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).

  4. PFS Based on Investigator Assessment [ Time Frame: Baseline up to the last patient has completed the 16 weeks of treatment ]
    PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).

  5. Overall Survival (OS) [ Time Frame: Baseline up to the last patient has completed the 16 weeks of treatment ]
    OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause.

  6. Functional Assessment of Cancer Therapy - Lymphoma Lymphoma Subscale (FACT-Lym LymS) at Week 16 - Part B [ Time Frame: Baseline up to the last patient has completed the 16 weeks of treatment ]
    HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. Score range for the FACT-Lym LymS was 0 - 60, higher score represent less symptoms. Here in below table "n" signifies evaluable participants for the respective category.

  7. Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Total Score at Week 16 - Part B [ Time Frame: Baseline up to the last patient has completed the 16 weeks of treatment ]
    HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. FACT-Lym total score range was 0-168, higher score indicates better HRQoL. Here, in the below table "n" signifies evaluable participants for the respective category.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Indolent NHL:

    • Histologically confirmed diagnosis of follicular lymphoma (FL) grades 1, 2 or 3a, marginal zone lymphoma (including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue [MALT] lymphoma), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, chronic lymphocytic leukemia (CLL).
    • Relapsed after ≥ 2 prior chemotherapy- or immunotherapy-based regimens for indolent NHL, or refractory to 2 prior chemotherapy and/ or immunotherapy-based regimens.
  • Aggressive NHL:

    • Histologically confirmed diagnosis of grade 3b follicular lymphoma (FL), transformed indolent lymphoma, diffuse large B-cell lymphoma (DLBCL), mediastinal large B-cell lymphoma, mantle cell lymphoma (MCL), peripheral T-cell lymphoma unspecified, or anaplastic large cell lymphoma primary systemic type, or angioimmunoblastic T cell lymphoma.
    • Relapsed after ≥ 2 prior chemotherapy regimens, including the following: First-line treatment with standard anthracycline-containing regimen (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone or equivalent). At least 1 additional combination chemotherapy regimen. Patients relapsed after or refractory to first prior chemotherapy- and/or immunotherapy-based regimen for aggressive NHL and not eligible for high-dose regimen followed by transplant. High-dose chemotherapy, or chemoradiotherapy with autologous stem cell transplantation is considered 1 regimen. Patients with CD20 expressing neoplastic cells must have received prior rituximab, if available.
    • Patients with transformed indolent lymphoma must have received at least 2 prior chemotherapy- and/or immunotherapy-based regimens
    • Consent to provide fresh tumor tissue during screening
  • Indolent B-cell NHL lymphoma (study part B):

    • Histologically confirmed diagnosis of indolent B-cell NHL, with histological subtype limited to the following:

      • Follicular lymphoma (FL) grade 1-2-3a
      • Small lymphocytic lymphoma (SLL) with absolute lymphocyte count < 5 x 109/L at the time of diagnosis and at study entry
      • Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM)
      • Marginal zone lymphoma (MZL) (splenic, nodal, or extranodal)
    • Relapsed or refractory after ≥ 2 prior lines of therapy (refractory defined as not responding to a standard regimen or progressing within 6 months of the last course of a standard regimen). Patients must have received Rituximab and alkylating agents.
  • For all patients:

    • Male or female patients > 18 years of age
    • ECOG performance status ≤ 2 (ECOG: Eastern Cooperative Oncology Group)
    • Life expectancy of at least 3 months
    • Adequate bone marrow, liver and renal function as assessed within 7 days before starting study treatment
    • Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (LLN) for the Institution
    • Availability of archival tumor tissue

Exclusion Criteria:

  • Uncontrolled hypertension (blood pressure ≥ 150/90 mmHg despite optimal medical management)
  • Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks of start of study medication (CTCAE: Common Terminology Criteria for Adverse Events).
  • History or concurrent condition of interstitial lung disease
  • Unresolved toxicity higher than CTCAE grade 1 (NCI-CTC version 4.0) attributed to any prior therapy/procedure excluding alopecia. (NCI: National Cancer Institute)
  • Prior treatment with PI3K inhibitors
  • Systemic corticosteroid therapy (ongoing)
  • Hepatitis B or C. All subjects must be screened for hepatitis B and C up to 28 days prior to study drug start using the hepatitis virus panel laboratorial routine. Subjects positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA; subjects positive for HCV IgG will be eligible if they are negative for HCV RNA.
  • For Part B:

    • Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed disease and chronic lymphocytic leukemia (CLL)
    • History or concurrent condition of interstitial lung disease or severely impaired pulmonary function
  • Excluded medical conditions:

    • Previous or concurrent cancer that is distinct in primary site or histology from indolent B-cell NHL within 5 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, nonmelanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
    • Hepatitis B or C. All subjects must be screened for hepatitis B and C up to 28 days prior to study drug start using the hepatitis virus panel laboratorial routine. Subjects positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA; subjects positive for HCV IgG will be eligible if they are negative for HCV-RNA.
    • Type I or II diabetes mellitus with HbA1c > 8.5% or fasting plasma glucose > 160 mg/dL at screening.
    • Previous or concurrent cancer that is distinct in primary site or histology from indolent B-cell NHL within 5 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, nonmelanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01660451


Locations
Hide Hide 101 study locations
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United States, Alabama
Birmingham, Alabama, United States, 35213
United States, Arizona
Gilbert, Arizona, United States, 85234
United States, California
Anaheim, California, United States, 90801
United States, Colorado
Aurora, Colorado, United States, 80012
Englewood, Colorado, United States, 80113
Fort Collins, Colorado, United States, 80528
United States, Florida
Port Saint Lucie, Florida, United States, 34952
United States, Kentucky
Louisville, Kentucky, United States, 40207
United States, Michigan
Detroit, Michigan, United States, 48202
United States, Minnesota
Saint Louis Park, Minnesota, United States, 55426
United States, New York
Lake Success, New York, United States, 11042
United States, North Carolina
Goldsboro, North Carolina, United States, 27534
United States, Ohio
Canton, Ohio, United States, 44718
United States, Texas
San Antonio, Texas, United States, 78229
United States, Washington
Spokane, Washington, United States, 99208-1129
Australia, Australian Capital Territory
Garran, Australian Capital Territory, Australia, 2605
Austria
Linz, Austria, 4020
Belgium
Anderlecht, Belgium, 1070
Bruxelles - Brussel, Belgium, 1200
Gent, Belgium, 9000
Leuven, Belgium, 3000
Turnhout, Belgium, 2300
Wilrijk, Belgium, 2610
Bulgaria
Sofia, Bulgaria, 1431
Canada, New Brunswick
Saint John, New Brunswick, Canada, E2L 4L2
Canada, Quebec
Montreal, Quebec, Canada, H1T 2M4
Montreal, Quebec, Canada, H3T 1E2
Finland
Helsinki, Finland, 00290
Oulu, Finland, 90020
Tampere, Finland, 33521
Turku, Finland, FIN-20521
France
Brest, France, 29285
Creteil, France, 94010
La Roche Sur Yon, France, 85925
Lille, France, 59037
PARIS cedex, France, 75475
Pessac, France, 33600
Pierre Benite, France, 69495
Poitiers, France, 86021
Rouen, France, 76038
Vandoeuvre-les-nancy, France, 54500
Germany
München, Bayern, Germany, 81377
Potsdam, Berlin, Germany, 14467
Münster, Nordrhein-Westfalen, Germany, 48149
Recklinghausen, Nordrhein-Westfalen, Germany, 45659
Mainz, Rheinland-Pfalz, Germany, 55131
Dresden, Sachsen, Germany, 01307
Berlin, Germany, 10967
Berlin, Germany, 13353
Greece
Athens, Greece, 11526
Hong Kong
Hong Kong, Hong Kong
Shatin, Hong Kong
Hungary
Budapest, Hungary, 1083
Budapest, Hungary, 1097
Kaposvar, Hungary, 7400
Ireland
Galway, Ireland, H91 YR71
Israel
Petach Tikva, Israel, 4941492
Ramat Gan, Israel, 5262000
Zerifin, Israel, 7030000
Italy
Napoli, Campania, Italy, 80131
Bologna, Emilia-Romagna, Italy, 40138
Roma, Lazio, Italy, 00161
Brescia, Lombardia, Italy, 25123
Milano, Lombardia, Italy, 20089
Torino, Piemonte, Italy, 10126
Korea, Republic of
Busan, Busan Gwang''yeogsi, Korea, Republic of, 49201
Seoul, Seoul Teugbyeolsi, Korea, Republic of, 03080
Seoul, Korea, Republic of, 06351
New Zealand
Christchurch, New Zealand
Poland
Gdynia, Poland, 81-519
Krakow, Poland, 30-510
Portugal
Lisboa, Portugal, 1099-023
Russian Federation
Kemerovo, Russian Federation, 650066
Moscow, Russian Federation, 129128
Nizhny Novgorod, Russian Federation, 603126
Omsk, Russian Federation, 644013
Saratov, Russian Federation, 410053
St. Petersburg, Russian Federation, 197101
Singapore
Singapore, Singapore, 169608
Singapore, Singapore, 169610
Spain
Majadahonda, Madrid, Spain, 28222
Marbella, Málaga, Spain, 29603
Barcelona, Spain, 08036
Madrid, Spain, 28050
Sevilla, Spain, 41009
Valencia, Spain, 46026
Sweden
Uddevalla, Sweden, 451 80
Turkey
Ankara, Turkey, 06100
Istanbul, Turkey, 34093
Izmir, Turkey, 35100
Izmir, Turkey, 35340
United Kingdom
Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
Plymouth, Devon, United Kingdom, PL6 8DH
Southampton, Hampshire, United Kingdom, SO16 6YD
Harrow, London, United Kingdom, HA1 3UJ
Liverpool, Merseyside, United Kingdom, L7 8XP
Sutton, Surrey, United Kingdom, SM2 5PT
Birmingham, West Midlands, United Kingdom, B9 5SS
Leeds, United Kingdom, LS9 7TF
Manchester, United Kingdom, M20 4BX
Romford, United Kingdom, RM7 0AG
Sponsors and Collaborators
Bayer
Investigators
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Study Director: Bayer Study Director Bayer
Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01660451    
Other Study ID Numbers: 16349
2012-002602-52 ( EudraCT Number )
First Posted: August 8, 2012    Key Record Dates
Results First Posted: January 8, 2018
Last Update Posted: January 11, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Clinical trial, phase II
Phosphatidylinositol 3-Kinase
Class I, Non-Hodgkin's lymphoma
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases