Ofatumumab-based Induction Chemoimmunotherapy in Previously Untreated Patients With CLL/SLL

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01145209
• Collaborator: University of Virginia (Other), GlaxoSmithKline (Industry)
• Enrollment: 32
• Location: 1
• Arms: 2
• Duration (Months): 146.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Background:

• Ofatumumab was approved by the U.S. Food and Drug Administration to treat patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not responded to standard chemotherapy. Ofatumumab is a substance that recognizes specific types of white blood cells called B-lymphocytes, which become cancerous in CLL/SLL. Ofatumumab attaches to a molecule called CD20, which is found on the surface of B-cells, and destroys them. Previous studies have shown that ofatumumab can decrease the number of B-cells in patients with CLL/SLL who have been treated with chemotherapy, but more research is needed to determine it if can also be used to treat patients with previously untreated CLL/SLL.

Objectives:

• To determine a safe and effective dose of ofatumumab, along with chemotherapy, to treat chronic lymphocytic leukemia or small lymphocytic lymphoma.

Eligibility:

• Individuals at least 18 years of age who have been diagnosed with CLL or SLL that has not been treated with chemotherapy.

Design:

• Eligible participants will be screened with a physical exam, blood samples, lymph node and bone marrow biopsies, and imaging studies.

• Participants will be separated into 2 groups: all participants will receive ofatumumab and fludarabine, and some participants will be selected to also receive cyclophosphamide (based on results of certain blood tests).

• Participants will receive the study drugs (ofatumumab and fludarabine, and optional cyclophosphamide) by infusion for a maximum of 6 days, followed by 21 days off drug.

• Participants will have 6 cycles of treatment according to a schedule set by the study doctors, and may have their dose levels adjusted if side effects develop.

• Participants who have disease remaining after 6 cycles will receive additional ofatumumab every 2 months, starting 2 months after the end of the 6th cycle and continuing for a total of 4 doses, before entering the follow-up phase of the trial. Participants who do not have residual disease after 6 cycles will not receive additional therapy, and will immediately enter the follow-up phase of the trial.

• Participants will have a follow-up exam every 2 to 4 months for 2 years after the end of treatment, and then as required by the study doctors for as long as the study remains open. These visits will involve a full medical exam, blood samples, lymph node and bone marrow biopsies, and imaging studies.

Condition or Disease	Intervention/Treatment	Phase
Small Lymphocytic Lymphoma; CLL (Chronic Lymphocytic Leukemia)	Drug: Fludarabine Phosphate; Biological: Ofatumumab; Drug: Cyclophosphamide	Phase 2

Detailed Description

OUTLINE:

Patients with adverse interphase cytogenetics (11q22 or 17p13 deletion) receive FCO induction therapy:

• Ofatumumab is given IV on day 1 (300 mg) and day 8 (1000 mg) of course 1 and on day 1 (1000 mg) of all subsequent courses.

• Fludarabine phosphate (25mg/m2/d) and cyclophosphamide (250mg/m2/d) are given IV on days 2 through 4 of course 1 and on days 1 through 3 of all subsequent courses. Patients age 70 or older will be given reduced doses of fludarabine (20mg/m2/d) and cyclophosphamide (150mg/m2/d).

• Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.

Patients without adverse interphase cytogenetics receive FO induction therapy:

• Ofatumumab is given IV on day 1 (300mg) and day 8 (1000mg) of course 1 and on day 1 (1000mg) of all subsequent courses.

• Fludarabine phosphate (25mg/m2/d) is given IV on days 2 through 6 of course 1 and on days 1 through 5 of all subsequent courses.

• Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.

All patients are evaluated for minimal residual disease (MRD) by four-color flow cytometric analysis of the peripheral blood after completion of FO or FCO induction therapy, and are subsequently stratified into two groups:

• Patients who are MRD-positive and without evidence of disease progression proceed to consolidation therapy beginning approximately 5 months after completion of induction therapy, consisting of ofatumumab (1000mg) given IV on day 1 of all courses. Treatment repeats every 2 months for up to 4 courses in the absence of disease progression. Patients are followed clinically 2 and 6 months after the last dose of ofatumumab is given, and then every 6 months thereafter.

• Patients who are MRD-negative and without evidence of disease progression are followed clinically every 4 months for 1 year and every 6 months thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Ofatumumab-Based Induction Chemoimmunotheraphy Followed by Consolidation Ofatumumab Immunotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Oct 31, 2017
• Anticipated Study Completion Date: Sep 15, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FO Arm (fludarabine and ofatumumab) For patients with non-high risk FISH changes	Drug: Fludarabine Phosphate; Given IV; Other Names: Fludara ; Biological: Ofatumumab; Given IV; Other Names: Arzerra
Experimental: FCO Arm (fludarabine, cyclophosphamide, and ofatumumab) For patients with high risk FISH changes	Drug: Fludarabine Phosphate; Given IV; Other Names: Fludara ; Biological: Ofatumumab; Given IV; Other Names: Arzerra ; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan Neosar

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival Rate 2 Years After Initiation of Induction Therapy [2 years]

   Death or disease progression defined by the 2008 IWCLL guideline as follows; Greater than or equal to 50% increase in the SPD of at least 2 lymph nodes (at least one node must be greater than or equal to 2 cm); appearance of any new lymph nodes on physical examination or imaging Greater than or equal to 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin or CT scan or appearance of palpable hepatomegaly or splenomegaly, which was not previously present Greater than or equal to 50% increase in the absolute number of circulating lymphocytes to at least 5000/ul Transformation to a more aggressive histology Occurrence of any cytopenia attributable to CLL. After treatment: the progression of any cytopenia (unrelated to autoimmune cytopenia), as documented by a decrease of Hb levels by more than 20 g/L (2 g/dL) or to less than 100 g/L (10 g/dL), or by a decrease of platelet counts by more than 50% or to les

Secondary Outcome Measures

1. Number of Grade 3 and 4 Treatment Related Adverse Events [2 years]

   Number of Grade 3 and 4 treatment related adverse events as defined by CTCAE version 3.0 criteria. CTCAE (Common Terminology Criteria for Adverse Events) provides a list of adverse event (AE) terms commonly reported. Each AE term is defined and accompanied by a grading scale that indicates the severity of the AE. The CTCAE v3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 is a Mild AE; Grade 2 is a Moderate AE; Grade 3 is a Severe AE; Grade 4 is a Life-threatening or disabling AE; and Grade 5 is a Death related to AE

2. Participants With Minimal Residual Disease (MRD) Negativity [2 years]

   Participants with minimal residual disease (MRD) negativity following the completion of induction chemoimmunotherapy.

3. Participants With MRD Negativity at the Completion of Consolidation Immunotherapy Who Failed to Achieve MRD Negativity [2 years]

   Participants with MRD negativity at the completion of consolidation immunotherapy who failed to achieve MRD negativity following completion of induction chemoimmunotherapy

4. Participants With Complete Response Rates Following Induction Chemoimmunotherapy. [2 years]

   Participants with complete response rates to induction chemoimmunotherapy. Criteria for complete response (CR): CR requires all of the following: Peripheral blood lymphocytes < 4000/uL Absence of significant lymphadenopathy by physical examination and appropriate radiographic techniques (CT or MRI). All lymph nodes must have regressed to <=1.5cm in greatest diameter Absence of hepatomegaly or splenomegaly by physical examination, or appropriate radiographic techniques. Spleen, if enlarged before therapy must have regressed in size and must not be palpable by physical exam. Absence of constitutional symptoms Normal CBC, defined as: - Polymorphonuclear cells ≥ 1,500/uL - Platelets > 100,000/uL (untransfused) - Hemoglobin > 11 g/dL (untransfused) Bone marrow biopsy demonstrates normal cellularity for age, with less than 30% of nucleated cells being lymphocytes. Lymphoid nodules should be absent

5. Participants Overall Response Rates Following Induction Chemoimmunotherapy. [2 years]

   Participants with complete response rates to induction chemoimmunotherapy. Criteria for complete response (CR) requires all of the following: Peripheral blood lymphocytes < 4000/uL. No significant lymphadenopathy. Lymph nodes regressed to <=1.5cm. No hepatomegaly or splenomegaly. Spleen, if enlarged before therapy must have regressed in size and not be palpable. Absence of constitutional symptoms. Bone marrow biopsy demonstrates normal cellularity for age, with less than 30% of nucleated cells being lymphocytes. No lymphoid nodules. Criteria for partial response (PR) requires at least one element of an abnormal CBC and at least one of the following: ≥ 50% decrease in peripheral blood lymphocyte count; ≥ 50% reduction in the sum of the products of lymph nodes up to 6 nodes or nodal masses. No new sites or increase in size of nodes; ≥ 50% reduction in pathologic enlargement of the liver and/or spleen by 50%.

6. Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy [Up to 2 years]

   Participants overall survival rate 2 years after initiation of induction chemoimmunotherapy

7. Median Relationship of CD20 Expression With MRD Negativity Rate [2 years]

   Median relationship of biomarker, CD20 expression with MRD negativity clinical response rate. Flow cytometry was use to quantified surface CD20 on peripheral blood.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

Histologically confirmed CLL or SLL as defined by the following:

• B-lymphocytosis greater than 5000 cells/micro L (may be less than 5000 cells/micro L if lymphadenopathy is present with histologic confirmation of lymph node involvement by SLL).

• Immunophenotypic profile consistent with CLL as demonstrated by flow cytometry

• Appropriate immunophonotype (CD5/19/23+)

• Clonality of lymphocytosis confirmed by flow cytometry

• large lymphocytes less than 55 % of blood lymphocytes

Active disease as defined by at least one of the following:

• Weight loss greater than or equal to10 percent within the previous 6 months

• Extreme fatigue

• Fevers of greater than 100.5 degree F for greater than or equal to 2 weeks without evidence of infection

• Night sweats for more than one month without evidence of infection

• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia

• Massive or progressive splenomegaly

• Massive nodes or clusters or progressive lymphadenopathy

• Progressive lymphocytosis with an increase of greater than 50% over a 2 month period, or an anticipated doubling time of less than 6 months 0

Measurable disease (defined as two dimensional disease on imaging or quantifiable leukemic disease).

Ages 18 and over.

EXCLUSION CRITERIA:

Prior monoclonal antibody therapy with agents having anti-CLL activity

Prior cytotoxic chemotherapy with agents having anti-CLL activity (Fludarabine, Cyclophosphamide, Bendamustine, Chlorambucil)

Transformed CLL

Active autoimmune hemolytic anemia or thrombocytopenia

Any medical condition that requires the chronic use of corticosteroids

Active or latent Hepatitis B infection

HIV infection

Severe chronic obstructive pulmonary disease, severe cardiac disease, or other uncontrolled medical condition that would, in the opinion of the principal investigator, place the subject at an unreasonable risk of life-threatening adverse events due to chemoimmunotherapy

ECOG performance status 3 or worse

Creatinine greater than or equal to 2 mg/dL or creatinine clearance less than or equal to 30 mL/min

Bilirubin greater than or equal to 2 mg/dL or active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment)

Female patients: Current pregnancy or unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential or currently breastfeeding. Male patients who are unwilling to follow the contraception requirements described in this protocol.

Psychiatric illness/social situations that would limit the patient s ability to tolerate and/or comply with study requirements.

Unable to understand the investigational nature of the study or give informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)
• University of Virginia
• GlaxoSmithKline

Investigators

• Principal Investigator: Inhye Ahn, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 5, 2017

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Ahn I, Farooqui M, Lee YS, Marti G, Soto S, Tian X, Stetler-Stevenson M, Yuan CM, Maric I, Wiestner A. Risk-Adapted Induction and Maintenance with Ofatumumab in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL). Blood 2015 126(23):1750-1750.
• Desai S, Mo C, Gaglione EM, Yuan CM, Stetler-Stevenson M, Tian X, Maric I, Wake L, Farooqui MZ, Drinkwater DC, Soto S, Valdez J, Hughes TE, Nierman P, Lotter J, Marti GE, Pleyer C, Sun C, Superata J, Nichols C, Herman SEM, Lindorfer MA, Taylor RP, Wiestner A, Ahn IE. Risk-adapted, ofatumumab-based chemoimmunotherapy and consolidation in treatment-naïve chronic lymphocytic leukemia: a phase 2 study. Leuk Lymphoma. 2021 Aug;62(8):1816-1827. doi: 10.1080/10428194.2021.1888379. Epub 2021 Mar 2.

• Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
• ClinicalTrials.gov Identifier: NCT01145209
• Other Study ID Numbers: 100141; 10-H-0141
• First Posted: Jun 16, 2010
• Last Update Posted: Aug 2, 2022
• Last Verified: Apr 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Heart, Lung, and Blood Institute (NHLBI): Arzerra; Chemoimmunotherapy; SLL; Monoclonal Antibody Therapy; CLL; Ofatumumab
• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Ofatumumab

Study Results

Participant Flow

Arm/Group Title	FCO Arm (Fludarabine, Cyclophosphamide, and Ofatumumab)	FO Arm (Fludarabine and Ofatumumab)
Arm/Group Description	Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes	Fludarabine and ofatumumab for patients with non-high-risk FISH changes
Period Title: Overall Study
STARTED	13	19
COMPLETED	10	18
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	FO Arm (Fludarabine and Ofatumumab)	FCO Arm (Fludarabine, Cyclophosphamide, and Ofatumumab)	Total
Arm/Group Description	Fludarabine and ofatumumab for patients with non-high-risk FISH changes	Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes	Total of all reporting groups
Overall Participants	19	13	32
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	15 78.9%	8 61.5%	23 71.9%
>=65 years	4 21.1%	5 38.5%	9 28.1%
Sex: Female, Male (Count of Participants)
Female	7 36.8%	5 38.5%	12 37.5%
Male	12 63.2%	8 61.5%	20 62.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 15.8%	0 0%	3 9.4%
Not Hispanic or Latino	16 84.2%	13 100%	29 90.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 5.3%	3 23.1%	4 12.5%
White	17 89.5%	10 76.9%	27 84.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 5.3%	0 0%	1 3.1%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival Rate 2 Years After Initiation of Induction Therapy
Description	Death or disease progression defined by the 2008 IWCLL guideline as follows; Greater than or equal to 50% increase in the SPD of at least 2 lymph nodes (at least one node must be greater than or equal to 2 cm); appearance of any new lymph nodes on physical examination or imaging Greater than or equal to 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin or CT scan or appearance of palpable hepatomegaly or splenomegaly, which was not previously present Greater than or equal to 50% increase in the absolute number of circulating lymphocytes to at least 5000/ul Transformation to a more aggressive histology Occurrence of any cytopenia attributable to CLL. After treatment: the progression of any cytopenia (unrelated to autoimmune cytopenia), as documented by a decrease of Hb levels by more than 20 g/L (2 g/dL) or to less than 100 g/L (10 g/dL), or by a decrease of platelet counts by more than 50% or to les
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed the induction period.

Arm/Group Title	FO Arm	FCO Arm
Arm/Group Description	Fludarabine and ofatumumab for patients with non-high-risk FISH changes	Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes
Measure Participants	18	10
Count of Participants [Participants]	14 73.7%	9 69.2%

2. Secondary Outcome

Title	Number of Grade 3 and 4 Treatment Related Adverse Events
Description	Number of Grade 3 and 4 treatment related adverse events as defined by CTCAE version 3.0 criteria. CTCAE (Common Terminology Criteria for Adverse Events) provides a list of adverse event (AE) terms commonly reported. Each AE term is defined and accompanied by a grading scale that indicates the severity of the AE. The CTCAE v3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 is a Mild AE; Grade 2 is a Moderate AE; Grade 3 is a Severe AE; Grade 4 is a Life-threatening or disabling AE; and Grade 5 is a Death related to AE
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

All patients included in safety analysis. It was pre-specified to recombine Arms/Groups for this assessment and report irrespective of randomized group.

Arm/Group Title	FO + FCO Arms
Arm/Group Description	Participants received Fludarabine and ofatumumab for patients with non-high-risk FISH changes or Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes.
Measure Participants	32
Neutropenia Grade 3	4
Thrombocytopenia Grade 3	2
Nausea Grade 3	1
Infusion reaction Grade 3	1
Neutropenia Grade 4	17
Lymphopenia Grade 4	2

3. Secondary Outcome

Title	Participants With Minimal Residual Disease (MRD) Negativity
Description	Participants with minimal residual disease (MRD) negativity following the completion of induction chemoimmunotherapy.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed the induction period.

Arm/Group Title	FO ARM	FCO ARM
Arm/Group Description	Fludarabine and ofatumumab for patients with non-high-risk FISH changes	Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes
Measure Participants	18	10
Count of Participants [Participants]	4 21.1%	6 46.2%

4. Secondary Outcome

Title	Participants With MRD Negativity at the Completion of Consolidation Immunotherapy Who Failed to Achieve MRD Negativity
Description	Participants with MRD negativity at the completion of consolidation immunotherapy who failed to achieve MRD negativity following completion of induction chemoimmunotherapy
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Participants who achieved MRD negativity at the completion of consolidation immunotherapy

Arm/Group Title	FO Arm	FCO Arm
Arm/Group Description	Fludarabine and ofatumumab for patients with non-high-risk FISH changes	Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes
Measure Participants	14	4
Count of Participants [Participants]	14 73.7%	4 30.8%

5. Secondary Outcome

Title	Participants With Complete Response Rates Following Induction Chemoimmunotherapy.
Description	Participants with complete response rates to induction chemoimmunotherapy. Criteria for complete response (CR): CR requires all of the following: Peripheral blood lymphocytes < 4000/uL Absence of significant lymphadenopathy by physical examination and appropriate radiographic techniques (CT or MRI). All lymph nodes must have regressed to <=1.5cm in greatest diameter Absence of hepatomegaly or splenomegaly by physical examination, or appropriate radiographic techniques. Spleen, if enlarged before therapy must have regressed in size and must not be palpable by physical exam. Absence of constitutional symptoms Normal CBC, defined as: - Polymorphonuclear cells ≥ 1,500/uL - Platelets > 100,000/uL (untransfused) - Hemoglobin > 11 g/dL (untransfused) Bone marrow biopsy demonstrates normal cellularity for age, with less than 30% of nucleated cells being lymphocytes. Lymphoid nodules should be absent
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed the induction period.

Arm/Group Title	FCO Arms	FO Arm
Arm/Group Description	Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes	Fludarabine and ofatumumab for patients with non-high-risk FISH changes
Measure Participants	10	18
Count of Participants [Participants]	6 31.6%	2 15.4%

6. Secondary Outcome

Title	Participants Overall Response Rates Following Induction Chemoimmunotherapy.
Description	Participants with complete response rates to induction chemoimmunotherapy. Criteria for complete response (CR) requires all of the following: Peripheral blood lymphocytes < 4000/uL. No significant lymphadenopathy. Lymph nodes regressed to <=1.5cm. No hepatomegaly or splenomegaly. Spleen, if enlarged before therapy must have regressed in size and not be palpable. Absence of constitutional symptoms. Bone marrow biopsy demonstrates normal cellularity for age, with less than 30% of nucleated cells being lymphocytes. No lymphoid nodules. Criteria for partial response (PR) requires at least one element of an abnormal CBC and at least one of the following: ≥ 50% decrease in peripheral blood lymphocyte count; ≥ 50% reduction in the sum of the products of lymph nodes up to 6 nodes or nodal masses. No new sites or increase in size of nodes; ≥ 50% reduction in pathologic enlargement of the liver and/or spleen by 50%.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed the induction period.

Arm/Group Title	FCO Arm	FO Arm
Arm/Group Description	Participants received Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes.	Fludarabine and ofatumumab for patients with non-high-risk FISH changes
Measure Participants	10	18
Complete Response	6 31.6%	2 15.4%
Partial Response	4 21.1%	16 123.1%

7. Secondary Outcome

Title	Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy
Description	Participants overall survival rate 2 years after initiation of induction chemoimmunotherapy
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed the induction period.

Arm/Group Title	FO Arm	FCO Arm
Arm/Group Description	Fludarabine and ofatumumab for patients with non-high-risk FISH changes	Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes
Measure Participants	18	10
Alive	18 94.7%	10 76.9%
Deaths	0 0%	0 0%

8. Secondary Outcome

Title	Median Relationship of CD20 Expression With MRD Negativity Rate
Description	Median relationship of biomarker, CD20 expression with MRD negativity clinical response rate. Flow cytometry was use to quantified surface CD20 on peripheral blood.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed the induction period. It was pre-specified to have arms/groups recombine for this assessment and report irrespective of randomized group.

Arm/Group Title	Minimal Residual Disease (MRD) Positivity	Minimal Residual Disease (MRD) Negativity
Arm/Group Description	Participants with Minimal Residual Disease (MRD) positivity following induction therapy received consolidation Ofatumumab for 4 cycles.	No additional therapy received for participants that had Minimal Residual Disease (MRD) negativity.
Measure Participants	18	9
Median (Full Range) [sites per cell]	10247	15131

Adverse Events

Time Frame	2 years
Adverse Event Reporting Description	Based on CTCAE version 4 for non-hematologic toxicities and 2008 IWCLL guidelines for hematologic toxicities
Arm/Group Title	FCO (Fludarabine, Cyclophosphamide, and Ofatumumab)		FO (Fludarabine and Ofatumumab)
Arm/Group Description	Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes		Fludarabine and ofatumumab for patients with non-high-risk FISH changes
All Cause Mortality
	FCO (Fludarabine, Cyclophosphamide, and Ofatumumab)		FO (Fludarabine and Ofatumumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/19 (0%)
Serious Adverse Events
	FCO (Fludarabine, Cyclophosphamide, and Ofatumumab)		FO (Fludarabine and Ofatumumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/13 (30.8%)		4/19 (21.1%)
Blood and lymphatic system disorders
Febrile neutropenia	2/13 (15.4%)		1/19 (5.3%)
Gastrointestinal disorders
Diarrhea	1/13 (7.7%)		0/19 (0%)
General disorders
Pyrexia	0/13 (0%)		1/19 (5.3%)
Injury, poisoning and procedural complications
Rib fracture	1/13 (7.7%)		0/19 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/13 (0%)		1/19 (5.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/13 (7.7%)		1/19 (5.3%)
Bowen's disease	0/13 (0%)		1/19 (5.3%)
Lung adenocarcinoma	1/13 (7.7%)		0/19 (0%)
Malignant melanoma	0/13 (0%)		1/19 (5.3%)
Malignant melanoma in situ	0/13 (0%)		1/19 (5.3%)
Squamous cell carcinoma	0/13 (0%)		1/19 (5.3%)
Vascular disorders
Jugular vein thrombosis	1/13 (7.7%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	FCO (Fludarabine, Cyclophosphamide, and Ofatumumab)		FO (Fludarabine and Ofatumumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100%)		19/19 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	1/13 (7.7%)		0/19 (0%)
Lymphadenopathy	1/13 (7.7%)		0/19 (0%)
Lymphopenia	1/13 (7.7%)		1/19 (5.3%)
Cardiac disorders
Chest pain	2/13 (15.4%)		0/19 (0%)
Dizziness	4/13 (30.8%)		4/19 (21.1%)
Dyspnea	3/13 (23.1%)		1/19 (5.3%)
Oedema peripheral	1/13 (7.7%)		2/19 (10.5%)
Ear and labyrinth disorders
Ear hemorrhage	0/13 (0%)		1/19 (5.3%)
Endocrine disorders
Thyroid mass	1/13 (7.7%)		0/19 (0%)
Eye disorders
Eye pain	1/13 (7.7%)		0/19 (0%)
Keratitis	0/13 (0%)		1/19 (5.3%)
Gastrointestinal disorders
Abdominal pain	0/13 (0%)		1/19 (5.3%)
Constipation	2/13 (15.4%)		2/19 (10.5%)
Diarrhea	2/13 (15.4%)		3/19 (15.8%)
Dry mouth	0/13 (0%)		1/19 (5.3%)
Dysgeusia	1/13 (7.7%)		0/19 (0%)
Dyspepsia	0/13 (0%)		2/19 (10.5%)
Gastritis	1/13 (7.7%)		0/19 (0%)
Gingival pain	1/13 (7.7%)		0/19 (0%)
Hemorrhoids	0/13 (0%)		1/19 (5.3%)
Nausea	11/13 (84.6%)		6/19 (31.6%)
Oral candidiasis	0/13 (0%)		1/19 (5.3%)
Oropharyngeal pain	1/13 (7.7%)		1/19 (5.3%)
Stomatitis	1/13 (7.7%)		0/19 (0%)
Vomiting	3/13 (23.1%)		1/19 (5.3%)
General disorders
Chills	2/13 (15.4%)		3/19 (15.8%)
Decreased appetite	0/13 (0%)		1/19 (5.3%)
Fatigue	8/13 (61.5%)		11/19 (57.9%)
Flushing	1/13 (7.7%)		2/19 (10.5%)
Hyperhidrosis	1/13 (7.7%)		1/19 (5.3%)
Influenza like illness	1/13 (7.7%)		2/19 (10.5%)
Night sweats	1/13 (7.7%)		1/19 (5.3%)
Oedema	0/13 (0%)		1/19 (5.3%)
Pyrexia	2/13 (15.4%)		2/19 (10.5%)
Hepatobiliary disorders
Hepatitis viral	0/13 (0%)		1/19 (5.3%)
Immune system disorders
Hypersensitivity	5/13 (38.5%)		6/19 (31.6%)
Rhinitis allergic	2/13 (15.4%)		2/19 (10.5%)
Infections and infestations
Lung infection	0/13 (0%)		1/19 (5.3%)
Upper respiratory tract infection	3/13 (23.1%)		9/19 (47.4%)
Urinary tract infection	0/13 (0%)		3/19 (15.8%)
Injury, poisoning and procedural complications
Arthropod bite	0/13 (0%)		1/19 (5.3%)
Contusion	0/13 (0%)		2/19 (10.5%)
Fracture	0/13 (0%)		1/19 (5.3%)
Joint dislocation	1/13 (7.7%)		0/19 (0%)
Phlebitis	0/13 (0%)		1/19 (5.3%)
Investigations
Alanine aminotransferase increased	2/13 (15.4%)		2/19 (10.5%)
Aspartate aminotransferase increased	2/13 (15.4%)		2/19 (10.5%)
Blood bilirubin increased	1/13 (7.7%)		1/19 (5.3%)
Blood creatine phosphokinase increased	1/13 (7.7%)		0/19 (0%)
Hemoglobin	2/13 (15.4%)		0/19 (0%)
Haptoglobin	0/13 (0%)		1/19 (5.3%)
International normalized ratio increased	0/13 (0%)		1/19 (5.3%)
Neutrophil count decreased	9/13 (69.2%)		13/19 (68.4%)
Platelet count decreased	2/13 (15.4%)		2/19 (10.5%)
White blood cell count increased	1/13 (7.7%)		1/19 (5.3%)
Metabolism and nutrition disorders
Dehydration	1/13 (7.7%)		0/19 (0%)
Hypernatremia	1/13 (7.7%)		0/19 (0%)
Hyperuricemia	1/13 (7.7%)		0/19 (0%)
Hypophosphatemia	0/13 (0%)		1/19 (5.3%)
Osteopenia	1/13 (7.7%)		0/19 (0%)
Pica	0/13 (0%)		1/19 (5.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/13 (7.7%)		0/19 (0%)
Arthritis	0/13 (0%)		2/19 (10.5%)
Back pain	1/13 (7.7%)		0/19 (0%)
Musculoskeletal pain	5/13 (38.5%)		8/19 (42.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/13 (0%)		1/19 (5.3%)
Bowen's disease	0/13 (0%)		1/19 (5.3%)
Nervous system disorders
Abnormal dreams	2/13 (15.4%)		0/19 (0%)
Cerebral ischemia	0/13 (0%)		1/19 (5.3%)
Cognitive disorder	1/13 (7.7%)		1/19 (5.3%)
Confusional state	0/13 (0%)		2/19 (10.5%)
Headache	3/13 (23.1%)		6/19 (31.6%)
Insomnia	1/13 (7.7%)		7/19 (36.8%)
Neuralgia	0/13 (0%)		2/19 (10.5%)
Paresthesia	0/13 (0%)		1/19 (5.3%)
Speech disorder	0/13 (0%)		1/19 (5.3%)
Psychiatric disorders
Anxiety	0/13 (0%)		1/19 (5.3%)
Depression	0/13 (0%)		1/19 (5.3%)
Renal and urinary disorders
Dysuria	1/13 (7.7%)		0/19 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	2/13 (15.4%)		4/19 (21.1%)
Epistaxis	0/13 (0%)		1/19 (5.3%)
Pneumonitis	0/13 (0%)		1/19 (5.3%)
Rhinorrhea	0/13 (0%)		2/19 (10.5%)
Sinus congestion	0/13 (0%)		2/19 (10.5%)
Skin and subcutaneous tissue disorders
Dermatitis	0/13 (0%)		1/19 (5.3%)
Dry skin	0/13 (0%)		1/19 (5.3%)
Nail disorder	0/13 (0%)		1/19 (5.3%)
Pruritus	2/13 (15.4%)		1/19 (5.3%)
Rash	6/13 (46.2%)		5/19 (26.3%)
Skin hyperpigmentation	0/13 (0%)		1/19 (5.3%)
Skin ulcer	0/13 (0%)		1/19 (5.3%)
Vascular disorders
Hypertension	0/13 (0%)		1/19 (5.3%)
Hypotension	2/13 (15.4%)		1/19 (5.3%)

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.