Imatinib and Rituximab in Treating Cutaneous Sclerosis in Patients With Chronic Graft-Versus-Host Disease

• Sponsor: Lee, Stephanie (Other)
• Overall Status: Completed
• CT.gov ID: NCT01309997
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 72
• Locations: 10
• Arms: 2
• Duration (Months): 57
• Patients Per Site: 7.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomized phase II trial is evaluating how well imatinib mesylate works compared to rituximab in treating cutaneous sclerosis in patients with chronic graft- versus-host disease (GVHD). Both imatinib and rituximab have been reported to decrease skin thickening and improve skin and joint flexibility in people with cutaneous sclerosis due to chronic GVHD.

Condition or Disease	Intervention/Treatment	Phase
Graft Versus Host Disease; Systemic Scleroderma	Drug: imatinib mesylate; Biological: rituximab	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the best clinical response rate of cutaneous sclerosis (skin and/or fascial thickening) after 6 months of initial therapy with either imatinib (imatinib mesylate) or rituximab.

SECONDARY OBJECTIVES:

1. To determine the best response at either the 3 or 6 month assessment.

2. To determine the response rate at the 3 month assessment.

3. To determine the proportion of subjects who are able to taper corticosteroid after 6 months of imatinib or rituximab therapy.

4. To determine the incidence of treatment failure to initial treatment with either imatinib or rituximab.

5. To evaluate if the Scleroderma Health Assessment Questionnaire (SHAQ) findings correlate with severity of cutaneous sclerosis clinical findings and response to study treatment.

6. To correlate the detection of antibody against platelet derived growth factor receptor alpha (PDGFR A) with clinical response.

7. To correlate change in B cell relevant parameters from baseline to 6 months or early crossover (antibody levels, skin collagen expression, B cell subsets) with therapeutic agent and best clinical response while on initial treatment.

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

ARM I: Patients receive imatinib mesylate by mouth (PO) once daily (QD) for 6 months in the absence of progression of sclerosis or unacceptable toxicity. Subjects with a significant clinical response will continue to receive study drug for an additional 6 months.

ARM II: Patients receive rituximab intravenously (IV) on days 1, 8, 15, and 22 (first cycle). A second cycle of treatment with rituximab is repeated at 3 months for a total of 8 doses of rituximab in the absence of progression of sclerosis or unacceptable toxicity.

Patients with progression, treatment intolerance at any time up to 6 months, or no clinical response at 6 months will crossover to the other treatment arm.

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study of Imatinib and Rituximab for Cutaneous Sclerosis After Allogeneic Hematopoietic Cell Transplantation
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (enzyme inhibitor) Patients receive imatinib mesylate PO QD for 6 months in the absence of progression of sclerosis or unacceptable toxicity.	Drug: imatinib mesylate; Given PO; Other Names: CGP 57148 Gleevec Glivec
Experimental: Arm II (monoclonal antibody) Patients receive rituximab IV on days 1, 8, 15, and 22. A second treatment cycle is repeated at 3 months for a total of 8 doses of rituximab in the absence of progression of sclerosis or unacceptable toxicity.	Biological: rituximab; Given IV; Other Names: IDEC-C2B8 IDEC-C2B8 monoclonal antibody Mabthera MOAB IDEC-C2B8 Rituxan

Outcome Measures

Primary Outcome Measures

1. Significant Clinical Response [6 months]

   Assessed by decline in an affected area's skin score as measured with the Vienna Skin Scale (from 4 [worst] to 2, 3 to 1, or 2 to 0 [best]) without a concurrent increase of two or more points in another area OR by an increase in the range of motion of the shoulders, elbows or wrists by two points (in a 1-7 scale where 1 is worst and 7 is best) or of the ankles by one point (in a 1 to 4 scale where 1 is worst and 4 is best) without a concurrent worsening in another area.

Secondary Outcome Measures

1. Patients Who Were Able to Taper Corticosteroids [6 months]

   Patients who achieved a greater than or equal to 50% reduction in the daily corticosteroid dose at 6mo compared to baseline

2. Cumulative Incidence of Treatment Failure [6 months]

   Defined as discontinuation of randomized treatment due to chronic GVHD progression or treatment intolerance or no significant clinical response in sclerosis.

3. Number of Patients Achieving Improvement in Cutaneous Sclerosis [6 months]

   Assessed by decrease of >= 0.2 units (where 0 is best and 3.0 is worst ) in the Scleroderma Health Assessment Questionnaire (SHAQ).

4. Baseline Histopathologic Score in the Two Treatment Arms [Enrollment]

   Instrument: Nash dermal fibrosis grade. Measures extent of sclerosis in skin biopsies by histologic examination. Scale ranges from grade 0-5. Nash grade 5 is most severe fibrosis (0 is better outcome, 5 is worse outcome). No subscales are used in Nash grade. Please see table 1 in the reference for grading of dermal fibrosis. Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood 2007;110:1388-96.

5. Patients With Any Percentage Decline in Any Grade of Sclerosis Without Increase in Percentage of Higher Grades of Sclerosis in Other Areas on the Vienna Skin Scale [6 months]

   Maximum of 10 body areas. Each area can be graded 0 (best) to 4 (worst). Each of those grades requires a percentage of involvement. Improvement is measured by reduction of involvement in any grade and any body area.

6. Percentage of CD27+ B Cells in Responders (SCR) and Non-responders [6 months]

   %CD27+ B cells

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis within the past 18 months of cutaneous sclerosis after hematopoietic cell transplant (HCT) with sclerotic skin, morphea, myofascial involvement or joint contractures; must have a score of 2 or greater on the Vienna skin scale in any area, or a range-of-motion (ROM) score of 5 or less at the shoulder, elbow or wrist, or 3 or less at the ankle

• No medication added for the treatment of graft versus host disease (GVHD) within the past 4 weeks

• Receiving corticosteroids at a dose greater than required for treatment of adrenal insufficiency, unless the physician documents why steroids are contraindicated

• Age 2-99 years

• Karnofsky performance status >= 60% at enrollment

• All females of childbearing potential must have a negative serum or urine pregnancy test =< 7 days prior to starting study therapy

• All females of childbearing potential must agree to use a form of Food and Drug Administration (FDA) approved contraception from enrollment to one month after study treatment ends

• Subject has the ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• Total bilirubin > 1.5x upper limit of normal (ULN)

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN

• Renal insufficiency (serum creatinine > 2.0 mg/dl)

• Platelets < 30,000/ul or absolute neutrophil count < 1500/ul

• Known hypersensitivity to rituximab or other anti-B cell antibodies

• Known imatinib intolerance or allergy

• Evidence of any active viral, bacterial, or fungal infection that is progressive despite appropriate treatment

• Hepatitis B surface antigen positive

• Hepatitis B core antibody positive, unless hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is undetectable

• Hepatitis C antibody positive, unless hepatitis C virus (HCV) ribonucleic acid (RNA) is undetectable

• Pregnant, lactating, or planning a pregnancy while in the study

• Distal leg skin score 3 or higher as the only manifestation of sclerosis

• Prior treatment of chronic GVHD with imatinib, rituximab, or any other monoclonal B-cell antibody (e.g. ofatumumab)

• Receipt of imatinib within the previous 6 months for any indication

• Receipt of any monoclonal B-cell antibody (e.g. rituximab, ofatumumab) within the previous 12 months for any indication

• Treatment with anti-B-cell cellular therapy (e.g. chimeric antigen-receptor-engineered cells) at any time after transplant

• Current treatment with extracorporeal photopheresis (ECP) at the time of enrollment

• History of psychiatric disorder that would interfere with normal participation in this study

• Inability or unwillingness of subject and/or parent guardian to provide informed consent or comply with study protocol

• Use of non-FDA approved drugs within 4 weeks of participation

• Patient with any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with the study requirements

• Patients with uncontrolled substance abuse

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	Stanford University Hospitals and Clinics	Stanford	California	United States	94305
3	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
4	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
5	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
6	Weill Cornell Medical College	New York	New York	United States	10065
7	University of North Carolina	Chapel Hill	North Carolina	United States	27599
8	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
9	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109
10	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Lee, Stephanie
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Stephanie Lee, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Lee, Stephanie, Principal Investigator, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
• ClinicalTrials.gov Identifier: NCT01309997
• Other Study ID Numbers: 2343.00; NCI-2011-00098; RDCRN 6502; 2343.00; U54CA163438; P30CA015704
• First Posted: Mar 7, 2011
• Last Update Posted: Jun 15, 2016
• Last Verified: May 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Lee, Stephanie, Principal Investigator, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium: Imatinib; Rituximab; Chronic Graft-vs-Host Disease
• Additional relevant MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Graft vs Host Disease; Rituximab; Imatinib Mesylate

Study Results

Participant Flow

Arm/Group Title	Arm I (Enzyme Inhibitor)	Arm II (Monoclonal Antibody)
Arm/Group Description	Patients receive imatinib mesylate PO QD for 6 months in the absence of progression of sclerosis or unacceptable toxicity. During the 6mo study treatment period, if drug intolerance or disease progression is observed, they are crossed over to rituximab.	Patients receive rituximab IV on days 1, 8, 15, and 22. A second treatment cycle is repeated at 3 months for a total of 8 doses of rituximab in the absence of progression of sclerosis or unacceptable toxicity. During the 6mo study treatment period, if drug intolerance or disease progression is observed, they are crossed over to imatinib.
Period Title: Overall Study
STARTED	35	37
Remained on First Arm Only	16	14
Crossed Over to Second Arm	19	23
COMPLETED	30	31
NOT COMPLETED	5	6

Baseline Characteristics

Arm/Group Title	Arm I (Enzyme Inhibitor)	Arm II (Monoclonal Antibody)	Total
Arm/Group Description	Patients receive imatinib mesylate PO QD for 6 months in the absence of progression of sclerosis or unacceptable toxicity. During the 6mo study treatment period, if drug intolerance or disease progression is observed, they are crossed over to rituximab.	Patients receive rituximab IV on days 1, 8, 15, and 22. A second treatment cycle is repeated at 3 months for a total of 8 doses of rituximab in the absence of progression of sclerosis or unacceptable toxicity. TDuring the 6mo study treatment period, if drug intolerance or disease progression is observed, they are crossed over to imatinib.	Total of all reporting groups
Overall Participants	35	37	72
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	31 88.6%	30 81.1%	61 84.7%
>=65 years	4 11.4%	7 18.9%	11 15.3%
Sex: Female, Male (Count of Participants)
Female	18 51.4%	22 59.5%	40 55.6%
Male	17 48.6%	15 40.5%	32 44.4%

Outcome Measures

1. Primary Outcome

Title	Significant Clinical Response
Description	Assessed by decline in an affected area's skin score as measured with the Vienna Skin Scale (from 4 [worst] to 2, 3 to 1, or 2 to 0 [best]) without a concurrent increase of two or more points in another area OR by an increase in the range of motion of the shoulders, elbows or wrists by two points (in a 1-7 scale where 1 is worst and 7 is best) or of the ankles by one point (in a 1 to 4 scale where 1 is worst and 4 is best) without a concurrent worsening in another area.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Patients were not eligible for evaluation if they discontinued participation or had missing 6 mo data.

Arm/Group Title	Arm I (Enzyme Inhibitor)	Arm II (Monoclonal Antibody)
Arm/Group Description	Patients who were randomized to receive imatinib mesylate PO QD for 6 months in the absence of progression of sclerosis or unacceptable toxicity.	Patients who were randomized to receive rituximab IV on days 1, 8, 15, and 22. A second treatment cycle was repeated at 3 months for a total of 8 doses of rituximab in the absence of progression of sclerosis or unacceptable toxicity.
Measure Participants	30	31
Number [participants]	9 25.7%	10 27%

2. Secondary Outcome

Title	Patients Who Were Able to Taper Corticosteroids
Description	Patients who achieved a greater than or equal to 50% reduction in the daily corticosteroid dose at 6mo compared to baseline
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Patients with no corticosteroid dose data missing from baseline or 6mo.

Arm/Group Title	Arm I (Enzyme Inhibitor)	Arm II (Monoclonal Antibody)
Arm/Group Description	Patients randomized to receive imatinib mesylate as their first therapy. They may take this from 1 mo-18 mo.	Patients randomized to receive rituximab IV as their first therapy. They may receive from 1-2 four week cycles.
Measure Participants	27	32
Number [participants]	7 20%	9 24.3%

3. Secondary Outcome

Title	Cumulative Incidence of Treatment Failure
Description	Defined as discontinuation of randomized treatment due to chronic GVHD progression or treatment intolerance or no significant clinical response in sclerosis.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Only patients who were evaluable for SCR are included.

Arm/Group Title	Arm I (Enzyme Inhibitor)	Arm II (Monoclonal Antibody)
Arm/Group Description	Patients randomized to receive imatinib mesylate PO QD as their first therapy. They may take this from 1 mo-18 mo.	Patients randomized to receive rituximab IV as their first therapy. They may receive from 1-2 four week cycles.
Measure Participants	30	31
Number [participants]	24 68.6%	26 70.3%

4. Secondary Outcome

Title	Number of Patients Achieving Improvement in Cutaneous Sclerosis
Description	Assessed by decrease of >= 0.2 units (where 0 is best and 3.0 is worst ) in the Scleroderma Health Assessment Questionnaire (SHAQ).
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Only patients evaluable at 6 mo are included.

Arm/Group Title	Arm 1 (Enzyme Inhibitor)	Arm II (Monocolonal Antibody)
Arm/Group Description	Patients randomized to receive imatinib mesylate PO QD as their first therapy. They may take this from 1 mo-18 mo.	Patients randomized to receive rituximab IV as their first therapy. They may receive from 1-2 four week cycles.
Measure Participants	30	31
Number [participants]	2 5.7%	9 24.3%

5. Secondary Outcome

Title	Baseline Histopathologic Score in the Two Treatment Arms
Description	Instrument: Nash dermal fibrosis grade. Measures extent of sclerosis in skin biopsies by histologic examination. Scale ranges from grade 0-5. Nash grade 5 is most severe fibrosis (0 is better outcome, 5 is worse outcome). No subscales are used in Nash grade. Please see table 1 in the reference for grading of dermal fibrosis. Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood 2007;110:1388-96.
Time Frame	Enrollment

Outcome Measure Data

Analysis Population Description

Only patients with skin biopsies at enrollment are included.

Arm/Group Title	Arm 1 (Enzyme Inhibitor)	Arm II (Monoclonal Antibody)
Arm/Group Description	Patients randomized to receive imatinib mesylate PO QD as their first therapy. They may take this from 1 mo-18 mo.	Patients randomized to receive rituximab IV as their first therapy. They may receive from 1-2 four week cycles.
Measure Participants	32	31
Median (Full Range) [units on a scale]	2	2

6. Secondary Outcome

Title	Patients With Any Percentage Decline in Any Grade of Sclerosis Without Increase in Percentage of Higher Grades of Sclerosis in Other Areas on the Vienna Skin Scale
Description	Maximum of 10 body areas. Each area can be graded 0 (best) to 4 (worst). Each of those grades requires a percentage of involvement. Improvement is measured by reduction of involvement in any grade and any body area.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Only patients who were evaluable at 6mo are included.

Arm/Group Title	Arm I (Enzyme Inhibitor)	Arm II (Monoclonal Antibody)
Arm/Group Description	Patients randomized to receive imatinib mesylate PO QD as their first therapy. They may take this from 1 mo-18 mo.	Patients randomized to receive rituximab IV as their first therapy. They may receive from 1-2 four week cycles.
Measure Participants	30	31
Number [participants]	14 40%	9 24.3%

7. Secondary Outcome

Title	Percentage of CD27+ B Cells in Responders (SCR) and Non-responders
Description	%CD27+ B cells
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab Responders	Rituximab Non-responders	Imatinib Responders	Imatinib Nonresponders
Arm/Group Description	Attained a SCR with rituximab	Did not attain a SCR with rituximab	Attained a SCR with imatinib	Did not attain a SCR with imatinib
Measure Participants	3	10	3	11
Mean (Full Range) [percentage of CD27+ B cells]	10	4.3	14.2	17.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Enzyme Inhibitor), Arm II (Monoclonal Antibody)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Imatinib Responders, Imatinib Nonresponders
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.64
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	18 months
Arm/Group Title	Imatinib as Initial Therapy		Rituximab as Initial Therapy		Imatinib as Secondary Therapy		Rituximab as Secondary Therapy
Arm/Group Description	Arm I = imatinib, adverse event occurred after the start date of imatinib and if applicable, prior to start date of rituximab.		Arm I = rituximab, adverse event occurred after the start date of rituximab and if applicable, prior to start date of imatinib.		Arm II = imatinib, adverse event occurred after the start date of imatinib. (All participants in this group received rituximab prior).		Arm II = rituximab, adverse event occurred after the start date of rituximab. (All participants in this group received imatinib prior).
All Cause Mortality
	Imatinib as Initial Therapy		Rituximab as Initial Therapy		Imatinib as Secondary Therapy		Rituximab as Secondary Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Imatinib as Initial Therapy		Rituximab as Initial Therapy		Imatinib as Secondary Therapy		Rituximab as Secondary Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/35 (31.4%)		19/37 (51.4%)		19/23 (82.6%)		15/19 (78.9%)
Blood and lymphatic system disorders
Febrile Neutropenia	0/35 (0%)	0	1/37 (2.7%)	1	0/23 (0%)	0	1/19 (5.3%)	1
INR increased	0/35 (0%)	0	0/37 (0%)	0	0/23 (0%)	0	1/19 (5.3%)	1
Neutropenia	1/35 (2.9%)	1	2/37 (5.4%)	2	1/23 (4.3%)	1	2/19 (10.5%)	2
Cardiac disorders
Aortic valve disease	0/35 (0%)	0	1/37 (2.7%)	1	0/23 (0%)	0	0/19 (0%)	0
Other, specify: congestive heart failure	0/35 (0%)	0	0/37 (0%)	0	0/23 (0%)	0	1/19 (5.3%)	1
Other, specify: coronary vasculopathy	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Gastrointestinal disorders
Diarrhea	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Mucositis oral	0/35 (0%)	0	1/37 (2.7%)	1	0/23 (0%)	0	0/19 (0%)	0
Vomiting	0/35 (0%)	0	1/37 (2.7%)	1	0/23 (0%)	0	0/19 (0%)	0
General disorders
Edema limbs	1/35 (2.9%)	1	0/37 (0%)	0	0/23 (0%)	0	0/19 (0%)	0
Fatigue	0/35 (0%)	0	1/37 (2.7%)	1	0/23 (0%)	0	0/19 (0%)	0
Fever	0/35 (0%)	0	1/37 (2.7%)	1	1/23 (4.3%)	1	1/19 (5.3%)	1
Flu like symptoms	0/35 (0%)	0	0/37 (0%)	0	0/23 (0%)	0	0/19 (0%)	0
Other, specify: Pneumoperitoneum	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Infections and infestations
Lung infection	2/35 (5.7%)	2	2/37 (5.4%)	3	4/23 (17.4%)	4	1/19 (5.3%)	1
Other specify: Norovirus	1/35 (2.9%)	1	0/37 (0%)	0	0/23 (0%)	0	0/19 (0%)	0
Other, specify: unknown etiology	0/35 (0%)	0	0/37 (0%)	0	0/23 (0%)	0	1/19 (5.3%)	2
Sepsis	0/35 (0%)	0	0/37 (0%)	0	2/23 (8.7%)	2	0/19 (0%)	0
Skin infection	1/35 (2.9%)	1	0/37 (0%)	0	0/23 (0%)	0	0/19 (0%)	0
Urinary tract infection	0/35 (0%)	0	1/37 (2.7%)	1	0/23 (0%)	0	0/19 (0%)	0
Injury, poisoning and procedural complications
Fracture	0/35 (0%)	0	1/37 (2.7%)	1	0/23 (0%)	0	0/19 (0%)	0
Metabolism and nutrition disorders
Anorexia	0/35 (0%)	0	1/37 (2.7%)	1	0/23 (0%)	0	0/19 (0%)	0
Dehydration	0/35 (0%)	0	1/37 (2.7%)	1	1/23 (4.3%)	1	0/19 (0%)	0
Hyperglycemia	1/35 (2.9%)	1	0/37 (0%)	0	0/23 (0%)	0	0/19 (0%)	0
Musculoskeletal and connective tissue disorders
Avascular necrosis	0/35 (0%)	0	0/37 (0%)	0	0/23 (0%)	0	1/19 (5.3%)	1
Other, specify: mastectomy	0/35 (0%)	0	0/37 (0%)	0	0/23 (0%)	0	1/19 (5.3%)	1
Pain in extremity	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Other, specify: brain tumor	0/35 (0%)	0	1/37 (2.7%)	1	0/23 (0%)	0	0/19 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/35 (2.9%)	1	0/37 (0%)	0	0/23 (0%)	0	1/19 (5.3%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/35 (0%)	0	2/37 (5.4%)	2	2/23 (8.7%)	3	0/19 (0%)	0
Hypoxia	0/35 (0%)	0	0/37 (0%)	0	0/23 (0%)	0	1/19 (5.3%)	1
Pneumonitis	1/35 (2.9%)	1	1/37 (2.7%)	2	0/23 (0%)	0	1/19 (5.3%)	1
Pneumothorax	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Respiratory failure	2/35 (5.7%)	2	0/37 (0%)	0	3/23 (13%)	3	0/19 (0%)	0
Vascular disorders
Hypotension	0/35 (0%)	0	0/37 (0%)	0	0/23 (0%)	0	1/19 (5.3%)	1
Thromboembolic event	0/35 (0%)	0	1/37 (2.7%)	1	0/23 (0%)	0	1/19 (5.3%)	1
Other (Not Including Serious) Adverse Events
	Imatinib as Initial Therapy		Rituximab as Initial Therapy		Imatinib as Secondary Therapy		Rituximab as Secondary Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/35 (34.3%)		12/37 (32.4%)		21/23 (91.3%)		1/19 (5.3%)
Blood and lymphatic system disorders
Anemia	1/35 (2.9%)	1	0/37 (0%)	0	1/23 (4.3%)	4	1/19 (5.3%)	1
Eye disorders
Retinal detachment	1/35 (2.9%)	1	0/37 (0%)	0	0/23 (0%)	0	0/19 (0%)	0
Gastrointestinal disorders
Nausea	1/35 (2.9%)	1	0/37 (0%)	0	0/23 (0%)	0	0/19 (0%)	0
General disorders
Infusion related reaction	0/35 (0%)	0	1/37 (2.7%)	1	0/23 (0%)	0	0/19 (0%)	0
Pain	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Infections and infestations
Lung infection	1/35 (2.9%)	1	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Skin infection	0/35 (0%)	0	1/37 (2.7%)	1	0/23 (0%)	0	0/19 (0%)	0
Investigations
Alanine aminotransferase increased	1/35 (2.9%)	1	0/37 (0%)	0	0/23 (0%)	0	0/19 (0%)	0
Aspartate aminotransferase increased	1/35 (2.9%)	1	0/37 (0%)	0	0/23 (0%)	0	0/19 (0%)	0
Creatinine increased	1/35 (2.9%)	1	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
White blood cell decreased	1/35 (2.9%)	1	1/37 (2.7%)	1	0/23 (0%)	0	0/19 (0%)	0
Forced expiratory volume decreased	0/35 (0%)	0	1/37 (2.7%)	1	1/23 (4.3%)	1	0/19 (0%)	0
Lymphocyte count decreased	0/35 (0%)	0	1/37 (2.7%)	2	1/23 (4.3%)	1	0/19 (0%)	0
Neutrophil count decreased	0/35 (0%)	0	1/37 (2.7%)	1	1/23 (4.3%)	1	0/19 (0%)	0
Metabolism and nutrition disorders
Anorexia	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Hyperglycemia	0/35 (0%)	0	3/37 (8.1%)	4	3/23 (13%)	3	0/19 (0%)	0
Hypophosphatemia	2/35 (5.7%)	2	1/37 (2.7%)	2	1/23 (4.3%)	1	0/19 (0%)	0
Musculoskeletal and connective tissue disorders
Avascular necrosis	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	2	0/19 (0%)	0
Myalgia	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	1/35 (2.9%)	1	0/37 (0%)	0	0/23 (0%)	0	0/19 (0%)	0
Other, specify: squamous cell carcinoma	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Pregnancy, puerperium and perinatal conditions
Unintended pregnancy	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Psychiatric disorders
Agitation	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Renal and urinary disorders
Renal calculi	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Reproductive system and breast disorders
Gynecomastia	1/35 (2.9%)	1	0/37 (0%)	0	0/23 (0%)	0	0/19 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Respiratory failure	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0
Vascular disorders
Hypertension	0/35 (0%)	0	2/37 (5.4%)	3	0/23 (0%)	0	0/19 (0%)	0
Hypotension	0/35 (0%)	0	0/37 (0%)	0	1/23 (4.3%)	1	0/19 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.