Phase 2 Trial of Prophylactic Rituximab Therapy for Prevention of CGVHD

Study Overview
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Brief Summary
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To determine if rituximab administered after allogeneic transplantation decreases the incidence of chronic graft-vs-host disease (cGvHD)

Detailed Description
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To test if prophylactic anti-B-cell therapy (weekly rituximab) given within 60 to 90 days after allogeneic transplantation will decrease allogeneic donor B-cell immunity and possibly the incidence of chronic graft-vs-host disease (cGvHD).

Official Title
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An Open-label, Phase 2 Trial of Prophylactic Rituximab Therapy for Prevention of Chronic Graft Versus Host Disease After TLI/ARG Nonmyeloablative Allogeneic Stem Cell Transplantation

Conditions
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Leukemia, Mast-Cell, Mantle-cell Lymphoma

Intervention / Treatment
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* Procedure: Total lymphoid irradiation
* Drug: Rituximab
* Drug: Anti-thymoglobulin, rabbit (ATG, rabbit ATG)
* Drug: Cyclosporine
* Drug: Mycophenylate mofetil
* Drug: Filgrastim
* Drug: Granisetron
* Drug: Solumedrol
* Drug: Acetaminophen
* Drug: Diphenhydramine
* Drug: Hydrocortisone


Participation Criteria
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Eligibility Criteria
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Recipient Inclusion Criteria: Between 18 and 76 years of age Chronic lymphocytic leukemia (CLL): Unmutated IgG VH gene status Mutated IgG VH genes (> 2% nucleotide change compared to somatic sequence) Complete remission benefit most from allogeneic hematopoietic stem cell transplant (HSCT). (Physicians will be encouraged to provide aggressive chemotherapy prior to nonmyeloablative transplantation.) Mantle cell lymphoma (MCL): Transplant physicians believe subject would benefit from allogeneic HSCT. Adequate renal (Cr < 2.4 mg/dL) and hepatic (Bilirubin < 3.0 mg/dL, Aspartate aminotransferase (AST) < 100 IU) function. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for six months after completion of treatment. All subjects must provide written informed consent Donor Inclusion Criteria: Genotypically or phenotypically human leukocyte antigen (HLA)-identical. Age < 76 unless cleared by institutional PI Capable of giving written, informed consent. Must consent to peripheral blood stem cell (PBSC) mobilization with G-CSF and apheresis Recipient Exclusion Criteria: Recipient has a 9 of 10 or 10 of 10 HLA identical donor (high resolution molecular genotyping at HLA A, B, C and DrB1, and DQ) Pregnancy Lactating Serious uncontrolled infection HIV seropositivity Hepatitis B or C seropositivity Cardiac function: ejection fraction < 40% or uncontrolled cardiac failure Pulmonary: Diffusing capacity - carbon monoxide (DLCO) < 50% predicted Liver function abnormalities: elevation of bilirubin to ≥ 3 mg/dL and/or AST > 100 Renal: creatinine > 2.4 Karnofsky performance score ≤ 60% Patients with poorly controlled hypertension (systolic blood pressure > 150 or diastolic blood pressure > 90 repeatedly). Known life-threatening hypersensitivity to rituximab or other anti-B cell antibodies. Inability to comply with the allogeneic transplant treatment. Uncontrolled central nervous system (CNS) involvement with disease Donor Exclusion Criteria: Identical twin to subject Contra-indication to subcutaneous G-CSF at a dose of 16 mg/kg/d for 5 consecutive days Serious medical or psychological illness Prior malignancy within the preceding five years, with the exception of non-melanoma skin cancers. HIV seropositivity

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 76 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prophylactic Rituximab<br>Rituximab will be infused after a non-myeloablative transplantation regimen of total lymphoid irradiation (TLI) + anti-thymoglobulin (ATG), with the intention of reducing chronic graft-vs-host disease (cGvHD) | Procedure: Total lymphoid irradiation<br>* Total lymphoid irradiation (TLI) administered at 80cGy for 10 days<br>* Other names: TLI;Drug: Rituximab<br>* Rituximab 375 mg/m2 administered as an intravenous (IV) infusion once weekly for 4 doses.<br>* Other names: Rituxan;Drug: Anti-thymoglobulin, rabbit (ATG, rabbit ATG)<br>* Rabbit anti-thymoglobulin (ATG) administered from Day -11 through Day -7 (5 doses) at 1.5 mg/kg/day, for a total dose of 7.5 mg/kg.<br>Drug: Cyclosporine<br>* Cyclosporine (CSP) administered orally at 6.25 mg/kg twice-a-day (BID) from Day -3 until through Day +56 post-peripheral blood progenitor cell (PBPC) infusion. Dose may be adjusted to maintain a therapeutic level of cyclosporine, or in response to renal insufficiency. If at Day +56, chimerism assessment demonstrates > 40% donor cells in the CD3+ lineage, and the patient is without evidence of GvHD, then cyclosporine taper will begin (6% reduction per week).<br>* Other names: Sandimmune;Drug: Mycophenylate mofetil<br>* Mycophenylate mofetil (MMF) will be administered at 15 mg/kg po Day 0, at 5 to 10 hours after mobilized PBPC infusion is complete<br>* Other names: CellCept;Drug: Filgrastim<br>* Filgrastim provided as needed for neutrophil support<br>* Other names: Neupogen;Drug: Granisetron<br>* Granisetron administered as an anti-nausea agent (anti-emetic) at 1 mg orally 30 to 60 minutes before TLI<br>* Other names: Sancuso;Drug: Solumedrol<br>* Solumedrol, an anti-inflammatory glucocorticoid containing methylprednisolone sodium succinate, administered at 1 mg/kg as a premedication for anti-thymoglobulin (ATG)<br>* Other names: A-Methapred;Drug: Acetaminophen<br>* Acetaminophen administered orally at 650 mg 1 hour prior to infusion of PBPC<br>* Other names: Tylenol;Drug: Diphenhydramine<br>* Diphenhydramine administered by intravenous infusion at 50 mg 1 hour prior to infusion of PBPC<br>* Other names: Benadryl;Drug: Hydrocortisone<br>* Hydrocortisone administered by intravenous infusion at 100 mg 1 hour prior to infusion of PBPC<br>* Other names: Westcort;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chronic Graft-vs-Host Disease (cGvHD) | The cumulative percentage of participants who develop chronic graft-vs-host disease (cGvHD). Chronic cGvHD was defined as at least one instance of a clinically-accepted marker for cGvHD (see Filipovich, et al. Biology of Blood and Marrow Transplantation. 2005;11:945-955) | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Relapse | Subjects who Relapsed following after Allogeneic HSCT | 4 years | 
| Mortality | Number of participants who died within 100 days and within 1 year, non-relapse and associated with relapse. | Day 100 and 1 year | 
| Overall Survival |  | 4 years |