To study the safety and side effects of Ofatumumab in the treatment of chronic graft-versus-host disease (GvHD). This study will also evaluate effectiveness of Ofatumumab when added to standard steroid treatment for chronic graft-versus-host disease

This is a phase I-II trial to examine the safety and efficacy of prednisone and escalating dose of ofatumumab for the primary therapy of chronic GVHD.

Inclusion Criteria:

• Hematopoietic cell transplantation (HCT) recipients newly requiring systemic glucocorticoid therapy (at ≥ 1mg/kg/day prednisone or equivalent) for chronic GVHD
• Participants can be enrolled and begin study therapy with ofatumumab within 14 days from initiation of 1 mg/kg/day prednisone for therapy of chronic GVHD.

Exclusion Criteria:

• Relapse of primary hematologic malignancy that served as indication for HCT.
• Previous systemic glucocorticoid therapy (at ≥ 1mg/kg/day prednisone or equivalent) for chronic GVHD
• Prior systemic glucocorticoid therapy for acute GVHD is permitted
• Prior or ongoing systemic immune suppressive agents (including, but not limited to common examples such as calcineurin inhibitors, sirolimus, mycophenolate mofetil) provided for either prevention or treatment of acute GVHD are permitted and part of routine standard of care
• Current active hepatic or biliary disease (with exception of liver disease secondary to chronic GVHD, or patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment).
• Patients with abnormal liver function tests due to chronic GVHD are specifically not excluded from the study. This is a common manifestation of chronic GVHD, and thus a major target for the study therapy.
• Treatment with experimental non-FDA approved therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer
• Other past or current solid tumor malignancy
• Have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
• Prior treatment with anti-cluster of differentiation antigen 20 (CD20) monoclonal antibody or alemtuzumab within 3 months prior to start of therapy.
• Uncontrolled infectious complications not responsive to appropriate antimicrobial therapy.
• History of significant cerebrovascular disease (i.e. stroke or TIA) in the past 6 months or ongoing event with active symptoms or sequelae
• HIV positivity
• Uncontrolled, current significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities.
• A history of cardiac disease, such as coronary disease, arrhythmia or congestive heart failure that are on appropriate medical therapy and without evidence of current decompensation are eligible.
• Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient.
• Those patients with medical conditions that are controlled with medical therapy are eligible.
• Clinically active Hepatitis B defined as positive HBsAg; or positive HBcAb with detectable hepatitis B virus (HBV) DNA viral load. Patients who are HBcAb with undetectable HBV DNA viremia are eligible.
• Positive serology for hepatitis C (HC) defined as a positive test and confirmed by HC recombinant immunoblot assay (RIBA) or hepatitis C virus (HCV) RNA viral load
• Screening laboratory value exclusion criteria: platelets < 50 x 10^9/L (patients with platelet counts > 50 x 10^9/L supported by platelet transfusion are eligible); neutrophils < 1.0 x 10^9/L (patients with an absolute neutrophil count > 1.0 x 10^9/L supported by growth factors are eligible); creatinine > 2.0 times upper normal limit; total bilirubin >1.5 times upper normal limit (unless due to chronic GVHD); alanine transaminase (ALT) > 2.0 times upper normal limit (unless due to chronic GVHD); alkaline phosphatase > 2.5 times upper normal limit (unless due to chronic GVHD).
• Women who are pregnant or lactating. Women of childbearing potential must have a negative pregnancy test at screening.
• Women of child bearing potential must undergo pregnancy testing within 7 days of the first dose of study therapy. Women must also undergo pregnancy test at 6 months after the last dose.
• Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence.
• Males unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.

6 years, 6 months