Ofatumumab as Part of Reduced Intensity Conditioning (RIC) Regimen for Patients With High Risk Chronic Lymphocytic Leukemia (CLL) Undergoing Allogeneic Hematopoietic Cell Transplantation
Condition: Chronic Lymphocytic Leukemia
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Study type: Interventional
Phase: Phase 2

Summary: 
      A good proportion of patients with chronic lymphocytic leukemia (CLL) can be managed
      effectively with palliative chemotherapy. However, there is a group of younger patients with
      poor risk disease whose life expectancy is significantly reduced. As a result, reduced
      intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) has
      been investigated as a potentially curative procedure.

      Recently, the European Group for Blood and Marrow Transplantation (EBMT) published a set of
      guidelines suggesting situations where allo-HCT might be considered a therapeutic option for
      CLL patients. Their conclusions were that allo-HCT was reasonable for younger CLL patients
      refractory to fludarabine, relapsing within two years of intensive treatment, or with p53
      abnormalities requiring treatment.

      However, the results with RIC allo-HCT are not entirely satisfactory, and progression-free
      survival after allo-HCT revolves around 35-40% at 3-5 years following allo-HCT. This is due
      to non-relapse mortality, which is significantly associated with the development of
      graft-versus-host disease (GVHD), but also due to disease relapse. These relapses may occur
      early in the course of the transplantation, like any other hematological malignancy, but late
      relapses have also been reported.

      Several strategies have been tested in order to improve these results. The anti-CD20
      monoclonal antibody rituximab, given concomitantly with allo-HCT or donor lymphocyte
      infusions, may reduce graft-versus-host disease and facilitate disease control. This may be
      due, not only to direct cytotoxicity, but also to modulation of GVHD and the graft-versus CLL
      effect (GVCLL). Interestingly, rituximab has been shown to promote the cross-presentation of
      tumor-derived peptides by antigen-presenting cells, thus enhancing the formation of cytotoxic
      T-cell clones and a GVCLL effect. With the addition of rituximab to the conditioning regimen,
      rates at 4 years for current progression-free survival (CPFS) and overall survival were 44%
      and 48%.

      The investigators hypothesize that ofatumumab, having a more potent anti-CLL activity and
      complement-dependent cytoxicity than rituximab, could improve disease control and modulate
      the GVCLL effect more effectively, thus reducing the GVHD rate and subsequently improving the
      non-relapse mortality and progression-free survival in the long term.
    


Intervention name(s): Ofatumumab
Intervention type(s): Drug
Intervention description(s): We plan to add five doses of ofatumumab to the standard conditioning regimen (fludarabine + melphalan). Ofatumumab will be administered on days -20 (300 mg), -13 (2000 mg), -6 (2000 mg), +1 (1000 mg) and +8 (1000 mg) of the transplantation (day 0 being the day of the hematopoietic cell infusion). If the patient requires donor lymphocyte infusions within 3 years after the procedure, these infusions will also include one administration of 300 mg of ofatumumab, followed by a 1000 mg dose, 7 days later).
Other intervention name(s): Arzerra
Intervention MeSH terms: Ofatumumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment