Tag: CLL

Ofatumumab Approved for Use in Combination with Fludarabine and Cyclophosphamide to Treat Patients with Relapsed CLL

The Backstory

Last month, the FDA approved the use of ofatumumab in combination with fludarabine and cyclophosphamide to treat patients with relapsed chronic lymphocytic leukemia (CLL).

This is the 4th FDA approval received by ofatumumab for the treatment of patients with CLL. Ofatumumab was initially approved in 2009 for the treatment of patients with CLL who are refractory to fludarabine and alemtuzumab, and subsequently approved in April 2014 for use in combination with chlorambucil for previously untreated patients with CLL. In January 2016 ofatumumab was approved for the treatment of patients with recurrent or progressive chronic lymphocytic leukemia (CLL) who are in complete or partial response following at least two prior treatment therapies.

What is ofatumumab?

Ofatumumab is a human monoclonal antibody designed to target the CD20 molecules found on the surface of CLL cells and B-cell lymphocytes. CD20 molecules are found in over 90% of B-cell lymphomas. Ofatumumab is an immunotherapy that works by attaching itself to the CD20 molecule found on the surface of B-cells and directs the immune system to kill the cancerous B-cells.

Why was ofatumumab granted FDA approval?

The latest approval for ofatumumab was based on improved progression free survival (PFS) results in the phase III COMPLEMENT-2 study. PFS refers to the length of time following the course of treatment, that a patient’s disease does not get worse, or progress. In this study the median PFS of ofatumumab combined with chemotherapy was 28.9 months compared to 18.8 months for only the fludarabine and cyclophosphamide combination.

Were there any side effects?

Side effects were similar to the side effects found in previous trials. They included infusion reactions, neutropenia, thrombocytopenia, anemia, nausea, leukopenia, vomiting, pyrexia, rash, fatigue, and pneumonia.

How can you access ofatumumab now?

While all available WCM trials with ofatumumab for people with CLL have recently closed, our understanding of how best to use ofatumumab continues to increase. You can look to this space for further updates on CLL trials examining the use of ofatumumab.

A full list of trials open at WCM for patients with CLL is available on our Joint Clinical Trials website.

Ask the Expert: The Difference Between CLL Stage and SLL Stage

Question

What is the difference between CLL stage (Rai or Binet) and SLL stage (Ann Arbor)? Why does the same disease have two different staging systems?

Answer

Dr. Richard Furman, M.D.
Dr. Richard Furman, M.D.

Dr. Richard Furman writes: The purpose of a staging system is to help clinicians better determine prognosis and plan treatment for a patient’s disease. Although chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are the same disease, they were not recognized as the same disease until 1994. Since then they have been combined into one entity, CLL/SLL.

For historical reasons, CLL was staged based upon the Rai or Binet scheme (see below) and SLL was staged using the Ann Arbor lymphoma staging scheme (see below). Today most CLL specialists use the Rai stage because it is more clinically helpful. Using the Ann Arbor classification to stage SLL is problematic in scenarios where the disease has spread to the bone marrow. A person with SLL in their lymph nodes and bone marrow would immediately be characterized as an Ann Arbor stage IV, but their prognosis and treatment plan would be far better indicated as measured by the Rai stage I. Therefore the Rai stage, even without lymphocytosis, provides better prognostic and therapeutic information for a physician to treat their patient.

Rai Stages

0: lymphocytosis (an increase in number of lymphocytes in the blood).

I: Lymphocytosis + lymphadenopathy, (enlarged lymph nodes).

II: Lymphocytosis + splenomegaly (enlargement of the spleen) +/- lymphadenopathy

III: Lymphocytosis + anemia (decrease in red blood cells) +/- splenomegaly +/- lymphadenopathy

IV: Lymphocytosis + thrombocytopenia (decrease in platelets) +/- anemia +/- splenomegaly +/- lymphadenopathy

Ann Arbor Stages

I: Disease found in one group of lymph node

II: Disease found in two or more groups of lymph nodes on the same side of the diaphragm.

III: Disease found in two or more groups lymph nodes on both sides of the diaphragm.

IV: Extranodal disease (found outside of the lymph nodes), including bone marrow, liver, or other organs)

Note: if only one isolated area or organ involvement is present, then it would be a stage I, except for bone marrow.

Immunotherapy Targeting Immune Checkpoint Inhibitor with Durvalumab for the Treatment of Relapsed/Refractory Lymphoma or CLL

Picture2By Jia Ruan, M.D., Ph.D.

A functional immune system is vital to control the growth of many types of cancers. Tumors can grow when tumor cells evade the immune system by modulating the tumor microenvironment through expression of inhibitory molecules such as PD-1 and PD-L1. Interaction of PD-1 receptor on T-cells with its ligand PD-L1 on tumor cells leads to T-cell exhaustion, immune dysfunction, and tumor progression. Recently therapeutic targeting of inhibitory checkpoint molecules like PD-1 and PD-L1 have shown promise as effective immunotherapy across a number of tumor types including solid tumors and lymphomas. These immunotherapies work by augmenting the patient’s immune system. The first generation of these new inhibitors include anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab, which have gained FDA approval for the treatment of melanoma and non-small cell lung cancer.

Durvalumab, also known as MEDI4736, is a human immunoglobulin (Ig) G1к monoclonal antibody (mAb) that selectively binds to human PD-L1 with high affinity and blocks its ability to bind to programmed cell death-1 (PD-1) receptor on the T-cells. As a PD-L1 inhibitor, durvalumab activates the tumor-infiltrating T-cells, allowing them to destroy the tumor cells. Essentially durvalumab acts a catalyst to reactivate the body’s immune system and destroy cancerous tumor cells.

Clinical Trial Summary 

Weill Cornell Medicine has recently opened a clinical trial for patients with relapsed/refractory lymphoma or released/refractory chronic lymphocytic leukemia (CLL) previously treated with at least one systemic therapy. The purpose of this study is to test the safety and effectiveness of durvalumab, a monoclonal antibody against PD-L1, in combination with other specific anti-lymphoma therapies, including lenalidomide plus rituximab, ibrutinib, and bendamustine plus rituximab.

The study will consist of 3 parts: dose finding, dose confirmation, and dose expansion.  Four treatment arms will be investigated:

-Arm A (durvalumab plus lenalidomide and rituximab);

-Arm B (durvalumab plus ibrutinib);

-Arm C (durvalumab plus bendamustine and rituximab);

-Arm D (durvalumab monotherapy).

Study subjects will receive treatment for approximately one year and be in follow-up for anywhere from two to five years after treatment.