Hairy Cell Leukemia: Pathology and Treatment

Pathology

A majority of patients with classic Hairy Cell Leukemia (HCL) have a specific genetic mutation found in their tumor cells. This mutation is called the BRAF V600E mutation. We understand that the BRAF mutation is acquired after birth, usually in the process of a normal blood cell turning into an abnormal (cancer) cell. This occurs in B-cells, which is a common type of white blood cell that helps to fight infections. These white blood cells originate from stem cells found in the bone marrow. A stem cell can either turn into a red blood cell, white blood cell or platelet. As the number of these mutated B-cells multiply, the number of healthy red blood cells, white blood cells and platelets will decrease. This can increase the risk for infection and anemia, and cause easy bleeding. These abnormal cells may also collect in the spleen and cause swelling.

History of HCL Treatment

Before treatments were developed for HCL, the survival rate was only about 5 years. A splenectomy was among the earliest available therapies. The drug Interferon was later introduced with high success rates, however, patients often experienced side effects similar to flu-like symptoms. Pentostatin and Cladribine were then developed, which are still the most commonly used treatments today. Cladribine and Pentostatin do have side effects. Researchers found that lowering the dose of Pentostatin can significantly minimize side effects for many patients, without reducing the drug’s overall effectiveness.

Another drug, Rituximab, is also highly effective in HCL when combined with Pentostatin or Cladribine. Rituximab targets the CD20 marker in B-cells, which plays a role in the differentiation of B-cells into plasma cells. Similarly, a drug called moxetumomab pasudotox targets the CD22 marker present on B-cells.

BRAF Inhibitors and Other Treatment Options

Dr. Enrico Tiacci from the University and Hospital of Perugia, Italy has studied extensively the effectiveness of Vemurafenib, a BRAF inhibitor, in HCL treatment. Thirty-five percent of patients in his study achieved a complete remission. However, BRAF inhibitors may lose their effectiveness once treatment is suspended, with relapse being likely. Vemurafenib is non-toxic compared to chemotherapies, like Pentostain or Cladribine, and it helps doctors to give a more targeted treatment with less concern about toxicity. Dr. Thorsten Zenz, previously with the National Center for Tumor Diseases and German Cancer Research Center, found that Vemurafenib was also effective in lower doses, which further allowed flexibility with treatment dose. 

The drug Ibrutinib targets B-cell receptors and has shown positive results. Another third-line treatment is moxetumomab pasudotox. This drug binds to the cell and is internalized. The toxic agent in the drug causes the tumor cell to die.

Treatment Guidelines Specific to the United Kingdom

In the UK, doctors generally follow these guidelines to manage their patients’ HCL.

First-line treatment consists of the purine analogs, Cladribine and Pentostatin. If the patient relapses or the disease progresses, Rituximab may be given at second-line, with or after completion of the purine analog. Studies from the National Institutes of Health (NIH) in the U.S. suggest that taking Rituximab concurrently with a purine analog may be more effective than subsequent, however, this approach may also increase toxicity and lead to increased immunosuppression. Third-line treatment in the UK consists of previously used treatments, or the doctor may consider other options, such as BRAF inhibitors, with or without Rituximab. Ibrutinib and other BTK inhibitors may also be explored at this stage. 

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Source Information

An October 11, 2021 webinar presentation and discussion, hosted by the Hairy Cell Leukemia Foundation with speaker Dr. Francesco Forconi, served as a major source of information for this blog. Dr. Forconi is Professor of Haematology at the School of Cancer Sciences, University of Southampton and Consultant Haematologist at the University of Southampton Hospital Trust, UK. He graduated in Medicine and completed his specialist training in Haematology at the University of Siena, Italy. During his Haematology speciality training, he obtained research fellowships at the Princess Margaret Hospital and Toronto General Hospital, Canada and at the University of Eastern Piedmont, Italy. He then moved to Tenovus Laboratories, University of Southampton (UK). There he developed his interests in cancer B-cell immunology and anti-tumour DNA vaccines, which were the topics of his post-doctoral DM and PhD degrees. In 2004 he was appointed as Assistant Professor and Consultant in Haematology at the University of Siena Hospital Trust, and in 2011 as Associate Professor at the School of Cancer Sciences, University of Southampton, before being appointed as Professor of Haematology in 2020. Professor Forconi focuses his academic research on the structure and function of the tumour B-Cell Receptor (BCR) Immunoglobulin (Ig) in mature B-cell malignancies, including Chronic lymphocytic leukaemia (CLL) and, more recently, follicular lymphoma (FL) and subsets of diffuse large B-cell lymphomas (DLBCL). He is leading a multi-disciplinary research B-cell group, working with world-class immunologists, cellular biologists, glycobiologists, bioinformatics and clinical scientists in Southampton and collaborating with a number of international collaborators in Europe and North America. 

Author Information

We gratefully acknowledge the work of Kuyili Velagapudi, Spring 2022 Communications Intern. Kuyili is a Public Health and Communication Studies student at The College of New Jersey.