How Do CXCR4 Inhibitors Work?

C-X-C motif chemokine receptor 4 (CXCR4) inhibitors are a class of drugs used in the treatment of multiple myeloma, non-Hodgkin’s lymphoma and WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome. CXCR4 inhibitors work by increasing the count of blood cell forming (hematopoietic) stem cells (HSCs), lymphocytes, and neutrophils in peripheral blood circulation.

Multiple myeloma is a malignant type of blood cancer that develops in plasma cells in the bone marrow. Plasma cells are immune cells (lymphocytes) that produce antibodies to fight infections. Non-Hodgkin’s lymphoma (NHL) is a group of cancers of the lymphoid tissue caused by uncontrolled growth of abnormal lymphocytes.

One of the treatments for both multiple myeloma and non-Hodgkin’s lymphoma is stem cell transplantation. Stem cells are harvested from the patient’s own blood and infused back (autologous transplant) after destroying the myeloma or lymphoma cells with chemotherapy and radiation. CXCR4 inhibitors increase the availability of healthy HSCs in the blood.

WHIM syndrome is a rare primary deficiency of the immune system, named after the four common symptoms of the disease. People with WHIM syndrome have extremely low level of neutrophils, a type of immune cell that fights infections, and consequently, are highly susceptible to infections, especially respiratory, ear and skin infections. CXCR4 inhibitors increase neutrophil and lymphocyte count in blood.

CXCR4 is a protein on the outer membrane of white blood cells and cells of the central nervous system. CXCR4 receptors are attracted to stromal-derived factor-1 alpha (SDF-1a), another type of protein (ligand) found in high levels in the bone marrow. This helps in the migration of white cells and HSCs to the bone marrow, where they stay until they are needed elsewhere in the body.

CXCR4 inhibitors block the binding of CXCR4 with SDF-1a, which allows more hematopoietic stem cells and white cells to remain in circulation increasing the availability of stem cells for harvest and transplantation in the treatment of multiple myeloma and NHL. In the case of WHIM syndrome, it increases the count of neutrophils and lymphocytes, strengthening the immune defense against infections.

CXCR4 inhibitors are administered as subcutaneous (SC) injections into the tissue under the skin. One of the CXCR4 inhibitors is available in the form of oral capsules. CXCR4 inhibitors are approved by the FDA for the following:

Motixafortide (SC injection) in combination with filgrastim: To mobilize hematopoietic stem cells to the peripheral circulation for collection and subsequent autologous transplantation in adult patients with multiple myeloma

Plerixafor (SC injection) in combination with granulocyte-colony stimulating factor (G-CSF): To mobilize hematopoietic stem cells to the peripheral circulation for collection and subsequent autologous transplantation in adult patients with multiple myeloma or non-Hodgkin’s lymphoma

Mavorixafor (capsules): To increase the number of circulating mature neutrophils and lymphocytes in patients 12 years and older with WHIM syndrome.

Side effects of CXCR4 inhibitors include the following:

• Injection site reactions including:
• Pain and irritation
• Itching (pruritus)
• Redness (erythema)
• Hematoma
• Hemorrhage
• Hardening of tissue (induration)
• Inflammation
• Pruritus
• Flushing
• Rash
• Hives (urticaria)
• Erythema
• Back pain
• Abnormal skin sensations (paresthesia)
• Low blood potassium (hypokalemia)
• Nausea
• Diarrhea
• Vomiting
• Gas (flatulence)
• Fatigue
• Joint pain (arthralgia)
• Headache
• Insomnia
• Heart rhythm disturbance (QTc interval prolongation)
• Dermatitis
• Ear swelling
• Chills
• High temperature (pyrexia)
• Dizziness
• Tremor
• High blood pressure (hypertension)
• Spleen enlargement (splenomegaly)
• Spleen rupture
• Abnormal dreams and nightmares
• Severe allergic reactions (anaphylaxis)
• Anaphylactic shock

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of CXCR4 inhibitors include:

• Aphexda
• mavorixafor
• motixafortide
• Mozobil
• plerixafor
• Xolremdi