This is the eighth part of our series about the condition based on our patient booklet “Fast Facts for Patients: Waldenström Macroglobulinemia”. This is the first of two blog posts on further types of treatment for Waldenström macroglobulinemia (WM).

Monoclonal Antibodies

Monoclonal antibodies recognize, target and stick to proteins on the surface of cancer cells. They can stimulate the body’s immune system to destroy these cells.

Rituximab is used to treat B-cell lymphomas like WM. It recognizes the protein CD20, which is found on the surface of B cells. Rituximab is given by drip as an infusion directly into a vein (intravenous) or as an injection under the skin (subcutaneous).

  • Rituximab may be given with chemotherapy and/or steroids and the combination then has an “R” added (for example, bendamustine and rituximab [BR]; see below).
  • It may cause allergic reactions at the time of the infusion (and afterward, but this is rare). The first infusion is given over 6 hours to try to limit this reaction. Subsequent infusions can usually be given over 60–90 minutes.
  • If the starting IgM level is higher than 30g/L, giving rituximab may result in a steep rise or flare of IgM, triggering high blood viscosity that may last for several weeks. For this reason, the rituximab may be delayed for 1 or 2 cycles of the chemotherapy schedule.

Combination Treatment

Most people with symptoms will receive a combination of rituximab plus chemotherapy. The exact regimen depends on different factors, including your age and fitness. The most commonly used combinations are:

  • BR: intravenous bendamustine on days 1 and 2 of each cycle, with rituximab also given on day 1. The treatment is repeated every 28 days (a cycle), 4–6 times.
  • DRC: intravenous dexamethasone on day 1, intravenous rituximab on day 1, and oral cyclophosphamide twice daily for the first 5 days (days 1–5). This is repeated every 21 days (a cycle) for a total of 6 courses.
  • Single-agent rituximab: intravenous rituximab every week, for 4 doses. This may be repeated after 3 months (called an extended schedule).
  • Other combinations of chemotherapy agents may be used to induce a remission if you are being prepared for a stem cell transplant. Such combinations can be used to reduce the amount of WM in the body and to “mobilize” stem cells, which can then be used for the transplant.

Proteasome Inhibitors

These treatments aim to disrupt the cancer’s growth and survival by targeting chemical pathways within LPL cells.

  • Bortezomib is given by injection under the skin (subcutaneously) every week for 4 weeks, which may or may not be followed by a week’s break. It is important to highlight any symptoms of peripheral neuropathy that you have if you are taking this medication although given subcutaneously the risk is much lower than originally reported.
  • Carfilzomib is given by injection into a vein (intravenously). It appears to be well tolerated. It is not widely available outside clinical trials.
  • Ixazomib is taken by mouth (orally). It is under evaluation in combination with dexamethasone and rituximab. It is not yet available outside clinical trials.

Bruton Tyrosine Kinase Inhibitors

These medications are designed to target and inhibit an enzyme in cells called Bruton tyrosine kinase (BTK). Blocking the effects of BTK reduces the survival of LPL cells. BTK inhibitors are taken by mouth (orally) on a daily basis for as long as they are effective and tolerated.

Ibrutinib

Ibrutinib is the first BTK inhibitor to be developed and approved for WM based on its effectiveness. It has been in clinical use for the longest time so has the longest follow-up of all the BTK inhibitors in WM. It is taken once daily in 28-day cycles. It is given for as long as it works and is tolerated. It can be used on its own or with rituximab.

Ibrutinib stops LPL cells from interacting with their surroundings so that they do not thrive. It has a number of “off-target effects” which means that it may inadvertently adversely affect other tissues, causing side effects. These side effects include fatigue, low blood counts, disturbance of the heart rhythm (atrial fibrillation), high blood pressure, increased risk of bleeding, increased infections, aching joints, skin rashes, mouth ulcers and diarrhea. In most cases, side effects can be managed by pausing and reintroducing the treatment or reducing the dose.

You may be given additional medications to control your heart rate or blood pressure so that you can continue ibrutinib treatment. Doctors have gained a lot of experience of managing side effects that may develop over time so that you can continue your treatment.

Zanubrutinib

Zanubrutinib is a “next-generation” BTK inhibitor that has recently been approved for WM in the UK, USA and Europe. Zanubrutinib is more selective in its targeting actions in the body. It is taken twice daily as long as it is effective and tolerated.

In a head-to-head comparison trial, zanubrutinib showed a higher percentage of complete responses (CR) and very good partial responses (VGPR) (than ibrutinib. Continued follow-up of patients in clinical trials will determine whether this higher rate of deeper responses will translate into a longer-lasting remission.

Trials have also shown that side effects such as atrial fibrillation, infections, diarrhea and high blood pressure happen less often with zanubrutinib.

Other BTK Inhibitors

Other BTK inhibitors being tested in clinical trials are acalabrutinib, tirabrutinib and pirtobrutinib.

Class Effects of BTK Inhibitors

Class effects of BTK inhibitors (side effects of all BTK inhibitors) that are important to know when using these treatments.

  • Increased risk of infections. It is therefore common for preventative medication (prophylaxis) to be used at the same time. This typically includes an antiviral drug such as aciclovir (acyclovir in the USA) and an anti-pneumonia drug called cotrimoxazole. They are given continuously with the BTK inhibitor. If there is an additional risk of fungal infections (for example, if you are also taking steroids), then antifungal medication may also be used.
  • Increased risk of bruising and bleeding. This means that you will need to pause your BTK inhibitor therapy for 3–5 days before any invasive procedure (such as dental extractions or operations). The exact number of days will depend on the procedure. You will be able to restart your BTK inhibitor 3–5 days after the procedure when all bleeding has stopped. Your clinical team will guide you on this.
  • Interactions with other medications and foods. You may need to avoid certain medications or foods, or take some drugs with caution, when taking BTK inhibitors. It is important to read the information leaflet carefully and check with your clinical team about any medications, supplements or foods you should avoid.

 

 

Information based on Fast Facts for Patients: Waldenström Macroglobulinemia

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