AND OTHER PLATELET DISORDERS
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BTK inhibitor rilzabrutinib (WAYRILZ™) is approved by the Food and Drug Administration (FDA) for adults with persistent or chronic immune thrombocytopenia (ITP) who have received a prior treatment that did not work well enough.
Rilzabrutinib (WAYRILZ™) is the first Bruton’s Tyrosine Kinase (BTK) inhibitor approved by the FDA for the treatment of persistent and chronic ITP in adults when a prior treatment has not worked well enough. Rilzabrutinib comes in tablet form and is taken twice daily with or without food.
Bruton’s Tyrosine Kinase (BTK) is part of a network of proteins (found in certain cells of the immune system) which trigger platelet autoantibody production and platelet destruction. When the back end of the antibodies attached to platelets contact their receptors on immune cells, an important way that they trigger platelet destruction is to signal the immune cells into action. When platelets are coated with antibodies, they attach to cells and start the signaling pathway for destruction. This signal goes through BTK so blocking BTK blocks the signal. The immune cells then no longer react to the antibodies on the platelets and no longer destroy the platelets.
Rilzabrutinib works differently than other treatments by specifically targeting BTK. The drug limits platelet destruction by the immune system by blocking the action of the scavenger cells (macrophages), which in turn raises platelet counts in the body helping to reduce the risk of severe bleeding. The drug also inhibits the signal to produce autoantibodies (B-cell) which bind to platelets, reducing the potential for future platelet destruction. Rilzabrutinib does not suppress the immune system; it modulates the over-active immune system responses in ITP.
Dosage
Rilzabrutinib is taken as 400mg (one tablet) twice daily. There are no dosage adjustments for safety or effectiveness. Rilzabrutinib can be taken with or without food. If you experience diarrhea, nausea, or stomach area (abdominal) pain during treatment with WAYRILZ, taking it with food may reduce these side effects.
Before taking WAYRILZ, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking WAYRILZ with certain other medicines may affect how WAYRILZ works and can cause side effects. WAYRILZ may also affect how other medicines work. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
WAYRILZ may cause serious side effects, including:
The most common side effects of WAYRILZ include:
Sanofi has established HemAssist for patient support. Learn more online or by calling 1-833-723-5463 Monday through Friday 8am to 7pm ET.
In a study of 202 adults with persistent or chronic ITP, rilzabrutinib was compared to placebo (an inactive tablet that looked like the real medication) to see how effective it was in raising platelet counts with subjects taking it for up to 6 months of treatment. At the beginning of the study, the median platelet counts for people enrolled were equal to or less than 15,000 per microliter. On average, the people in the trial had had long-standing chronic ITP for 7.69 years. All individuals in the study had had at least one prior treatment, which was either corticosteroids, IVIg, TPO-RA, rituximab, or fostamatinib. The patients who benefited from rilzabrutinib did so regardless of whether they had had a specific prior treatment and whether they had responded temporarily to that treatment.
As part of the clinical trial design, patient's platelet counts were checked halfway through the trial, at month 3, to be eligible to complete the initial, double blind period of the trial. At month 3, 64% of rilzabrutinib patients and 32% of placebo patients had a platelet count response (≥50 x 109/L or between 30 x 109/L and <50 x 109/L and doubled from baseline) without rescue medication. At 6 months, 23% of rilzabrutinib patients and 0% of placebo patients had a durable platelet response (a weekly platelet count ≥50 x 109/L for ≥ two-thirds of at least 8 non-missing weekly scheduled platelet measurements during the last 12 weeks of the 24-week DB period in the absence of rescue therapy). Of those who responded to rilzabrutinib, most patients responded within 15 days of starting treatment.
One of the endpoints in the clinical trial was examining patient reported quality of life. Prior to the start of the study, patients completed a survey called the ITP-Patient Assessment Questionnaire that looked at how ITP affected different parts of their lives. At month 6, patients took the ITP-PAQ survey again. People taking WAYRILZ reported a 10.6 point increase vs 2.3 point increase in placebo in overall health related quality of life. The results of these analyses are descriptive and not statistically tested to determine a difference between treatment groups.
Various chemotherapy drugs, including vincristine (Oncovin®) and cyclophosphamide (Cytoxan®) have been used as a second or third-line treatment choice for chronic ITP patients. Each has a slightly different side effect profile. While they have been effective in a small percentage of cases, chemotherapy drugs can be quite toxic and have not been approved by the FDA to treat ITP.
Vincristine, a vinca alkaloid derived from the Madagascar periwinkle, inhibits the division of rapidly growing cells. It is frequently used in conjunction with other drugs or infusions for the treatment of lymphoma.1 Vincristine may be used in emergencies or in combination with other therapies for particularly difficult cases of ITP.6
Cyclophosphamide slows cell growth as well as suppresses the immune system. Most often used to treat lymphoma or other cancers, it alters T-cells2, a type of white blood cell, and may be preferentially considered for those ITP patients who have T-cell abnormalities.3
Rituximab (Rituxan® and MabThera®), a B-cell depletion therapy, is considered by some to be a chemotherapy treatment since it is often used to treat cancer.
The dose and duration of the chemotherapy agents varies with the age and size of the patient, other medications and additional medical conditions.
Vincristine is administered through an IV push. It is important that someone who is experienced with the treatment oversee the process since leakage into the surrounding tissue can cause severe problems or death.4
Cyclophosphomide can be given by tablet or injection.5
Chemotherapy agents can reduce the number of white blood cells and increase the chance of getting an infection. The side effects become more severe with increased or additional doses.
The most frequently reported side effects of vincristine are peripheral neuropathy (reduced sensation in fingers and toes), electrolyte imbalance, constipation and hair loss.1
Cyclophosphomide side effects include chemotherapy-induced nausea and vomiting, stomachache, diarrhea, and infertility. Delayed effects include the risk of developing bladder cancer or other tumors.2,5
Select a treatment table to view or download below.
Corticosteroid drugs—including prednisone, dexamethasone and deflazacort—are often the first-line treatment approach for ITP. Some research indicates that short courses of dexamethasone are preferable in treating newly diagnosed cases.1
Both prednisone and dexamethasone are types of corticosteroids, drugs based on a naturally occurring hormone produced by the adrenal glands involved in the control of inflammation, stress response, metabolism, behavior, electrolyte balance and more.2 Prednisone is prescribed for a number of diseases including asthma and other autoimmune diseases.
Prednisone and other corticosteroids disrupt the communication between the pituitary and adrenals, which can lead to adrenal insufficiency. It is very important that the corticosteroid dose be tapered gradually, especially after high dose or long-term use, giving the adrenals a chance to resume their natural hormone production.3
Dexamethasone, in combination with rituximab, has produced better results in newly diagnosed patients than dexamethasone alone.6
The usual starting dose of the corticosteroids prednisone or prednisolone for ITP patients is .5 to 2 milligram (mg)/ kilogram (kg) for two to four weeks before tapering, depending on the response.5 One kilogram is equal to 2.2 pounds; based on this, body weight would be divided by 2.2 to determine the starting dosage. For example, 120 pounds would equal a dose of 60 mg.
Dexamethasone is given at the rate of 40 mg per day for four days, equivalent to about 400 mg of prednisone a day. There is no taper. The series can be repeated periodically as needed.
A partial list of the possible side effects includes: cataracts, gastrointestinal discomfort, osteoporosis, obesity, moon face, hypertension (high blood pressure), diabetic metabolism (blood sugar changes), sleep disturbances (insomnia), psychiatric syndromes (mood changes), delayed wound healing, atrophy (muscle wasting, including the heart muscle), potassium loss, and changes in the skin.5
Side effects from corticosteroids can be difficult to manage and grow in severity if the treatment is continued for a long period of time.
The side effects of withdrawing from prednisone can also cause problems. It is important to work closely with your physician as the drug is discontinued.
While 50 to 90 percent of ITP patients see a rise in platelet counts with an initial high dose of corticosteroids, only 10 to 30 percent have a durable remission, and some of those may require further treatment.4
Anti-platelet antibodies generally attach to one of two regions on the platelets, either GPIIbIIIa or GPIb-IX. People with GPIb-IX antibodies do not respond as well to corticosteroids as those with GPIIbIIIa antibodies or no detectible antibodies.7
Select a treatment table to view or download below.
Immunosuppressants, including azathioprine (Imuran®), cyclosporine (Sandimmune®), diphenylsulfone (Dapsone®), Sirolimus (Rapamycin ®), and mycophenolate mofetil (Cellcept®), are considered a second or third-line treatment for ITP. This class of drugs is used to treat other autoimmune diseases, including multiple sclerosis (MS) and lupus, but none have gained FDA approval to treat ITP.
A class of drugs that suppress, or reduce, the strength of the body’s immune system, immunosuppressants are also referred to as anti-rejection drugs because they are used to make the body less likely to reject a transplanted organ, such as a liver, heart or kidney.
Azathioprine suppresses the division of white blood cells,1 but is slow to raise the platelet count and should be continued for about four months before determining whether it has been effective. It is sometimes given along with the corticosteroid prednisone.2
Side effects include excessive tiredness, pale skin, headache, confusion, dizziness, fast heartbeat, difficulty sleeping, weakness, shortness of breath, sore throat, fever, chills, and other signs of infection.3
Imuran can cause irreversible bone marrow failure for those with a particular polymorphism of the TPMT gene. GlaxoSmithKline has a DNA test to predict this possibility.
Cyclosporine blocks the action of T-cells, a type of white blood cell responsible for fighting infections.4 For patients with ITP, the response rate in one study was 55 percent, but the relapse rate was high.7
Cyclosporine may damage the kidneys, raise blood pressure and increase your risk of developing cancer. Side effects include flu-like symptoms, coughing, difficult or painful urination, changes in the skin, fatigue, and swollen glands.4
Grapefruit juice and perhaps citrus sodas can increase the level of circulating cyclosporine.5 Research has shown St. John's wort reduces the concentration of cyclosporine, making it less effective.6
Mycophenolate mofetil inhibits the proliferation of B and T lymphocytes, types of white blood cells. In a small study of ITP patients, seven of 18 responded, but three of the seven responders had some lower platelet episodes while taking the medication.8
Side effects include: bowel changes, insomnia, headache, dizziness, swelling, pain, difficulty breathing, rapid heartbeat, blood in stools or vomit.9 Extremely rare, but very serious side effects, include Pure Red Cell Aplasia, a type of anemia9 and progressive multifocal leukoencephalopathy, a rare, incurable neurological condition.10
Immunosuppressants should not be used in pregnant women, those about to become pregnant or women who are breastfeeding. These drugs can increase the risk of infections or activate latent viral infections, in addition to increasing the risk of developing certain types of cancer.3,4,9
Before taking immunosuppressants, be sure to tell your doctor if you have ever had cancer or are taking other medications that suppress the immune system.4
Select a treatment table to view or download below.
More of a strategy than a treatment, ‘Watchful Waiting’ means choosing to live with your or your child's current platelet counts while carefully monitoring the disease and treatment options. In watchful waiting, the person with ITP is given no conventional treatment. However, it is not a passive approach or employed without serious consideration.
Watchful waiting is often considered for children because they have a higher rate of spontaneous remission, the incidence of intracranial hemorrhage is low, and conventional treatments may cause problems. The decision to treat or not to treat is one made by the family along with a hematologist.
Many factors go into making the observation decision including the platelet count, bleeding symptoms, quality-of-life for the family and the child, and the child’s activity level. In all cases, it is important for the family to be able to recognize and have a plan for a bleeding emergency.
According to The American Society of Hematology ITP Guidelines (updated 2019), "Children with no bleeding or mild bleeding (defined as skin manifestations only, such as bruising and petechiae) should be managed with observation alone regardless of platelet count"
Adults who have a low, but safe platelet count are often encouraged to take the watchful waiting approach by their doctors. Some adults who have tried many treatments without success may also use the strategy. It is important for the adult with ITP who chooses observation to have a thorough understanding of dangerously low platelet count symptoms and a treatment plan to manage a bleeding emergency.
Select a treatment table to view or download below.
An ITP diagnosis and the low platelet count it causes are sometimes associated with a bacterial infection—and antibiotics used to treat bacterial infections have been shown to help raise platelet counts. There has been considerable research on the success of antibiotics used to treat H. pylori (helicobacter pylori) bacteria infections in those diagnosed with ITP. The treatment and eradication of other infections can also help raise the platelet count.
A number of studies have linked ITP and H. pylori1, a type of bacteria that infects more than 50 percent of the world's population2, which has also been associated with ulcers. Many ITP specialists recommend testing ITP patients for H. pylori since correcting the problem and possibly raising the platelet count through antibiotics is less costly and has fewer side effects than many other ITP treatments.
The success rate of raising platelet counts by treating H. pylori has been shown to vary by region and ethnicity. Clinical trials completed in Italy and Japan show more positive results than those from the U.S.5; however, some people in the United States have recovered by treating the infection.
Other bacterial diseases such as those caused by ticks3, including Lyme disease, Rocky Mountain spotted fever, ehrlichiosis and leptospirosis4 (transmitted by the urine of infected animals) can also result in low platelets and are typically treated with antibiotics. It is important patients report all physical complaints to their hematologist as well as a history of animal bites or unusual animal contact.
Certain antibiotics, including cephalosporin, penicillin and sulfa-containing drugs, may lower platelet counts in some people. Learn more about how antibiotics affect blood platelet levels.
A splenectomy is the surgical removal of the spleen, a small, hand-sized organ located in front of the left kidney and behind the stomach. The spleen acts like a large lymph node, helping to maintain a healthy immune system and cleaning the blood of foreign matter.
In ITP, the antibody-coated platelets are often removed from circulation by the spleen. Theoretically, if the spleen is removed, the platelets will remain in the blood stream. The spleen can also be the site of antibody production. Therefore removing the spleen may reduce the amount of anti-platelet antibodies in addition to removing the antibody-coated platelets.
Although the spleen is often the major site of antibody-coated platelet destruction, platelets may also be removed from circulation by the liver, by a combination of the spleen and liver, or within the blood stream. Therefore, splenectomies are not always successful in raising the platelet count and may fail over time, prompting a return of low platelets.
Splenectomies have been used to treat ITP since 1913. There are two types of splenectomies: laparoscopic where the spleen is removed through a few small holes in the abdomen and open, requiring a large incision. The laparoscopic splenectomy is preferred, when possible, since the healing time is reduced. It has the same rate of success as an open splenectomy and there are fewer complications.1
While a splenectomy may raise the platelet count, it does not eliminate ITP since the antibody-coated platelets remain in circulation. In pregnancy, these antibody-coated platelets may cross the placenta and have the potential for reducing the platelet count of the newborn.
Doctors vaccinate those about to have a splenectomy with polyvalent pneumococcal, meningococcal C conjugate, and H influenza b (Hib) vaccines. Timeframes may be different for those on other immune suppressing therapies.3
A small percent of the splenectomized ITP population develops an accessory (extra) spleen. Occasionally, a second surgery is suggested to remove the accessory spleen if the patient has relapsed following a successful first surgery.3
The immediate complication rate from surgery is about 10 percent, although estimates vary. The fatality rate from the surgery is about one percent for an open splenectomy and much less for a laproscopic procedure. Patients over 65 have a higher complication and fatality rate.3
Since the spleen is responsible for making antibodies, filtering the blood, and removing bacteria, those without a spleen have an impaired immune system. Because of this, splenectomized patients have a more difficult time recovering from pneumonia, meningitis, Hib flu,3 sepsis,9 hospital-based infections,7 malaria and other parasitic diseases,5 babesiosis (a tick-borne disease)10and gram-negative bacterial diseases from animal bites.11
People who have had a splenectomy have more microparticles in their blood, giving them an increased risk of dementia4 and heart attacks6 from blood clots. They are also more prone to blood vessel complications.8
About 10 to 15 percent of people have no meaningful response to the operation. For those who do respond, from 30 to 35 percent relapse over time.16 The published success rates are about 66 percent, although the measurement criteria for success and the duration of follow-up are not standardized in the studies.1 Splenectomies are more successful and last longer in younger people (under 40 years of age).2
Other Treatments as a Predictor
Previous response to corticosteroids (such as Prednisone), IVIG or other treatments are not very good predictors of splenectomy success.3, 12, 13
Age as Predictor
A study reported in the British Journal of Haematology (March 2001) found "the only positive predictive factor for the long-term response to splenectomy was age <40 years."2
Indium Screening Test as Predictor
Researchers in the United Kingdom, France and Spain feel that an indium white blood cell screening test has some value in predicting whether a splenectomy will successfully raise your platelet counts. The test determines whether your spleen, liver, or a combination of both is responsible for your platelet destruction.14, 15
Haptoglobin (Hp) as a Predictor
Researchers performed a detailed analysis of the blood, pre and post operation, of people undergoing splenectomy searching for some blood protein that was different in those who responded to splenectomy, versus those who didn’t. The researchers found that haptoglobin (Hp), a protein that binds to free hemoglobin released by red blood cells, of non-responders before the operation was significantly lower than those who responded or the healthy controls. The researchers suggested their theory predicted splenectomy success in about 80 percent of the cases.17
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Modified testosterone is a synthetic androgen (male sex hormone) sometimes used to treat ITP when other treatments have failed. Approved by the Food and Drug Administration (FDA) in the 1970s to treat endometriosis, the modified testosterone drug danazol (Danocrine®) is currently used to treat a number of diseases off-label, including ITP. It is a synthetic androgen (male sex hormone) that disrupts the production of estrogen.1
Danazol is considered a second-line treatment for ITP, used after other treatments are considered or fail. In a small trial, 67 percent of patients achieved a partial or complete response, however severe adverse effects were seen in almost 20 percent of the participants.2 ITP patients may take three to six months to respond.3
Danazol is a pill given at a dose of 200 milligrams (mg), two to four times daily (10 to 15 mg/kg/d).
Because it is a male hormone, danazol can have a masculinizing affect in females, promoting unwanted hair growth, deepening of the voice and decreasing breast size. In men, it can affect sperm production.
Danazol can cause fluid retention, which could be a factor in those with other conditions exacerbated by increased fluid volume including coronary disease, kidney disease and migraines.4
Older females and those without a spleen may have a higher response rate.2
Danazol is not to be used in pregnant women, those about to become pregnant or women who are breastfeeding.4 Danazol is metabolized in the liver and can elevate liver enzymes. It should not be given to those with liver problems and liver function should be checked periodically.4
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Anti-Rho(D), or Anti-D (WinRho®) is an intravenous (IV) drug infusion used to elevate platelet counts temporarily, and can be repeated over a period of time for extended relief. Often used as a "first line" therapy, the shorter infusion time and often lower cost of Anti-D can offer an advantage over intravenous immunoglobulin (IVIG) for some patients.
Anti-D is a blood product consisting of antibodies to the RH factor on red blood cells. It has been shown to achieve a temporary rise in the platelet count in about 80 percent of people and occasionally has a longer-term effect. 1Anti-D products were first licensed in 1995 for the treatment of ITP, and are used in both children and adults.
Anti-D is made from human plasma derived from a limited list of donors in a special program that stimulates the production of high levels of antibodies. The antibodies from the donors are combined in batches that undergo a viral inactivation and micro filtration process using solvent/detergent to remove or deactivate disease-causing agents that can be transmitted through blood infusions.2
Following a treatment with Anti-D, the patient's RH-positive red blood cells link to the anti-D antibodies; the anti-body coated red blood cells are then removed in the spleen. Since red blood cells are eliminated, the process often causes mild anemia. However, it is usually successful in keeping the antibody-coated platelets of the ITP patient in circulation.
For the product to be safe and effective, the patient must be RH positive, have a spleen and not be anemic or deficient in immunoglobulin antibody (IgA), an antibody that plays a crucial role in the immune function of mucous membranes. Before administering anti-D, the ITP Consensus Report recommends doctors determine the patient’s blood group, complete a direct antiglobulin test (DAT) to check for antibodies against red blood cells that may already be present and perform a reticulocyte count to test the rate of red cell production.6
According to the package insert, the suggested dosing is 50 mcg/kg of body weight although some clinical studies report greater success at a 75 mcg/kg dose.3 Because the antibodies are concentrated, a treatment with anti-D requires less product and a shorter infusion time than IVIg. Premedication with paracetamol/acetaminophen, or corticosteroids is advised to reduce the risk of fever and chills.6
Side effects developed following seven percent of infusions and included headaches, chills, fever and body aches. A remote risk of anaphylaxis (shock response) exists for patients with hypersensitivity to blood products.4,5
A very small number of people receiving anti-D experience intravascular hemolysis, the destruction of red blood cells in circulation. This type of red cell destruction can cause anemia, multi-system organ failure, difficulty breathing, and even death. In December 2009, the FDA revised the WinRho SDF package insert to highlight these warnings and suggest additional tests and patient monitoring to better able to identify and treat those patients at risk.4
Patients should immediately report symptoms of back pain, shaking chills, fever, discolored urine, decreased urine output, sudden weight gain, fluid retention/edema and/or shortness of breath to their physicians.4,5
Anti-D can interfere with the efficacy of live virus vaccines, therefore the manufacturers do not recommend live virus immunizations within three months after an anti-D treatment.4,5
Maltose (a sugar produced by the breakdown of starch) in IVIG products, such as the liquid formulation of WinRho SDF, has been shown to give false high blood glucose levels in certain types of blood glucose testing systems. Only systems that are glucose-specific should be used to test or monitor blood glucose levels in patients receiving this product.4,5
WinRho SDF was voluntarily withdrawn from the European market in August 2009 due to safety concerns.7
As with any treatment, Anti-Rho (D) or Anti-D intravenous (IV) infusion has side effects. The key to getting the best results while minimizing adverse effects is working closely with your healthcare team. Here you will find a downloadable, printable document of helpful tips in decreasing the serious side effects of Anti-Rho (D) or Anti-D IV infusion. Discuss this information with your healthcare team prior to treatment.
Select a treatment table to view or download below.
After either failure to respond to first-line ITP treatments or maintenance of a very low platelet count with bleeding, platelet growth factors or thrombopoietin (TPO) receptor agonists are often considered. These agents stimulate the bone marrow to produce more platelets. TPO receptor agonists have been shown to reduce bleeding events, and the need for concomitant medications like steroids and rescue treatments by raising platelet counts. Once thought to be only a disease of platelet destruction, research advances have shown that many people with ITP also have a platelet production problem which is believed to be caused by the same antibodies and cells that attack the platelets.14 In these cases, they are thought to also attack the megakaryocytes (the cells that make platelets) in the bone marrow.15
Thrombopoietin (TPO) is a protein made in the liver. It is a natural stimulator of platelet production in the bone marrow. TPO receptor agonists (TPO-RA) bind to the same receptor on cells in the bone marrow just as when TPO is produced by the body. This prompts cells in the bone marrow to produce even more platelets, with variable responses depending upon many individual factors.
Types of platelet growth factors or TPO-RA, including: avatrombopag (Doptelet®), eltrombopag (Promacta®/Revolade®), and romiplostim (Nplate®) stimulate the bone marrow to produce more platelets. About 50-80% of people with ITP who receive treatment with platelet growth factors see an increase in their platelet count above 50,000 μL. This response is often sustained while on treatment for many.9,16
It is estimated that approximately 20% of individuals receiving a TPO-RA will be able to eventually discontinue these treatments while maintaining an elevated platelet count. The exact number of such individuals eventually able to discontinue treatment is unknown and especially it is unknown how frequently this will continue to occur as these agents are taken for more than 1-2 years.8,9 In general, the goal of these treatments is a platelet count above 50,000μL, not a normal platelet count.
The TPO receptor agonists avatrombopag (Doptelet®), eltrombopag (Promacta®/Revolade®), and romiplostim (Nplate®), are approved by the U.S. Food and Drug Administration (FDA) for adults with ITP who have either responded poorly or not had a sustained off-treatment response to at least one other ITP medical therapy. Eltrombopag and romiplostim are also approved for use in children with ITP; romiplostim is approved for a patient with ITP at any time starting at or soon after diagnosis. As of November 2019, avatrombopag is not approved for use in children with ITP. These TPO receptor agonists are available for use in many other countries with varying eligibility criteria to access them.
Another TPO receptor agonist, lusutrombopag (Mulpleta®) was approved by the FDA only for adult patients with liver disease and a platelet count less than 50,000 μL and require a short course of treatment in advance of a required surgical procedure of any kind, including advanced dental work. Since this drug is not used on a daily basis for treatment by those with ITP, we will not include any further information about this drug on this website at this time.
The most common adverse reactions reported with all three TPO-RAs include headaches, joint and muscle pain, dizziness, gastrointestinal issues, rash, flu, upper respiratory infections, and the potential for platelet counts to drop too low. There had been concern regarding bone marrow fibrosis, but extensive testing has demonstrated that this does not appear to be a clinically significant problem. The potential for platelet counts to drop too low after response to TPO agents if discontinued abruptly is the reason that small and slow changes in dose (tapering) is recommended when attempting to discontinue all agents.9
The most important serious adverse event is venous or arterial thromboembolism (blood clot). In long-term studies, this has been seen in 6-7% of patients using TPO-Ras.13 While venous thromboembolism (TEE) does not occur related to the platelet count, arterial thromboembolism, such as heart attack and stroke, may be related to the platelet count and may be more prevalent in the elderly.
Finally, with all agents there is a risk that malignant or pre-malignant cells in the bone marrow may respond to a TPO agent with progression to a more serious state.9
The International Consensus Report (2019) and the American Society of Hematology Guidelines for ITP (2019) both provide the most up-to-date clinical recommendations for who should consider TPO-RA therapy use.
Avatrombopag is a pill taken daily. While there are no dietary restrictions, it is recommended that the pill be taken with food in order to have its absorption (and subsequent blood levels) be more consistent. In June 2019 the FDA approved this drug for adults with ITP who had an insufficient response to a previous treatment; it had already been approved in April-May 2018 for patients who with chronic liver disease and thrombocytopenia scheduled to undergo surgery including minor procedures, regardless if the procedure is related to the liver. As of November 2019, avatrombopag is only available in the United States. There is very limited data on long term use of this drug in treating ITP or any condition, as it is still relatively new. Individuals with ITP receiving this drug will need to have their platelet counts monitored weekly until their count is above 50,000/μL, and then monthly thereafter. Platelet counts must be measured for at least four weeks following discontinuation of avatrombopag.22
Avatrombopag is a pill that is taken with food. Dosing ranges depend on how an individual’s platelet count responds to the drug. The recommended starting dose is 20 mg once a day (this dose is referred to as a level 4 dose). The dose, or frequency of dosing, can be adjusted to reach and maintain a safe platelet count of at least 50 000/μL. Do not exceed 40 mg per day.
If an individual using avatrombopag cannot reach a platelet count of at least 50,000/μL after four weeks at the maximum dose of 40mg per day (level 6) (or if the platelet count is higher than 400,000/μL) the drug should be tapered and discontinued. In some cases, an individual who achieves a platelet count of 20-40,000/μL on 40mg daily and even this level cannot be achieved by another acceptable treatment, then treatment may be continued following discussion between the patient and the health care provider.22
Individuals taking other medications may need to follow a different dosing regimen.
As of November 2019, there are no specific side effects unique to avatrombopag.11 Issues such as the exact risk for thrombosis and marrow fibrosis in particular have not yet been established.9 Unique to avatrombopag is the potential for side effects such as bleeding that can mimic ITP including petechiae, bruising, nosebleeds and bleeding from the gums.4,11
Eltrombopag is a pill taken daily with important dietary restrictions. The drug gained FDA approval in November 2008 for use in adults with ITP who have not shown a significant response to at least one other ITP treatment. For example, a non-significant response could include patients who achieve a high platelet count only for a very short period following IVIG or patients receiving high dose daily steroids but with very low platelet levels. Eltrombopag received FDA approval in June 2015 for treatment of ITP in children between the ages of 1-18 years.
This drug should not be used by those with a pre-existing liver disease (or risk of worsening liver disease or clotting too much); liver tests should be monitored throughout treatment. This drug should also not be used by individuals with myelodysplastic syndrome (MDS) as there could be a risk of progression to leukemia.
Individuals with ITP receiving eltrombopag will need to have their platelet counts monitored weekly until their count is above 50,000/μL, and then monthly thereafter. Platelet counts must be measured for at least four weeks following discontinuation.21
The pill is given as a 25, 50 or 75 mg (milligram) daily dose. The recommended starting dose for adults and children over 6 years is 50 mg. It must be taken on an empty stomach as food affects the absorption and the presence of calcium or iron will inactivate the drug. The ideal recommendation therefore is to not eat at all for 2 hours before AND for 2 hours after taking eltrombopag. In particular, however, dairy and broccoli and other calcium or iron rich foods should be avoided even longer before and after eltrombopag. Individuals with ITP who are of Japanese heritage may require a lower starting dose.9 Children between the ages of 1-6 years should begin with a lower dose of 25mg per day dose.9,18
After two weeks, if a platelet count of at least 50,000 μL has not been reached and the time and way of taking eltrombopag reviewed with the hematologist, the dose can be increased (not more often than every 2 weeks) by 25mg per day up to a maximum daily dose of 75mg per day.
If after two weeks from starting eltrombopag the platelet count is between 200,000μL - 400,000μL it is recommended to reduce the dose by half or by 25mg/day. If platelet counts do not increase to at least 50,000 μL at the maximum dose after one month, eltrombopag should be tapered and discontinued.
If an individual achieves a platelet count of 20-40,000μL on 40mg daily and this level cannot be achieved by another acceptable treatment, then treatment might continue following discussion with an appropriate health care provider.
If the platelet count reaches above 400,000μL, eltrombopag should either be temporarily discontinued for one week, or the dose can be reduced by 25mg daily. Once a dose change has been made further change should not be instituted for at least 2 weeks until a new equilibrium has been reached.21 (Complete prescribing information)
Eltrombopag is well-tolerated with minimal adverse effects reported. Side effects include the low potential risk for hepatic toxicity (liver damage) and transaminitis (high levels of certain liver enzymes).2,3,5,6,10 The risk of cataracts has not been clarified yet.7,9 Less than 2% of patients have reported the development of skin rashes and troublesome diarrhea.19
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Romiplostim is a manufactured so-called peptibody (part small protein and part antibody) liquid that is given through weekly subcutaneous (under the skin) injections. In August 2008 the FDA approved romiplostim for adults with ITP who have failed at least one other treatment for the disease at any time starting from diagnosis.3 It received FDA approval in December 2018 for children over a year old with ITP who haven’t had success with corticosteroids, IVIG, or splenectomy.
This drug should not be used in individuals with myelodysplastic syndrome (MDS) in patients with a low platelet count due to a secondary condition.
Individuals with ITP receiving these injections will need to have their platelet counts monitored weekly, and then monthly once a stable platelet count of 50,000/μL has been reached. Platelet counts must be measured for at least two weeks following discontinuation.20
Romiplostim is given as a weekly injection. The recommended initial injection dose each week for both adults and children is 1mcg/kg (microgram/kilogram), however this may be too low for many individuals. In some clinical settings, a starting dose of 3 mcg/kg is used instead.
From there, dose increases depend on platelet count response and weight. Children need to be weighed before each dose, however adults only need to be weighed before the first injection unless a change in weight has occurred. If after two weeks a platelet count of at least 50,000/μL has not been reached, the dose can be increased by a minimum of 1mcg/kg per week up to a maximum weekly dose of 10mcg/kg.
If after two weeks from starting eltrombopag the platelet count is between 200,000/μL - 400,000/μL for at least two weeks, it is recommended to reduce the dose by 1mcg/kg. If platelet counts do not increase to at least 50,000/μL at the maximum dose after a few weeks (or the platelet count reaches above 400,000/μL) the drug is discontinued.
If an individual achieves a platelet count of 20-40,000/μL on romiplostim and this level cannot be achieved by another acceptable treatment, then treatment might continue following discussion with an appropriate health care provider.
If the platelet count falls below 200,000/μL romiplostim injections can resume at a 1mcg/kg reduced dose. It is important not to change the dose too much too quickly as this can lead to the platelet count cycling. When discontinuing these treatments, experienced health care providers reduce the dose gradually to avoid a sharp drop in the platelet count.20 (Complete prescribing information)
Romiplostim is well-tolerated with minimal adverse effects reported. Side effects include the low potential risk of developing neutralizing antibodies to the treatment, reducing an individual’s response to the drug, thus affecting the platelet count.1,12,13,16,17 These antibodies are more frequent in children with chronic ITP.9
Since these treatments can be expensive for patients depending on insurance, the manufacturers of avatrombopag (Doptelet®), eltrombopag (Promacta®/Revolade®), and romiplostim (Nplate®) have established programs to assist those in the United States who are uninsured or who cannot afford the insurance co-payments. All of these programs endeavor to make each of the treatments accessible to all patients, but each is different and require each individual patient to contact and work with each group to make this happen.
See PDSA’s educational booklet Health Insurance and Assistance Programs for ITP Patients for more helpful information.
Since these treatments stimulate thrombopoietin (TPO) production, individuals with ITP who have high TPO levels on their own may not benefit. In one study, patients with TPO levels greater than 95pg/mL (picogram per milliliter) did not respond well to the TPO agents. Some laboratories offer a test to measure TPO levels, however this approach is not standard practice as of November 2019. Patients with higher levels of reticulated platelet (newly made platelets) responded better to TPO agents.14
About 50-80 percent of people with ITP who receive treatment with platelet growth factors respond with an increase in platelet count (depending upon the definition of such an increase, usually 50,000/uL) often sustained for as long as the treatments are given. Furthermore, it is estimated that approximately 20% of individuals receiving a TPO are able to eventually discontinue these treatments while maintaining a safe platelet count; the true number of such people eventually able to discontinue treatment is unknown, especially as TPO agents are becoming more frequently used past one or two years. In general, the goal of these (or any) treatments is a platelet count over 50,000/uL, not a normal platelet count.2,9,11,13-16 This stable platelet count is more than enough to achieve all of the benefits desired by patients, allowing them to live a more normal life and minimizing worry over a low platelet count and ITP’s accompanying side effects.16
Select a treatment table to view or download below.
The most common B-Cell Lymphocyte Depletion Therapy used to treat ITP is the intravenous infusion drug rituximab (Rituxan® and MabThera®). Known as a monoclonal antibody, rituximab was approved by the Food and Drug Administration (FDA) in 1997 for use in the treatment of mild cases of B-cell non-Hodgkin Lymphoma (NHL), a type of cancer, and in 2006 for rheumatoid arthritis.1 Other anti-CD20 treatments, including veltuzumab, an oral pill version, are in clinical trials.9
The major goal of B-Cell Depletion Therapy is to destroy malignant B lineage cells or autoimmune disease-producing B cells in patients with cancers or autoimmune diseases, while at the same time retaining protective B cell immunity.
Rituximab has been shown to reduce the number of B cells in your body—type of white blood cell that, when activated, multiply and produce antibodies. Antigens trigger antibody production. An antigen and antibody fit together like a key in a lock. When an antigen lock (in this case CD20) and antibody key (anti-CD20 in rituximab) join in a B cell, the body eliminates the complex since the B cell's work is assumed to be done.
Since rituximab reduces the number of B cells that contain CD20, it reduces the total number of cells that produce antibodies. This may include the antibodies that attach to platelets. There is also evidence that rituximab alters T cells, another type of white blood cell, and that this may be the reason rituximab raises the platelet count of some patients with ITP.5
The short-term response rate for rituximab is about 60 percent. Approximately 25 percent of patients achieve a longer-term (five year) rise in platelet count.6,10 To enhance the response, rituximab is sometimes used in combination with dexamethasone (a corticosteroid similar to prednisone) in newly diagnosed patients.11 It can also be repeated with some success in those people who initially responded.12
Rituximab can be given before or after a splenectomy, or surgical removal of the spleen. However, systemic infection is a concern,8 especially when it is used in combination with other therapies that suppress the immune system. Because rituximab removes the cells involved in immune memory, vaccines are not always effective.13
Note: The B cells that are eliminated are not specific B cells that target cancer or ITP. Rituximab reduces the general population of all B cells that include CD20. It could take up to nine months for someone to replace those B cells and have their immune system and antibody production (including the helpful antibodies) back in working order.
Rituximab can also activate hepatitis B or C. It is important your doctor checks for antibodies to these diseases before beginning the treatment.
The usual dose of rituximab for patients with ITP is 375 mg/m2 once weekly for four weeks, the same regimen used for NHL patients. In some small trials, lower doses have been shown to be as effective as the higher dose in raising platelet counts.3,4
Rituximab is to be given only as an IV infusion, not an IV push or bolus. Patients with pre-existing cardiac and pulmonary conditions or who experienced cardiopulmonary adverse events in the past need to be closely monitored.2
The manufacturer recommends premedication with acetaminophen (Tylenol®) and an antihistamine (such as Benadryl™) before each infusion.2
About 77 percent of patients experience reactions including fever, chills, weakness, nausea and headaches with the first infusion of rituximab. These reactions often decrease with subsequent doses.2 While rituximab can prompt serious, sometimes fatal, infusion reactions, these usually occur from 30 to 120 minutes after administering the first dose.2 An allergy-type reaction called serum sickness can occur from seven to 21 days after a treatment. In a review of published studies about three percent of ITP patients treated with rituximab had become extremely ill or died.6
"Physicians who are thinking about treating a patient with Rituxan for any condition should tell their patients about the chance of PML [progressive multifocal leukoencephalopathy] because there is no effective treatment for the disease."7,14
Rituximab can also reduce IgG (antibody) levels on very rare occasions. The reduced IgG levels may appear months after the infusions and be long-lasting. The authors of a study recommend an IgG level test before beginning rituximab and periodically after the treatment.17
There have been few studies that give us clues about predicting the success of rituximab for treating ITP. In one study, children who responded to steroids had a better response to rituximab.15 In a separate study, people with the FCGR3A V/V genetic type were more likely to respond to rituximab. Those who had very high levels of CD8 (proteins that work with T-cells) didn't respond despite a drop in anti-platelet antibodies.16
Select a treatment table to view or download below.
Intravenous immunoglobulin (IVIG) is a type of antibody treatment used as a “front line” therapy to temporarily elevate platelet counts.
IVIG is a solution of IgG (immunoglobulin G) antibodies normally present in adult human blood.1 IgG antibodies are extracted from the combined plasma of more than 1,000 screened donors and treated to eliminate bacterial and viral contaminants. It is used to treat immune deficiency and many other conditions on-label and off-label.1
Different companies manufacture IVIG and each brand has slightly different features and side effect profiles. The Immune Deficiency Foundation Chart provides more information.
- What Patients Need to Know About Plasma
- Alternative Treatments to IVIG in ITP Patients
IVIG is given intravenously for a period of several hours. There are two different dosage options: .4 grams (g) / kilograms (kg) per day for five days, or infusions of 1 g/kg per day for one to two days. The higher-dose, shorter-term administration leads to a more rapid rise in platelet count, but higher toxicities.3
The most common side effects of IVIG include: headache, fever, chills, nausea or vomiting, muscle pain or chest pain. Fortunately, slowing down the rate of infusion can help eliminate these problems or decrease their severity. Premedication with acetaminophen, antihistamines or occasionally steroids can also help decrease side effects.4
Rare and more serious side effects include: blood clots8, hemolytic anemia, pulmonary edema and aseptic meningitis syndrome.5
Patients who are IgA (immunoglobulin A) deficient have a greater chance of developing anaphylactic shock.1 IVIG can cause renal dysfunction and renal failure, especially with preparations that are very concentrated or have a high sugar content.9
As with any treatment, IVIG infusion has side effects. The key to getting the best results while minimizing adverse effects is working closely with your healthcare team. Here you will find a downloadable, printable document of helpful tips in decreasing the serious side effects of IVIG infusion. Discuss this information with your healthcare team prior to treatment.
IVIG temporarily increases the platelet count in about 80 percent of ITP patients.2 The duration of the response varies and the treatment can be repeated when the platelet count drops.
IVIg does not work very well for those ITP patients who have anti-GPIbalpha antibodies on their platelets.6,7
Select a treatment table to view or download below.
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IMPORTANT!
The Platelet Disorder Support Association does not provide medical advice or endorse any medication, vitamins or herbs. The information contained herein is not intended nor implied to be a substitute for professional medical advice and is provided for educational purposes only. Always seek the advice of your physician or other qualified healthcare provider before starting any new treatment, discontinuing an existing treatment and to discuss any questions you may have regarding your unique medical condition.
