PDSA E-News: August 31, 2022

Comparison of Rituximab Response in Adults with Difficult to Treat ITP Due to the Presence of an Accessory Spleen

Doctors with patient in exam roomThis study is among the few to examine how the presence of an accessory spleen affects the response of adults with chronic ‘refractory’ ITP to rituximab, a monoclonal antibody treatment. An accessory spleen is a collection of splenic tissue that is separate from the main organ. Approximately 10% of individuals in the general population have an accessory spleen. They can arise during normal development or can be released from the spleen after trauma and can be difficult to detect. They can also grow from splenic tissue left behind following splenectomy.

A total of 15 adult patients with chronic and ‘refractory’ ITP who had a previous splenectomy were included in the study and were followed for up to 96 weeks. Participants were excluded from taking part in the study if they had severe infections, heart failure, were pregnant, or had active hepatitis B. As part of the study, each participant was given 375 mg/m2 of rituximab each week for four weeks. A spleen scintigraph (a nuclear scanning procedure where radioactive dye is injected so images can be taken of the spleen) was performed on each participant before rituximab treatment.

Results revealed that 5 out of the 15 participants had an accessory spleen before starting rituximab. Participants with an accessory spleen were more likely to be older when they received a diagnosis if ITP, although there was a wide range of ages (25-68 years). Participants with an accessory spleen were also more likely to use rituximab at an older age than those who didn’t have an accessory spleen, although again, there was a wide age range (between 43-75 years compared to 30-60 years). Comorbid disorders (the presence of additional health concerns) were more prevalent among those with an accessory spleen, compared to those without one however, likely due to the small sample size, this difference was not significant (on statistical analysis.

Participants with an accessory spleen appeared less likely to have a quick (or early) response to rituximab, defined as a platelet count response within 42 days. However, this difference in early response was not statistically significant. Late responses (a platelet count response occurring 42 days or later following rituximab) was lower in the accessory spleen group; this difference was also not statistically significant. No significant differences however, in terms of sustained response (response lasting at least 6 months), were observed between patients with and without an accessory spleen. Overall, the majority of patients without an accessory spleen and half of patients with an accessory spleen lost their response to rituximab; thus, there appeared to be a small relationship between the presence of accessory spleen and the rate of loss of response to rituximab.

The authors concluded that adults with chronic ‘refractory’ ITP who relapse following a splenectomy should be evaluated for the presence of accessory spleen. Additional patients will need to be studied to determine if detection of an accessory spleen should influence subsequent therapy.



Comments from PDSA’s Medical Advisors:

The general consensus on splenectomy for ITP is that four out of five patients will respond initially; however, one of the four responders will relapse, usually within 2 years or less. Long term side effects of splenectomy are better characterized than they were 5 years ago in regard to risk of thrombosis. Uncertainty remains as to which patients are optimally managed by splenectomy. As a result, in some places, splenectomy remains a common clinically and cost-effective treatment option and in other settings it is not commonly used. The 2019 ASH guidelines recommend waiting for 1 year from diagnosis of ITP before considering splenectomy. In some patients who undergo splenectomy, a small bit of splenic tissue may remain after surgery and, over time, may increase in size. This can either be because a small so-called “accessory spleen” was not seen at surgery and not removed OR if in the course of surgery, a small amount of tissue is left behind. Even after many studies, the value of seeking and removing an accessory spleen remains controversial.

One viewpoint is that if your platelets respond to splenectomy but then you relapse, the relapse might be caused by an accessory spleen. In this setting it might be good to remove it. On the other hand, if a patient with ITP has their spleen removed and does not respond to the surgery, it may be unlikely that removing an accessory spleen will help the ITP. However, there are a few studies looking at the impact of an accessory spleen on response to treatment in those who relapse after splenectomy. To complicate matters, Marchese et al. (2019) reported that ‘younger age poses risk for failure to radiologically identify an accessory spleen and that that rate of detection for an accessory spleen increases with age’.

This study explores how well rituximab works in patients after a “failed” splenectomy in regard to whether or not the ITP patient has an accessory spleen or not. The study involves too few patients to draw important management decisions concerning the use of rituximab after splenectomy, but it does NOT support an important effect of having an accessory spleen in the response to rituximab. Overall, this study does not appear to be practice changing either about rituximab or about whether or not to remove an accessory spleen if one is found.

Diagnosis Immune Thrombocytopenia (ITP) Including Secondary ITP, and Selection of Second Line Therapy

Doctor with patient in officeThis study uses two case examples involving adults with ITP to highlight the benefits of selected treatments with special considerations for pregnant and ‘refractory’ patients and when to consider secondary ITP.

Case 1: A 20-year-old female began to experience heavy menstrual bleeding and unexplained bruising coupled with petechiae. She also had mild anemia with a low MCV (a test that measures the size and volume of red blood cells often used to assess iron deficiency) and a platelet count of 5,000L. Her liver, spleen, and lymph nodes were normal in size. Examination of her blood cells under a microscope revealed large platelets. A diagnosis of ITP was made, and she was started on prednisone (1mg/kg) and iron supplements. Her bleeding resolved, her hemoglobin improved, and her platelet count and MCV normalized.

Insights gained from her response to prednisone:

  • Achieving a normal platelet count on prednisone is strong evidence supporting the diagnosis of ITP. The fact that the MCV improved as well suggests the low MCV was due to bleeding leading to iron deficiency.
  • These responses help to exclude an underlying bone marrow failure syndrome, as well as the inherited disorder thalassemia trait, or any of potentially serious causes of microangiopathic hemolytic anemia in which red cells are fragmented in the circulation.
  • Evans syndrome is a more severe autoimmune disease with antibodies not only to platelets but also to red blood cells. A clinician would have to consider this in this patient with low platelets and anemia, but the small red cell size would suggest this is not Evans. A simple test to see if there are antibodies on red cells (a DAT, direct antiglobulin test) will clarify this.

Over the next few months, her platelet counts decreased while tapering prednisone and mild bleeding symptoms returned. Therefore, second line therapy options were explored. The absence of any other symptoms, sign on physical examination or other abnormalities on laboratory testing means there is somewhat less of a concern that she has a secondary ITP (meaning ITP that accompanies another condition) but this possibility must be kept in mind.

Additional considerations for ITP patients who do not show an improvement in hemoglobin:

  • A B12 or folate deficiency, thrombotic thrombocytopenic purpura (TTP), or hemolytic uremic syndrome (HUS) could be investigated if anemia persists. In these cases, there may also be elevated reticulocytes (red blood cells immature in development yet). Additional clinical and laboratory features would be evident in patients with these disorders
  • Pending having a good platelet count, hormonal therapy (especially progesterone based) may reduce (in some women) the heavy menstrual bleeding and elevate the hemoglobin.
  • Immunoglobulin analysis (for an immune deficiency) and an ANA (test for Lupus and similar autoimmune disease) are useful.
  • Screening for viruses that could impact treatment and ITP such as H. pylori (in certain places), HIV, and Hepatitis B and C could be considered.

An inherited thrombocytopenia is much less likely if there is an improvement in platelet count due to corticosteroids.

Case 2: 63-year-old male taking medications for blood pressure and cholesterol health developed bruises and petechiae and significant bleeding from his gums when brushing his teeth. He had minimal other complaints and an otherwise unremarkable physical examination. His platelet count was 8,000, but the remainder of his CBC was normal as was his blood smear. A tentative diagnosis of ITP was made. He stopped taking his baby aspirin and received a short 4-day pulse treatment with dexamethasone (40mg/day) and one round of IVIG. His platelets increased dramatically to well over 50,000, but only for a short time. He tried avatrombopag with limited success and then opted for rituximab. He responded to a platelet count of 60,000, but then his platelet counts decreased after 4 months. After adding a third-line agent, mycophenolate mofetil (MMF), his platelets remained stable around 40,000-50,000.

  • The robust response to “ITP-directed” therapies such as corticosteroids and IVIG is reassuring but does not exclude secondary causes such as immunodeficiencies. More aggressive treatment should be considered in older ITP patients as their overall risk to develop and intracranial hemorrhage is higher than in younger adults. There is a tricky balance, however, due to more toxicity of Rx in elderly.

Things to consider in both case examples if first- or second-line therapies are ‘not working’:

  • Ensure ITP is the correct diagnosis. A bone marrow biopsy might be indicated to help exclude other causes of a low platelet count but other blood testing for alternative diagnoses is imperative.
  • Some patients who did not respond to one TPO-RA may respond to another e.g., try romiplostim or eltrombopag since avatrombopag did not work well. TPO-RA are thought to be optimal for more elderly patients.
  • In young women, rituximab may be a very beneficial treatment, but it will prevent response to a COVID vaccine for up to one year. This not only refers to initial vaccination but also to receipt of booster vaccination. This has led to a reduced use of this treatment.
  • If a single therapy isn’t working well, it can be helpful to add an additional therapy such as MMF. combination therapies can be more effective and permit lower doses of each agent to be employed.
  • Remain vigilant for evidence of other underlying diseases (e.g., infections, immunodeficiencies) that are associated with secondary forms of ITP and for drug-induced thrombocytopenia.

For the risks and benefits of possible second line treatment options, a review on upcoming new therapies, and the treatment of refractory and pregnant individuals in various age-groups, please click on the link below to read the full article.



Comments from PDSA’s Medical Advisors:

The comprehensive comments above summarize well the management of potentially difficult patients.
Optimal care is a mix between art and science. On the one hand, care must be individualized in many ways. If a patient does well with second line treatment, usually only monitoring will be required but relapses occur and knowing what to expect is integral to monitoring. An example is long-term response to Rituxan that may last a year but then falter. The article tries to pick a number of contingencies that might affect management. The role of fatigue or otherwise impaired health-related quality of life is an entire other discussion, but nonetheless affects a high percent of patients with ITP and may drive further investigation into cause because successful non-toxic treatment can be extremely important to affected patients. Of note, some have been feeling bad for so long that they do not remember what it feels like to feel normal and thus falsely answer “fine” when queried by their physician.



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