PDSA e-News: October 29, 2019

Illustration of spleen in the bodySplenectomy in the context of new medical therapies for ITP

This retrospective study focused on 84 adult ITP patients from a single center recruited over 23 years (from 1994-2017) who underwent a planned (elective) or unplanned in hospital (nonelective) splenectomy to determine efficacy. The majority of participants in the study had their splenectomy performed laparoscopically (small abdominal incision) and had used approximately three different medical therapies before their splenectomy.

Results revealed 83.5% had a complete response to the surgery, defined as having a platelet count over 100, 000L without any bleeding episodes. 7.6% had a partial response where their platelet count after surgery was between 50, 000/μL – 100,000/μL without any bleeding events. 8.9% had no response to the splenectomy and had a platelet count of less than 50,000/μL or continued bleeding events. Transient responses were also observed and referred to an initial response with a quick loss of response before the follow-up period following the splenectomy. A loss of response to the splenectomy was observed in 19% of those who had a complete response, defined as a platelet count that dropped to less than 50,000/μL and/or had bleeding episodes that returned after initially showing a complete or partial response to the surgery over a period of time. A loss of response was more likely if the initial platelet count was very low at the time of diagnosis. The serious complication rate was 2.4% which is less than the reported complication rate following medical therapies used before the splenectomy was performed.

Those who had a complete sustained response were less likely to have a loss of response, and more likely to have had a response to past medical therapies for ITP, particularly steroids (less likely to be refractory). They were also less likely to have an accessory spleen.

Comment from PDSA medical advisors:

Authors of this study provide a contemporary analysis of the outcomes of splenectomy in adults with ITP. Over the past 20 years, the use of splenectomy has dramatically decreased. The reasons are many, but I believe the decrease is primarily because patients prefer not to undergo splenectomy when there are now a number of improved medical treatments: thrombopoietic agents like romiplostim/nplate and eltrombopag/promacta and avatrombopag/doptelet, Rituxan/rituximab, and fostamatinib/tavalisse. Thus, the need for urgent splenectomy and willingness of patients to undergo the procedure has decreased sharply. This has led to fewer splenectomies being performed, restricted use of this procedure to the most severely affected patients (often after a protracted course of multiple medical approaches), and less training of surgeons in performing splenectomy in patients with ITP with very low platelet counts.

In this study, splenectomy was deemed urgent in over half of the patients because of persistent bleeding or “dangerously low” platelet counts in the face of “maximal medical therapy.” A laparoscopic approach to splenectomy was feasible in almost all recent patients. The long-term risks of infection and thromboembolism after splenectomy are very real, but must be balanced with the equally real risks of protracted medical interventions especially (but not only) if they include corticosteroids or immune suppression. It is reassuring that the high initial and persistent response rates and low incidence of surgical complications reported with splenectomy in this paper are comparable to those previously reported in patients with better controlled disease who underwent elective splenectomy.

There is a big piece which is “unknown” and makes assessment of the appropriateness of splenectomy very difficult. It is increasingly recognized that a fraction of adults who are diagnosed with ITP will improve within one year from diagnosis and no longer require treatment. Selecting which adults this will be and knowing what the fraction is remain something of a mystery. Clearly better responders to initial treatment and those with milder disease are more likely to improve so that treatment is not indefinitely required but this is far from certain in any given individual. Furthermore, whether the fraction who improve is really 20% or 50% is remarkably uncertain after all this time. The idea that certain patients will improve is the reason that both the ASH Guidelines and the International Consensu Report recommend waiting for one year from diagnosis if possible in case it turns out that an approach to “cure” (splenectomy) is not actually required.

It is disappointing that there is not a better path to lasting improvement with treatments other than splenectomy. The high hopes for rituximab ended up not being fulfilled. While there is a basis for thinking that adolescent females and women of child-bearing age do better in terms of cure with this agent, overall it has not been as successful as hoped for. There continues to be exploration of other agents to combine with it but this is for the future.

Overall, it is important for hematologists and their patients to be reminded periodically that splenectomy is both feasible and is associated a high durable response rate in most patients with ITP without undue long-term side effects. As described in two articles in 2018 (the title of one was “Splenectomy: Down but not Out”) splenectomy is a reasonable option to pursue if ITP has persisted for one year and does not look like it is improving to the point that treatment may no longer be required in the future. While this article does not provide remarkable new information, it does confirm past studies of the utility of splenectomy in patients with chronic ITP.



Nplate bottlesNplate® (romiplostim) now approved for earlier use in adults with immune thrombocytopenia

The U.S. Food and Drug Administration (FDA) recently announced that the thrombopoietin receptor agonist (TPO) romiplostim has now been approved for earlier use in adults with newly diagnosed and persistent ITP. The approval is based on results from an open-label single-arm Phase 2 clinical trial that assessed the efficacy and safety of romiplostim in adults diagnosed with ITP for less than six months who had an insufficient response to first line therapy, including corticosteroids. Insufficient response is defined as not achieving a platelet count of at least 30,000 μL. The majority of patients enrolled had ITP for at least two months. Results revealed romiplostim increased platelet counts significantly in 93% of adult patients with a low risk of significant adverse effects. Common side effects reported included headache, dizziness, diarrhea, upper respiratory tract infection, cough, nausea and oropharyngeal pain. 2% experienced thrombocytosis (too high of a platelet count). Results also revealed that one third of adult patients who received romiplostim after they failed to respond to corticosteroids sustained an elevated platelet count above 50,000 μL for at least six months without any additional therapies required. Access to this drug earlier within an individual’s ITP journey means that there is hope for longer intervals of time with safe higher platelet counts, and less exposure to adverse reactions from prolonged corticosteroid use.

Comment from PDSA medical advisors:

What does this mean? A little background first. ITP is divided by the time since diagnosis of ITP into the following divisions:

a) Newly Diagnosed: from time of diagnosis until 3 months later
b) Persistent: 3 months to 12 months from diagnosis
c) Chronic: after 12 months from diagnosis

Treatments licensed for ITP since Romiplostim (8/08) and Eltrombopag (Promacta, Revolade) (11/08) have been licensed for chronic ITP in patients who previously “failed” at least one prior treatment. This now includes the more recently licensed treatments i.e. Fostamatinib (Tavalisse) and Avatrombopag (Doptelet).

As physicians and patients have become more comfortable with the use of TPO agents, they have been introduced earlier and earlier in treatment, i.e. before waiting 12 months from diagnosis. This is consistent with two trends in ITP treatment. First, the ASH Guidelines and the International Consensus Report both recommend not using steroids for more than six weeks, meaning that steroids should not be relied upon in patients with persistent ITP still needing treatment. Second, the ASH guidelines also recommend not doing splenectomy until at least one year from diagnosis, i.e. in patients with chronic disease. Therefore, by inference, second line agents such as TPO agents and rituximab are recommended for patients with persistent ITP.

In 2016 a group of physicians lead by Adrian Newland in London published a study in which romiplostim was used before patients met criteria for chronic disease. Specifically, they treated 75 adults with ITP in the “early” persistent phase of the disease with romiplostim following the dosing recommendations in the package insert. No one could be treated for more than one year. They discovered that 32% of the patients (~1/3) could slowly discontinue romiplostim and not require any additional treatment to prevent bleeding. Based on these results and considerable emerging experience and safety data, the FDA has just approved “early use” of romiplostim. This means that romiplostim (Nplate) has been approved for use in patients with persistent ITP (ITP of more than 3 but less than 12 months since diagnosis) who have failed one prior line of therapy, such as corticosteroids.

This is very exciting. The initial approval restricting the use of romiplostim to patients whose ITP was of more than 12 months duration meant that an insurance company could reject approval for this treatment or make it difficult to get approval prior to this time. In practice this only happened sometimes, but it nonetheless was and could be a barrier to patient access. This is no longer true for romiplostim based on this new approval.

It is not clear how many ITP patients treated with romiplostim (or eltrombopag or any other treatment) will be able to discontinue therapy. Nor is it clear how long romiplostim (or any other treatment) must be taken until discontinuation is possible. Although it could take from 3-6 months to 3-10 years, it appears that life-long treatment with TPO agents may NOT be required in all patients. Additional studies are needed to more clearly establish the long-term outcomes of treatment with TPO agents and, if possible, to identify when and in whom therapy can be discontinued.




Special Thanks to our e-News Sponsors:
Amgen logoNovartis logo



back to top

Charity NavigatorGuideStar Seal NORD Member Badge 2021THSNA logo