Burden of immune thrombocytopenia (ITP): Special considerations for refractory ITP

Summary

It is known that patients with immune thrombocytopenia (ITP) have fatigue and impairment of health-related quality of life (HRQoL). However, it is hypothesized that patients with refractory ITP have additional burdens that should be considered. Specifically, fatigue is more pronounced in patients with refractory disease, there are additional side effects from second- and third-line treatments, additional anxiety about the long-term course of the disease, impairment in HRQoL resulting from heavy menstrual bleeding and concerns related to family planning. The burden of disease, therefore, should be carefully assessed and considered in these patients. However, researchers have utilized numerous tools for evaluating HRQoL and fatigue, making comparison of data across studies challenging. There is a need to standardize assessment using either disease-specific or generic instruments that can be easily implemented in routine clinical practice. Additionally, whether treatment of low platelet count and bleeding symptoms will have a positive influence on HRQoL remains to be seen and published evidence is conflicting. Nevertheless, improvement of HRQoL is a major treatment goal for both patients and physicians and should be especially considered when treating patients with refractory ITP.

Graphical Abstract:

Patients with refractory immune thrombocytopenia have additional burdens that need to be considered. This patient burden includes an impaired health-related quality of life, additional side effect concerns related to second and third-line treatments, anxiety about the long-term course of the disease, fears related to family planning, and it is hypothesized that fatigue is more pronounced in patients with refractory disease. The burden of disease therefore should be carefully assessed and considered in these patients. There is a need to standardize assessment using either disease-specific or generic instruments that can be easily implemented in routine clinical practice.

INTRODUCTION

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by isolated thrombocytopenia due to premature platelet destruction and decreased platelet production in the absence of other causes or disorders that may be associated with thrombocytopenia.¹ Studies have reported that patients with ITP have reduced work productivity and were more likely to take sick leave from their jobs compared to age–sex matched controls.² Patients may also suffer from fatigue as one of the most debilitating aspects of their disease, and health-related quality of life (HRQoL) can be severely impaired by ITP.^3,4

Studies have reported that improvement of fatigue and impaired HRQoL is one of the most important treatment goals for both medical doctors and patients with ITP.⁵ However, assessment of fatigue and/or HRQoL is rarely systematically undertaken at diagnosis or in the clinical course of ITP despite valid disease-specific instruments. Another challenge is that fatigue is by no means specific for ITP and therapeutic options are—provided that ITP is the only cause for fatigue—limited even with new treatment strategies.

Persons with refractory ITP have additional concerns related to the impact of ITP on their lives. For example, HRQoL is severely impaired due to bleeding risks and symptoms requiring adaptations in the activities of daily living. It is also hypothesized that the issue of fatigue is even more pronounced in patients with refractory ITP. Other considerations specifically for persons with refractory disease include the impact of side effects from second- and third-line treatment, anxiety about the course of the disease, the necessity of further treatment and concerns related to family planning.⁶ There is unfortunately no agreement on the definition of refractory ITP. The International Working Group (IWG) defined refractory ITP as disease that does not respond to or relapses after splenectomy—requiring treatment to reduce the risk of clinically relevant bleeding.⁷ For the purpose of this article, refractory ITP was defined as patients with ITP requiring at least second-line treatment as the treatment goal was not achieved with prior treatment or defined as chronic ITP in need for disease-directed therapy. The focus of this article was the impact of refractory ITP on the patients’ burden of disease.

CURRENT PATIENT REPORTED OUTCOME INSTRUMENTS UTILIZED IN ITP

Studies assessing the burden of disease on patients with ITP have used multiple instruments. Here, we will highlight a few of the more common instruments, recognizing that this list is not comprehensive (Table 1).

TABLE 1.

Overview on studies assessing the burden of ITP cited in the article.

Reference	Name	Patient population	Characteristics of the study
Klaasen et al.8	Kids’ ITP Tools (KIT)	Children/adolescents 2–17years	- ITP disease specific - Three questionnaires (child 7–17 years; parents on behalf of a child aged 2–17—parent proxy; parents—parent impact)
Mathias et al.9	ITP-Patient Assessment Questionnaire (ITP-PAQ)	Adults ≥18 years	- ITP disease specific - 44 items, six domains
Cooper et al.10	ITP Life Quality Index (ILQI)	Adults ≥18 years	- ITP disease specific - 10 items
Ware et al.12	Medical Outcome Study 36-Item Short Form Survey (SF-36)	Patients ≤14 years	- Generic—to be used in any disease - 36 items, eight domains
Varni et al.13	Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL MFS)	Children/adolescents 2–18years	- Generic—to be used in paediatric cancer - Three domains - Children self-report (5–18 years); parent proxy report (2–18 years)
Grace et al.14	Hockenberry Fatigue Scale; Fatigue Scale-Child, FS-C; Fatigue Scale Adolescent, FS-A	Children/adolescents 7–17	- Generic - 10 items for FS-C (7–12 years) - 13 items for FS-A (13–17 years)
Fisk et al.15	Fatigue Impact Scale (FIS)	n/a	- Generic - 40 items, three domains
Smets et al.16	Multidimensional Fatigue Inventory (MFI)	n/a	- Generic - 20 items, five domains

There are valid, ITP-specific patient-reported outcome (PRO) tools available for use. The Kids’ ITP Tools (KIT) instrument is a disease-specific HRQoL measure comprised of three questionnaires—one for the child (age 7–17 years of age; child self-report), one for the parent to complete on behalf of the child (age 2–17 years of age; parent proxy) and one for the parent measuring the impact of ITP on the parent (parent impact).⁸ The ITP Patient Assessment Questionnaire (PAQ) for adults consists of 44 questions covering six domains (physical health, emotional health, social activity, work, women’s reproductive health and overall quality of life) and takes approximately 15 min to complete.⁹ Both KIT and ITP PAQ are integrated into most clinical trials to assess HRQoL when evaluating new treatment options. Unfortunately, neither ITP-specific tool is routinely utilized in daily clinical practice. Additionally, there is the ITP Life Quality Index (ILQI) which has 10 questions measuring the impact of ITP on: work or studies, time taken off work or education, ability to concentrate, social life, sex life, energy levels, ability to undertake daily tasks, ability to provide support, hobbies and capacity to exercise.¹⁰ This instrument is newly developed and there are current efforts to convert this instrument to a web-based platform. The web-based instrument would utilize computerized adaptive testing based on item response theory which reduces patient burden and increases item precision by selecting the next questions based off the patient’s previous response.¹¹

When disease-specific instruments were not used, HRQoL in ITP was commonly assessed with the Medical Outcome Study 36-Item Short Form Survey (SF-36). The SF-36 has 36 questions covering eight domains of health (vitality, bodily pain, general health perceptions, mental health, physical functioning, physical role functioning, emotional role functioning and social functioning). The SF-36 is a generic instrument which can be used in any disease and has been validated in multiple languages.¹²

In children and adolescents with ITP, fatigue has been assessed with the Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL MFS). The PedsQL MFS is a generic tool which measures three domains: general fatigue, sleep/rest fatigue and cognitive fatigue. The instrument is valid for child self-report for ages 5–18 years and parent proxy report for children aged 2–18 years.¹³ Additionally, the Hockenberry Fatigue Scale has two versions. The version for children (Fatigue Scale-Child, FS-C, age 7–12 years) has 10 items and the version for adolescents (Fatigue Scale-Adolescent, FS-A, age 13–17 years) has 13 items.¹⁴ Fatigue in adults with ITP has been assessed with the Fatigue Impact Scale (FIS), consisting of 40 items evaluating the effect of fatigue on cognitive, physical and psychosocial functioning and takes about 10 min for completion.¹⁵ The Multidimensional Fatigue Inventory (MFI) is a 20-item instrument which evaluates five domains (general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue.¹⁶

HRQoL IN PATIENTS WITH REFRACTORY ITP

Treatment for ITP might be considered for concerns other than bleeding risks such as for improvement of HRQoL, although this is rarely done in clinical practice and of questionable success with available therapies.¹⁷ This remains one of the most important treatment goals considered by medical doctors and patients.⁶

One study evaluated HRQoL in 73 adult patients with chronic ITP compared with that of the general US population and additionally compared HRQoL to patients with hypertension, arthritis, diabetes mellitus, congestive heart failure, missing or paralysed limb or cancer using the SF-36 instrument.⁴ Results showed HRQoL in chronic ITP was significantly worse than that of the general US population and also worse than that of patients with hypertension, arthritis or cancer. HRQoL in patients with chronic ITP was similar to that of patients with diabetes and was better than that of patients with congestive heart failure or a missing or paralysed limb. Additionally, patients with ITP who required therapy had a worse HRQoL compared to those who were not receiving treatment, suggesting that HRQoL was worse in patients with a more severe disease.

The ITP World Impact Survey (I-WISh) was a cross-sectional survey including 1507 patients with a diagnosis of ITP and 472 physicians to establish the impact of ITP on HRQoL and productivity from two perspectives—from patients and treating physicians.¹⁸ Patients reported that ITP reduced their energy levels (85% of patients) and their capacity to exercise (77%) as well as limited their ability to perform daily tasks (75%). Physicians reported that ITP symptoms (80% of physicians) and fatigue (66%) reduced patient HRQoL. Results from I-WiSH demonstrated the substantial impact of ITP on HRQoL both from the patient and physician’s perspective. Of note, fatigue was one of the few symptoms persisting at survey completion and was the top symptom patients wanted resolved (46%).⁶ However, data on the percentage of patients with refractory ITP were lacking, and recall bias was a major limitation of this retrospective study, as patients were asked to recall and estimate their QOL at the time of their ITP diagnosis.

FATIGUE IN PATIENTS WITH REFRACTORY ITP

To date, the cause of fatigue in patients with ITP is not well understood. However, fatigue is common among patients with ITP and one might assume that fatigue is even more pronounced in patients with refractory ITP. In a study assessing patients of the UK ITP Support Association and the US (Oklahoma) ITP Registry, results demonstrated that the prevalence of fatigue among UK (39%) and US (22%) patients was significantly greater than expected compared to the general population. Fatigue was associated with treatment with corticosteroids, bleeding symptoms, presence of other medical conditions, daytime sleepiness and orthostatic symptoms. However, fatigue was not associated with age, gender, ITP duration or splenectomy.³ Similarly, in the I-WISh study, fatigue was not associated with increasing age and there was no correlation between fatigue and low platelet count.⁶

In a review on the impact of primary ITP on HRQoL in adult patients, focusing on the impact of ITP and treatment of ITP on patients’ HRQoL, it was demonstrated that the majority of patients had moderately to severely diminished HRQoL and that fatigue—next to corticosteroid toxicity—was a critical issue.¹⁹ Again, the percentage of patients with refractory ITP was missing in this review which included 16 articles.

MENSTRUAL BLEEDING IN REFRACTORY ITP

It is known that heavy menstrual bleeding negatively impacts a person’s physical, mental and overall well-being.²⁰ Because ITP is more prevalent in women of reproductive age, heavy menstrual bleeding can impact the lives of women with refractory or chronic ITP. Treatment options for heavy menstrual bleeding are limited for women with ITP who want to preserve their fertility. These women may be treated with hormonal therapy with oral contraceptive pills or intrauterine devices which may be combined with antifibrinolytic treatment.²⁰ In a large international study of 1507 adult patients with ITP, 65% were female and 439 (45%) reported heavy menstrual bleeding at ITP diagnosis. At the time of completing the survey, 161 women were experiencing heavy menstrual bleeding and 62% (100/161) of them reported it as one of their most severe symptoms.⁶

Furthermore, an explorative cross-sectional cohort study conducted among 37 women with chronic ITP focused on understanding factors related to and the impact of menstruation on QOL. Researchers utilized the ITP-bleeding assessment tool and the pictorial bleeding assessment calendar to quantify bleeding and they used the menorrhagia multiattribute scale (MMAS) to quantify QOL as a result of heavy menstrual bleeding. In this study, 39% of women with chronic ITP had monthly bleeding that would be classified as heavy menstrual bleeding. The majority of patients (76%) had MMAS scores that indicated menstrual bleeding reduced their QOL.²⁰

PREGNANCY AND REFRACTORY ITP

For women with chronic or refractory ITP who desire to become pregnant, there are questions related to if their disease will worsen and if their child will be born healthy. A recent study was conducted among 171 pregnant women with ITP and 156 non-pregnant women with ITP and they were prospectively followed for 15 months. The majority of women in both arms of the study had chronic ITP at the time of enrolment. Sixteen (9%) of 171 pregnant women had pre-term delivery (<37 weeks gestation) and 16/166 (10%) experienced post-partum haemorrhage. Of the 171 neonates, there were platelet counts available for 136 neonates and approximately 27% of the babies were born with neonatal ITP. Two neonates experienced bleeding events: one neonate died from intracranial haemorrhage, one neonate received intravenous immune globulin (IVIg) and platelet transfusions and recovered.²¹ Risk factors for having an infant born with severe thrombocytopenia have been reported to be having a previous child born with severe thrombocytopenia.²² Additional risk factors that have been suggested include a maternal history of splenectomy and maternal disease severity.

CHILDREN WITH REFRACTORY ITP

There is no consensus on the definition of refractory ITP in children.²³ However, because children with ITP often require no therapy, the decision then to begin a second-line therapy is complex and reflects many different factors.¹ One of the goals of the ITP Consortium of North America (ICON)-1 prospective study was to describe the factors related to a physician’s decision to initiate second-line treatments for ITP in children.²⁴ The study enrolled 120 children, median age 11.7 years (range 1.2–17.8 years) and 62% female. Patients had received a median of three prior treatments (range 0–8) and 53% had chronic ITP. The overall results from this study revealed that the most frequently cited reason for starting a second-line therapy in children was improvement of the patient’s QOL. However, despite that QOL was the most important indication for initiating treatment, there were no differences in reported baseline KIT scores between the patients who had QOL ranked in the top three reasons versus patients who did not have QOL ranked in the top three. When comparing reasons for starting a second-line therapy by duration of disease, improving QOL was more likely to be ranked as one of the top three reasons in children with chronic ITP (65%) compared to those with newly diagnosed or persistent ITP (35%) (p = 0.006). Interestingly, when comparing reasons for starting a second-line therapy by the race of patients, physicians were more likely to rank QOL as the most important reason for children who identify as White but not for patients who were non-White race (i.e. top reasons in non-White patients included severity of bleeding symptoms, frequency of bleeding symptoms and severity of thrombocytopenia). Also, of note, improvement of fatigue symptoms was written in as the primary reason to initiate the second-line treatment for five children.²⁴

In a study of children and adolescents receiving second-line therapies for ITP, more than half of those reported moderate to severe fatigue.¹⁴ There was no correlation between fatigue and age, gender, bleeding symptoms, platelet count or platelet response to therapy. Furthermore, children with chronic ITP had better fatigue scores (lower mean scores) than children with newly diagnosed or persistent ITP. This paradox may result from children having greater anxiety earlier in their disease course and then over time children adapt to a new ‘normal’ or learn to deal with the fatigue.¹⁴ However, studies have shown that children with chronic ITP have statistically significant worse fatigue compared to healthy children.²⁵

THE INFLUENCE OF TREATMENTS ON REFRACTORY ITP—CAN THEY IMPROVE THE PATIENTS’ BURDEN OF THE DISEASE?

So far, there is no evidence for an association of the impairment of HRQoL, especially fatigue, in refractory ITP and age, gender, bleeding symptoms, platelet count or platelet response to therapy. As fatigue is one of the symptoms impacting HRQoL and is certainly a multifactorial problem one has different possible treatment approaches. Iron deficiency, Vitamin B12 or folate deficiency and all other causes of anaemia have to be excluded. Thyroid function has to be checked and any other autoimmune disorders have to be excluded. Cognitive/behavioural factors, such as illness beliefs, perceived stress or mood, have to be taken into consideration and a psychological support is warranted. Also, social factors, such as clarification of responsibilities of patients at work and of caregivers, and social support might ameliorate these problems with regard to HRQoL.²⁶

Very little is known about the influence of the anti-CD20-antibody Rituximab specifically on the HRQoL in refractory ITP. The same holds true for splenectomy, which should be reserved as a treatment modality for patients with chronic ITP after month 12. In a study of 26 splenectomized chronic ITP patients using SF-36 and comparing them with medically treated patients with thrombopoietin receptor agonists (TPO-RAs) or immunosuppressants and with the general population, splenectomized patients had a worse overall HRQoL profile compared to medically treated patients and compared to the general population.²⁷

There are three TPO-RAs available for the treatment of ITP (although approval status and indication are different in different countries): Romiplostim (a peptibody, stimulating the JAK–STAT pathway as well as megakaryocytic proliferation, maturation and platelet production), Eltrombopag (a small molecule, same mechanism of action as Romiplostim) and Avatrombopag (a small molecule, same mechanism of action as Romiplostim). In a randomized open label study, HRQoL was assessed using the 10-scale ITP PAQ.²⁸ ITP nonsplenectomized patients were randomized to receive either Romiplostim or standard of care (SOC) treatment. After 52 weeks, patients receiving Romiplostim had greater improvement in the HRQoL compared to the patients receiving SOC, but the magnitude of the difference was of uncertain clinical benefit.²⁸

The EXTEND study evaluated long-term safety, tolerability and efficacy of Eltrombopag in adults with chronic ITP using four validated HRQoL instruments. Results reported positive mean changes from baseline over time and positive associations with platelet response.²⁹ It was concluded that Eltrombopag alleviated fatigue in that setting.

One real-world study in primary ITP used a web-based instrument and included 46 patients. Results did not document a reduction of fatigue by the TPO-RAs Romiplostim and Eltrombopag—although they increased platelet counts.³⁰ In a meta-analysis including nine randomized controlled trials assessing the efficacy and QOL of Romiplostim in adults and children with ITP, no statistically significant difference in HRQoL was found in the study population compared to the control group.³¹ Although TPO-RAs increased platelet counts, they did not seem to improve HRQoL.

However, a qualitative study conducted among children and/or their caregivers suggested that the use of TPO-RAs improved a child’s QOL. Researchers in Canada used semi-structured telephone interviews to understand the lived experience of taking these medications. To be eligible for the study, children with ITP had to receive a TPO-RA medication for at least 4 weeks. Positive themes were that their child’s mental health had improved since taking the TPO-RA, their child was able to resume sports participation and overall reduced caregiver anxiety. Negative concerns were raised related to the costs of the medication, potential long-term side effects and challenges related to taking the TPO-RA on an empty stomach.³²

In conclusion, with the second-line treatment of patients with ITP with TPO-RAs, Rituximab and/or splenectomy, there was no published evidence that Rituximab or splenectomy led to an improvement in HRQoL. With regard to TPO-RAs, there were mixed results on their influence on HRQoL, but a clear and reproducible effect leading to an improvement of HRQoL was not easily recognizable based on the published evidence.

Whether newer treatments in the setting of refractory ITP will have a positive effect on HRQoL remains to be seen. Many new compounds, such as Fostamatinib (syk inhibitor, decreases antibody-dependent phagocytosis of platelets), Efgartigimod (anti-FcRn, decreases half-life of IgG, reduces plasma IgG both normal and pathogenic), Rozanolixizumab (anti-FcRn, same mode of action as Efgartigimod), Rilzabrutinib (BTKi, inhibits Fc gamma signal transduction, decreases platelet phagocytosis and autoantibody production) or Sutimlimab (anti-C1s, decreases complement-dependent cytotoxicity thereby platelet destruction) will have to prove their effect not only on platelet counts but also on HRQoL.³³

UNMET NEEDS WITH REGARD TO HRQoL IN REFRACTORY ITP

As there is no agreement on the definition of refractory ITP, issues with regard to HRQoL in this phase of ITP will remain rather vague—and expert opinion is needed as there is a paucity of evidence in this respect. Additionally, the fact that there is a great variety of instruments being utilized in ITP makes it challenging to compare the results from one study to another. One barrier to routine use of the ITP PAQ is the length of the instrument. There have been recent efforts to develop an ITP-specific valid instrument with a much-reduced patient burden (i.e. 10-item ITP Life Quality Index); however, this instrument has not been widely used yet and efforts are underway to improve the precision of the instrument. Furthermore, if a researcher chose a generic instrument, it is necessary to determine patient acceptability and determine if the instrument is valid with regard to the concerns that ITP patients face.

The focus of treatment in ITP is elevating platelet counts and preventing clinically significant bleeding. Although this is very importance at diagnosis, in a chronic disease, issues such as HRQoL may be of even more important than the risk of bleeding during the course of the disease. Currently, based on the published literature, the ability of our treatment armamentarium to positively influence HRQoL and fatigue report conflicting results. The indication to start therapy remains largely focused on low platelets and bleeding symptoms, although HRQoL and fatigue may be equally important to patients. We might not have tools to improve that in every patient. Nevertheless, it is important to draw attention to HRQoL as it is one of the priority treatment goals for patients and physicians.

It is crucial to perform further research on the pathophysiology of fatigue in ITP. It is also important to continue to assess HRQoL in every stage of disease. Additionally, qualitative studies need to be performed to understand the facilitators and barriers to the uptake of disease-specific instruments in the clinical care of these patients. Last but not least, further research on the economic impact of ITP on the lives of affected patients and health economic considerations with regard to the influence of HRQoL of all drugs for ITP seeking approval by health authorizations should be performed—because elevation of platelet counts and improvement in HRQoL are two sides of the same coin.

CONCLUSIONS

Although there is no accepted definition of refractory ITP, the burden of disease in this patient population goes beyond the need of treatment due to the risk of bleeding. It is known that HRQoL is affected in adults and children (and their parents) with ITP and has a multicausal aetiology. The effect of treatment of ITP for low platelets and bleeding symptoms on HRQoL remains unclear but is an important treatment goal for patients and physicians. Therefore, HRQoL should receive adequate attention and assessment in daily clinical practice, and improvement of HRQoL should be considered as an indication for the treatment of ITP. Moreover, we must agree on instruments to use in this population. It is important to standardize assessment of these outcomes with measures that have high patient acceptability, low patient burden, low burden on the healthcare provider, fit into the clinical workflow for providers and provide outcomes that include severity thresholds that aid in clinical interpretation.

DATA AVAILABILITY STATEMENT

For original data, please contact dee-terrell@ouhsc.edu.