Treatment of Primary Immune Thrombocytopenia (ITP)

**_Treatment_**

Treatment is not medically necessary in the following scenarios:

  1. Children with no bleeding or mild bleeding (skin manifestations only such as bruising and petechiae) regardless of platelet count
  2. Adults with platelet count  30 x109/L in the absence of bleeding

Treatment may be indicated with documentation of at least one of the following
conditions:

    1. Severe ITP (bleeding)
    2. Adult with platelets count 30 x109/L especially if risk factors for bleeding are present
    3. In preparation for procedures or surgery with risk of bleeding
    4. Professional or lifestyle risk factors for trauma

Risk factors for bleeding include predisposing comorbidities that increase the
risk of bleeding such as uncontrolled hypertension, active peptic ulcer
disease, anticoagulation, recent surgery, or head trauma.

**_First-Line Therapy_**

First-line pharmacologic treatment in children and adults is corticosteroids
in dosing regimens standard to ITP treatment.

Intravenous Immune globulin (IVIg) may be used first-line with documentation
of at least one of the following conditions:

  1. Documented need for rapid response (<48 hours)
  2. Documented contraindication or inability to tolerate corticosteroids
  3. Lack of response to corticosteroids

Lack of response is defined as platelet count <30 x109/L or less than 2-fold
increase in baseline platelets1.

Intravenous anti-D may be used first-line in adults with documentation of at
least one of the following conditions in patients who are Rh positive and
nonsplenectomized:

    1. Documented need for rapid response (<48 hours)
    2. Documented contraindication or inability to tolerate corticosteroids
    3. Lack of response to corticosteroids

**_Second-Line Treatment_**

Coverage of second-line treatment requires a documented lack of response to at
least one first-line therapy. Shared decision making to consider the risk and
benefit of the various second-line options should be documented in the medical
record. This should include a discussion of surgical and non-surgical options.

Splenectomy will be covered when all of the following criteria are met:

  1. Documented lack of response of at least one first-line therapy
  2. Documented risk for bleeding (at least one of the following) 
    1. Severe ITP (bleeding symptoms)
    2. Adult with platelets count 30 x109/L especially if risk factors for bleeding are present
    3. In preparation for procedures or surgery with risk of bleeding
    4. Professional or lifestyle risk for trauma
  3. Persistent or chronic disease (>6 months) OR documented indication for more immediate surgical intervention (<6months) such as serious bleeding
  4. Pre-operative vaccinations per CDC guidelines
  5. Patient desires treatment-free remission and willing to accept the risk associated with splenectomy (surgical, infection and thrombosis)

Thrombopoietin receptor agonist (TPO-RA) will be covered when all of the
following criteria are met:

  1. Documented lack of response of at least one first-line therapy
  2. Documented risk for bleeding (at least one of the following) 
    1. Severe ITP (bleeding symptoms)
    2. Risk factors for bleeding are present
    3. In preparation for procedures or surgery with risk of bleeding
    4. Professional or lifestyle risk factors for trauma
  3. Persistent or chronic disease (>6 months)

Rituximab will be covered when all of the following criteria are met:

  1. Documented lack of response of at least one first line therapy
  2. Documented risk for bleeding (at least one of the following) 
    1. Severe ITP (bleeding symptoms)
    2. Risk factors for bleeding are present
    3. In preparation for procedures or surgery with risk of bleeding
    4. Professional or lifestyle risk for trauma
  3. Persistent or chronic disease (>6 months)



Primary immune thrombocytopenia (ITP) is an acquired immune-mediated disorder
characterized by isolated thrombocytopenia, defined as a peripheral blood
platelet count less than 100 x 109/L in the absence of other underlying
causes2. The incidence ranges from 1-5 per 100,000 adults, but prevalence is
higher due to the chronic nature of the disorder3,4. International consensus
classifies ITP by duration into newly diagnosed (<3 months), persistent (3-12
months duration), and chronic ( 12 months duration)1 .

ITP can occur in both the pediatric and adult populations. In children, the
disease typically acute following a viral illness and is usually self-limited
remitting spontaneously within six months with about 15% developing chronic
ITP 5. In adults, ITP is extremely heterogeneous, ranging from asymptomatic to
severe bleeding. For most adults, the morbidity and mortality related to ITP
are low and severe bleeding is rare5. Risk of serious bleeding is increased
when platelet counts are less than 30 x 109/L, platelets remain persistently
low, increasing age, medical comorbidities, and failure to respond to
treatment 5 6,7. In the subset of patients at high risk for life-threatening
bleeding, the goal of therapy is the prevention of severe bleeding including
potentially life-threatening bleeding such as intracranial hemorrhage,
gastrointestinal bleeding, or skin and mucosal hemorrhage. Patients with
persistent severe thrombocytopenia that does not respond to therapy within the
first two years have considerable morbidity and a 6-fold increase in
mortality8.

Various terminologies have been used in the literature on ITP, which has made
it more difficult to compare studies as definitions are variable.
International consensus defined the following: Severe ITP is defined as the
presence of bleeding symptoms or occurrence of new bleeding symptoms requiring
additional therapeutic intervention usually with platelet counts < 20 x
109/L1,2. A response is defined as platelet count 30 x109/L but 100 x 109/L1
and at least doubling of the baseline platelet count and a complete response
defined as platelet count >100 x 109/L1. Lack of response is defined as
platelet count <30 x109/L or less than 2-fold increase in baseline platelets
and loss of response is defined as platelet count <30 x109/L or less than
2-fold increase in baseline platelets following a response 1.

The goal of treatment is to prevent severe bleeding, but the risk of bleeding
can be difficult to estimate. Individual considerations, including risk
factors and lifestyle, must be considered. Treatment is rarely indicated in
patients with platelet counts above 30 x 10/9L and should be based on symptoms
and signs rather than arbitrary platelet threshold2,9. The balance between the
risk of bleeding and treatment itself must be considered as overall morbidity
and mortality may be increased with treatment 8. Treatment is not medically
necessary in children with no bleeding or mild bleeding (skin manifestations
only such as bruising and petechiae) regardless of platelet count (grade 1B)
or adults with platelet count  30 x109/L in the absence of bleeding (grade
2C)10. Treatment is clearly indicated in the setting of severe ITP (bleeding)
and in preparation for procedures or surgery with risk of bleeding and may
also be indicated in an adult with platelets count 30 x109/L (grade 2C)
especially if risk factors for bleeding are present. Predisposing
comorbidities such as uncontrolled hypertension, active peptic ulcer disease,
anticoagulation, recent surgery or head trauma or lifestyle risk factors may
increase the risk of bleeding10,11.

Corticosteroids are the standard first-line treatment when treatment is
required and consistent with society guidelines (grade 1B)2,10. They are
inexpensive, easy to administer, and raise platelet counts within 2-5 days in
approximately 75% of patients. Effectiveness has been demonstrated in multiple
randomized control trails indicating approximately two-thirds of adults with
newly diagnosed ITP maintain a response at six months, but relapse occurs in
60-70% beyond 1-2 years 9,12. Long term used is limited by corticosteroid side
effects13.

Intravenous immune globulin (IVIg) has been demonstrated to be effective in
controlled trails with an initial response in 24-48 hours and duration of 2-6
weeks14. Side effects are typically mild, but rare adverse reactions can
occur. A meta-analysis comparing treatment with corticosteroids and IVIg with
the primary outcome of platelet count >20 x 10/9L at 48 hours in children
showed that 26% fewer children achieved this outcome who received steroids as
compared to IVIg without significant differences in clinical outcomes15. IVIg
may be used as first-line therapy when corticosteroids are contraindicated or
not tolerated (Grade 2C) or in combination with corticosteroids when a more
rapid increase in platelets is required (Grade 2B) such as serious bleeding
10.

Intravenous anti-D is an alternative to conventional IVIg suitable for those
who are Rh(D) positive and have not undergone splenectomy and is approximately
80% effective5. Anti-D has been shown to induce a longer response time than
IVIg and may also reduce the need for splenectomy5,16. Risks include hemolysis
(15%) and is contraindicated in those with a history of autoimmune hemolytic
anemia. There is an FDA black box warning against the use of in children due
to the risk of severe hemolysis.

Second line therapies are indicated in chronic and severe ITP when a patient
fails to respond to first-line therapy. 2011 International Consensus Report
ranked existing second-line therapies in alphabetical order due to
insufficient date to rank in order of efficiacy5,13. There are no randomized
controlled comparative studies or systematic review of the available data, and
a lack of sufficiently large numbers to make definitive
recommendations5,17,18. Another challenge in the literature is the primary
endpoint studies is usually platelet response, but how that translates into
clinical outcomes is unclear. According to a 2019 International Consensus
Report no study has addressed the correct sequence of subsequent therapies;
and panel recommendations are consensus-based.19The American Hematology
Association (AHA) 2019 Guidelines for ITP recommends "In adults with ITP
lasting 3 months who are corticosteroid-dependent or have no response to
corticosteroids, the ASH guideline panel suggests either splenectomy or a TPO-
RA (conditional recommendation based on very low certainty in the evidence of
effects)"20. Additionally, the AHA guidelines recommends rituximab over
splenectomy, and TPO-RA over rituximab both conditional recommendations based
on very low certainly evidence20. NEJM review paper summarizes "there were
weak recommendations for the use of rituximab and thrombopoietin-receptor
agonists before splenectomy"21. AHA encourages patient education and shared
decision-making. The 2019 guidelines state "If possible, splenectomy should be
delayed for at least 1 year after diagnosis because of the potential for
spontaneous remission in the first year. Patients who value avoidance of long-
term medication may prefer splenectomy or rituximab. Patients who wish to
avoid surgery may prefer a TPO-RA or rituximab. Patients who place a high
value on achieving a durable response may prefer splenectomy or TPO-RAs."20

Splenectomy has a long history in the treatment of chronic ITP, rates of
splenectomy have declined as alternative second-line treatments have emerged
with fewer than 25% of chronic patients undergoing splenectomy as second-line
treatment22. Splenectomy for patients who have failed corticosteroids therapy
is supported by the medical literature (Grade 1B) for patients who are
acceptable surgical candidates and offers the potential for a sustained
response without the need for maintenance therapies10,14. A systematic review
reported a complete response in two-thirds, a response in an additional 22%
with an overall response in 88% at one-year post splenectomy23. Splenectomy
has the advantage of offering the potential of long term complete and
sustained response without the need for maintenance therapy23,24. There is not
a reliable test to predict response, and 14% do not respond to splenectomy
with 10% to 20% of splenectomy responders eventually relapse25. Risk of
splenectomy includes operative risk, thrombosis, and life-time increased risk
of infections. Complications have been reported to be higher with open as
compared to laparoscopic surgical technique and in elderly patients (>65 years
old) 23,26. . Pre-operative vaccinations for elective splenectomy should be
given per CDC guidelines27.The potential benefit of splenectomy must be
balanced against the risk23 Consensus guidance recommends delaying splenectomy
for 12-24 months after diagnosis as some patients have a spontaneous remission
during this time if the patient is medically stable to delay the procedure
(Grade C recommendation)19,20. The likelihood of a response may be reduced in
older patients 28.. Several cohort studies reported patients who maintain a
post-splenectomy platelet count of >30 x 10/9L experienced no mortality from
bleeding which supports recommendation against further treatment in
asymptomatic patients after splenectomy who have platelet counts >30 x 10/9L
10. The 2019 International Consensus Report supports laparoscopic approach for
splenectomy (Grade B recommendation)19.

Thrombopoietin agonist (TPO-RA) are small molecule peptides and non-peptide
agents, romiplostim, eltrombopag and avatrombopag have been FDA-approved, for
treatment for chronic ITP. TPO-RA's have been studied in prospective
randomized control trials with a response in splenectomized and non-
splenectomized patients with chronic ITP with efficacy reported at
approximately 80% (Grade 1B)10,29-31. In most cases, the response is not
sustained; therefore, it is considered a maintenance medication with durable
response rate about 45%14. Cohort studies have reported sustained response in
up to 30% of patients, but the full impact of TPO-RAs on remission is yet to
be fully understood and, therefore, considered for maintenance32,33. A
Cochrane review reiterated the increased platelet but also reported that there
was no evidence to support that treatment with TPO-RA's improved incidence of
significant bleeding events34. Since the literature on TPO-PA does not address
the impact on significant bleeding events, further information is needed to
understand their impact on overall survivial34.

The studies do provide data on drug safety for up to 5 years with some
additional data extending to 10 years. A long term, single arm , open-label
study with primary outcome of long term safety of romiplostim reported 5 years
of data from 200 patients demonstrating infrequent treatment-related serious
adverse events, no new adverse events or tachyphylaxis emerging35 A similar
designed open-labeled study followed 300 patients on eltrombopag for median
duration of 2.37 years (maximum 8.76 years) reported hepatobiliary adverse
events in 15% unrelated to duration on the drug and, therefore it is
recommended to monitor liver function on this formula. In this study, the
question of bone marrow fibrosis was addressed with bone marrow biopsy
analysis that did not demonstrate a significant impact on bone marrow
reticulum36. Both studies report a rate of thrombosis of 6-6.5%, and mostly
affected patients had underlying risk factors35,36. An integrated analysis of
long term safety with the use of romiplostim including data from 14 trials and
pooling data from placebo and treatment arms report that the rate of
thrombosis was comparable among the groups, but the number who received
placebo were low and additional research to fully understand this effect is
lacking37. An advantage of this class is that it avoids immunosuppression and
disadvantages include the need for long term maintenance and side effects.

Rituximab is a chimeric monoclonal antibody directed against the B cell
surface protein CD20 and has been used off-label for the treatment of ITP. The
initial response to Rituximab is approximately 60%, and a long term remission
is reported in 15-30% of patients in prospective and retrospective cohort
studies, systematic reviews and meta-analysis in both splenectomized and non-
splenectomized patients (Grade 2C)10,38-40. There are multiple systematic
reviews and meta-analysis in the literature; however, most studies were not
randomized control trails and did not offer a control arm limiting the data
sets. A systematic review of patients who failed first-line therapies (19
studies, 313 adult patients half who had splenectomy) reported a complete
response in 44% and a response in 63% with a median duration of 11 months29. A
meta-analysis of non-splenectomized patients (5 RT/463 patients) reported a
complete response in 47% and response in 58%, which was comparable to a prior
meta-analysis that also included observational studies38,39. A multi-centered,
randomized, double-blinded, placebo controlled trial with the longest duration
comparing rituximab or placebo after initial corticosteroids demonstrated only
a modest response at 1.5 years41, however also reported a small benefit with
rituximab could not be ruled out based on longer duration of response,
numerically higher responses, and late reponders29. Factors predictive of a
response have not been clearly established, but older age and longer disease
duration (>10 years) seem to reduced response42,43. There is a lack of long
term safety data with reports of rare risk of progressive multifocal
leucoencephalopathy and hypogammaglobulinaemia 32,38. There is an FDA black
box warning for the potential to cause reactivation of hepatitis B
necessitating testing for hepatitis B before use. Rituximab is included as
second-line therapy in the 2018 ASH guidelines as it offers the potential for
a treatment-free remission without surgical intervention14.

Azathioprine, cyclosporine, cyclophosphamide, danazol, dapsone, mycophenolate
mofetil, vinblastine, and vincristine have been used off-label as second-line
therapies with limited published reports of any kind13,29,32. Fostamatinib, a
spleen tyrosine kinase (Syk) inhibitor, has been FDA-approved for the
treatment of chronic ITP in adults. A Phase 3 placebo-controlled RCTs in
patients with chronic ITP, a median of 3 prior ITP treatments and baseline
platelet count <20x109/L demonstrated response in 43% at 12 weeks and 18% at
24 weeks32. ASH practice guidelines for ITP state that research on these
therapies is inadequate to allow evidence-based recommendations at this
time10. 2018 ASH guideline update does not include any of these agents as
options for second-line therapy10.

One of the challenges in primary ITP treatment is determining who needs
treatment due to the heterogeneous nature of the disease and difficulty in
predicting bleeding. Treatment based on a platelet threshold has gradually
been replaced by clinical assessment of acute bleeding, the risk for bleeding,
and lower platelet thresholds to determine candidates for treatment. The risk
of fatal bleeding is lower than previously thought, and the potential
morbidity and mortality related to treatment must be balanced with the need
for treatment. The emergence of second-line treatment option has overall
improved outcomes and mortality in severe cases.

ASH evidence-based practice guidelines and international consensus support the
use of first-line treatment with corticosteroids 10,13,14. IVIg and Anti-D are
the appropriate first-line treatment in cases where a rapid rise in platelet
count is needed or corticosteroids are contraindicated or not tolerated (grade
2C) 10. IVIg and anti-D are associated with more side effects, and there is no
clear long-term benefit compared to corticosteriods14. Corticosteroids should
be discontinued once a response is achieved. Most patients will respond to
first-line therapy, and disease may remit spontaneously in the first 6-12
months.

Patients who develop chronic ITP and who fail to respond to first-line
treatment have a poorer prognosis and increase the risk of morbidity and
mortality related to ITP. The optimal treatment of this group is
controversial. The international consensus guidelines determined they could
not rank the second line options based of evidence since the literature was
not sufficient to make this determination, but the American Society of
Hematology (ASH) does support splenectomy and the use of TPO-RA in a select
patient population10,13,14. Since 2011 additional literature has emerged, but
the optimal treatment remains unclear14.

The decision for splenectomy includes the desirable effect of high remission
rate (77%, range 58-91%) balanced against the lifelong risk of infection,
thromboembolic events, and surgical complications14. Splenectomy is still
recommended as the standard therapy for patients with chronic ITP given the
high probability of durable platelet response29. Splenectomy rates have
declined since the emergence of newer medical therapies, especially in
patients who are not good surgical candidates such as patients who are elderly
and with multiple medical co-morbidities. Splenectomy is the recommended
second-line therapy due to the potential for a treatment-free response without
the need for maintenance therapy support by (Grade 1B) medical evidence (Grade
1B) 10,1318.

TPO-RA has been studied in RCT, systematic reviews, and meta-analysis and
determined to be effective agents to achieve a response with a durable
response rate of 45%. While there are reports of TPO-RA's inducing remission,
this is not supported by high-quality evidence and TPO-RA's are considered
maintenance medication14. Romiplostim requires weekly subcutaneous injection
and eltrombopag, a daily oral medication, can interfere with liver enzymes,
cannot be taken within four hours of polyvalent cations and requires
monitoring of liver function which may limit compliance. Avatrombopag is a
daily oral medication without dietary restrictions, but has not been as
rigorously studied. It has not been determined, the optimal duration of
therapy and when a trail off of medication may be indicated. The benefits
profile of TPO-RA includes avoiding immunosuppression, and this must be
balanced against the need for long term use and very limited long-term (>10
years) safety data14. ASH guidelines recommend TPO-RA for patients who need
second-line treatment who are determined to not be a candidate for
splenectomy, at risk for bleeding who relapse after splenectomy and have
failed at least one other therapy (grade 1B)10,14.

Rituximab has been studied in multiple trails with conflicting results but
overall favorable with durable response rate similar to TPO-RA of
approximately 40% (Grade 2C). The potential advantage of Rituximab is the
possibility for durable remission32. Rituximab is administered intravenously
weekly for four consecutive weeks, and if there is a response, it may reduce
the need for chronic maintenance therapy32. The use of Rituximab is off-label,
and high-quality evidence is lacking. It is included in the ASH Guidelines as
it offers the potential for treatment-free remission. The guidelines include a
trial of rituximab may be desirable before splenectomy as it has the potential
to be splenectomy sparing. If there is the rationale for the decision not to
perform splenectomy the literature and guidelines support Rituximab as a
second-line option and evidence-based reviews (other than the ASH Guidelines)
rank the quality of evidence as Grade 2B14,32.

There is a paucity of data or low-quality data surrounding the other
alternative second-line therapies, and they are not included in the 2018 ASH
Guidelines14. These options are considered investigational and not covered.