Clinical UM Guideline

 

Subject: Romiplostim (Nplate®)
Guideline #: CG-DRUG-75 Publish Date:    12/27/2017
Status: New Last Review Date:    11/02/2017

Description

 

This document addresses the use of romiplostim (Nplate, Amgen Inc., Thousand Oaks, CA), a subcutaneously administered thrombopoietin (TPO) receptor agonist that stimulates bone marrow megakaryocytes to produce platelets.

 

Clinical Indications

Medically Necessary:

Initial treatment with romiplostim is considered medically necessary when used for the treatment of thrombocytopenia in individuals who meet all of the following criteria:

  1. Chronic immune thrombocytopenia (ITP); AND
  2. Individual’s degree of thrombocytopenia (platelet count less than 30,000/mm3) and clinical condition increase the risk for bleeding; AND
  3. Individual demonstrated an insufficient response to corticosteroids, immunoglobulins (for example, IVIg or anti-D), or splenectomy.

Maintenance therapy with romiplostim for ongoing treatment of chronic ITP is considered medically necessary when the following criterion is met:

  1. Individual demonstrated response to therapy as evidenced by increased platelet counts, and the goal of ongoing treatment is to maintain an adequate platelet count (50,000-100,000/mm3)* to decrease the risk of bleeding.

*Note: If platelet count is greater than 100,000/mm3, adjust the dose using a cut-off platelet level of 100,000/mm3 as a substitute for 200,000/mm3 in the U.S. Food and Drug Administration (FDA) dosage and administration recommendations (please refer to: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125268s160lbl.pdf.).

Treatment of myelodysplastic syndrome (MDS) is considered medically necessary in individuals with severe or refractory thrombocytopenia following disease progression or no response to hypomethylating agents, or immunosuppressive therapy.

Not Medically Necessary:

Romiplostim is considered not medically necessary when the above criteria are not met, including but not limited to any of the following:

  1. Treatment used in an attempt to normalize platelet counts;
  2. Low platelet count caused by any condition other than chronic ITP.
Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J2796

Injection, romiplostim, 10 micrograms [Nplate]

 

 

ICD-10 Diagnosis

 

D46.0-D46.9

Myelodysplastic syndromes

D69.3

Immune thrombocytopenic purpura

D69.41-D69.49

Other primary thrombocytopenia

Discussion/General Information

According to the National Institutes of Health, ITP occurs in approximately 1 in every 16,000 adults, causing unusual bruising or bleeding due to an abnormally low number of platelets in the blood. Acute ITP generally lasts 6 months or less, occurring most commonly in the pediatric population. Chronic ITP is an autoimmune disorder characterized predominately by antibody-mediated platelet destruction lasting 6-12 months or longer, primarily in adults.

Romiplostim (Nplate) was granted approval in August 2008 by the U.S. Food and Drug Administration (FDA) for treatment of thrombocytopenia in individuals with chronic ITP who had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Romiplostim is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP. Treatment should only be used in individuals with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding. Romiplostim should not be used in an attempt to normalize platelet counts (Product Information Label, 2017).

The FDA approval was based, in part, on the findings of efficacy and safety from two double-blind, placebo controlled clinical trials of 125 adults with chronic ITP previously treated with at least one prior therapy and mean platelet count less than or equal to 30,000/mm3. Kuter and colleagues (2008) assessed the outcome effect from the trials; study 1 enrolled 63 splenectomized [mean time since splenectomy 6.6 years] and study 2 enrolled 62 non-splenectomised participants. Both studies randomized (2:1) to receive romiplostim or placebo weekly for 24 weeks. Romiplostim was administered subcutaneously at an initial weekly dose of 1 mcg/kg and subsequently titrated to achieve and maintain platelet counts between 50,000/mm3 and 200,000/mm3. The primary endpoint in both studies was comparison of durable platelet response (as defined by at least six platelet counts greater than or equal to 50,000/mm3 during the last 8 weeks of treatment) and treatment safety. Authors reported study results:

A durable platelet response was achieved by 16 of 42 splenectomised patients given romiplostim versus none of 21 given placebo (difference in proportion of patients responding 38% [95% CI 23.4-52.8], P=0.0013), and by 25 of 41 non-splenectomised patients given romiplostim versus one of 21 given placebo (56% [38.7-73.7], P<0.0001).

The majority of adverse events reported were of mild or moderate severity; significant bleeding events were reported in 6 of 84 (7%) of the romiplostim group and 5 of 41 (12%) of the placebo group treated. The authors concluded “romiplostim was a well-tolerated and effective treatment for patients with ITP. Platelet increases were seen within 1-2 weeks and were sustained throughout 24 weeks of treatment in both splenectomised and non-splenectomised patients.”

Specialty consensus opinion suggested that ongoing treatment with romiplostim may be used to maintain an adequate platelet count (50,000-100,000/mm3) to decrease the risk of bleeding. For platelet count greater than 100,000/mm3, dose adjustments can be made using a cut-off platelet level of 100,000/mm3 as a substitute for 200,000/mm3 in the FDA dosage and administration recommendations.

In a single arm, open label phase III trial, Kuter and colleagues (2013) evaluated the long-term safety and efficacy of romiplostim in 292 adults with chronic ITP. Participants received weekly subcutaneous romiplostim with treatment duration ranging from 1 to 277 weeks (mean 110 weeks). The authors reported the following results:

Outcome measures included adverse events (including bleeding, thrombosis, malignancy, and reticulin/fibrosis), platelet response (platelet count >50,000mm3), and the proportion of patients requiring rescue treatments. Treatment-related serious adverse events were infrequent and did not increase with longer treatment. No new classes of adverse events emerged. Thrombotic events occurred in 6.5% of patients and were not associated with platelet count.

The authors concluded that romiplostim was effective in both non-splenectomized and splenectomized participants and was associated with a low rate of treatment-related adverse events that was consistent across studies.

The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia provided guidance for treatment using thrombopoietin receptor agonists. Recommendations included treatment:

For adults at risk of bleeding who relapse after splenectomy or who have a contraindication to splenectomy and who have failed at least one other therapy.

Bussel and colleagues (2011) reported results from the first study of TPO receptor agonist in children with ITP according to the American Society of Hematology guidelines. The phase 1/2, multicenter study enrolled 17 children in the romiplostim group and 5 in the placebo group; participants received study treatment for 12 weeks. The authors concluded “overall the response of pediatric patients to romiplostim was similar to that of adults observed in 2 phase 3 studies of romiplostim in patients with ITP.” Preliminary findings of romiplostim in the pediatric population with ITP are encouraging, although the extension studies will provide longer-term results needed to confirm these findings. In a subsequent open-label, multicenter extension study, 20 of 22 children (median age 10.0 years) with chronic ITP received romiplostim, all achieving platelet counts of 50x109/L or greater (Bussel, 2015). In the second extension study, 12 of 14 eligible children chose to participate, each receiving up to 127 weeks of romiplostim. In conclusion authors reported:

That long-term romiplostim treatment in children with chronic ITP provides adverse event and platelet response outcomes similar to those seen in adults. Evaluation of patients enrolled in the ongoing phase 3 study of romiplostim in children ITP (NCT01444417, estimated enrolment of 60) will provide further data as to its safety and efficacy.

The FDA has not approved the use of romiplostim for MDS. Greenberg and colleagues (2013) reported results from a double-blind study evaluating the efficacy and safety of romiplostim in participants with low- or intermediate-risk MDS currently receiving decitabine. Twenty-nine eligible participants were enrolled, 15 participants to the romiplostim group and 14 to the placebo group. Bleeding events were reported in 27% of the romiplostim-treated population and 43% of the placebo population; 47% of the romiplostim-treated population received platelet transfusion, as did 57 % of the placebo-treated population. Authors reported the following results:

Overall clinical therapeutic response was achieved by 21% of placebo-treated and 33% of romiplostim-treated patients. Treatment was generally well tolerated. Progression to acute myeloid leukemia (AML) occurred in one patient per group. Adding romiplostim to decitabine treatment is well tolerated and may be beneficial, as indicated by trends toward higher platelet counts at the beginning of each treatment cycle and lower platelet transfusion rates and percentages of patients with bleeding events. Romiplostim in combination with decitabine appeared to be well tolerated in patients with low-, Int-1- and Int-2-risk MDS, and no additional toxicity issues were identified. Although the data showed no statistically significant advantage of romiplostim over placebo, clinical benefit of adding romiplostim to decitabine was suggested by trends to higher platelet counts at the beginning of each treatment cycle, higher platelet count nadirs in all but the last treatment cycle, lower platelet transfusion rates, and lower percentages of patients with bleeding events.

The NCCN Clinical Practice Guideline for Myelodysplastic syndromes (2017) offers a Category 2A recommendation for the treatment of individuals with lower risk MDS disease with severe or refractory thrombocytopenia using eltombopag or romiplostim. “Lower risk defined as IPSS-R (Very Low, Low, Intermediate), IPSS (Low/Intermediate-1), WPSS (Very low, low, intermediate)”.

Currently there are ongoing phase II clinical trials evaluating the use of romiplostim for treatment of hepatitis C-related thrombocytopenia and chemotherapy induced thrombocytopenia (CIT). Further research is needed to evaluate the utility of romiplostim in the treatment of these conditions.

Romiplostim (Nplate)

The following are warning and precautions from the Product Information Label (2017):
Warnings and Precautions

Definitions

Immune thrombocytopenia: A bleeding disorder where the blood is unable to clot, as a result of a low number of platelets or thrombocytes.

Maintenance therapy: Designed to maintain a condition to prevent a relapse.

References

Peer Reviewed Publications:

  1. Bussel JB, Hsieh L, Buchanan GR, et al. Long-term use of the thrombopoietin-mimetic romiplostim in children with severe chronic immune thrombocytopenia (ITP). Pediatr Blood Cancer. 2015; 62:208-213.
  2. Bussel JB, Kuter DJ, George JN, et al. A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia. Blood. 2011; 118:28-36.
  3. Fenaux P, Muus P, Kantarjian H, et al. Romiplostim monotherapy in thrombocytopenia patients with myelodysplastic syndromes: long-term safety and efficacy. Br J Haematol. 2017; 178:906-913.
  4. Gernsheimer TB, George JN, Aledort LM, et al. Evaluation of bleeding and thrombotic events during long-term use of romiplostim in patients with chronic immune thrombocytopenia (ITP). J Thromb Haemost. 2010; 8(6):1372-1382.
  5. Giagounidis A1, Mufti GJ, Fenaux P, et al. Results of a randomized, double-blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Cancer. 2014; 120(12):1838-1846.
  6. Greenberg PL, Garcia-Manero G, Moore M, et al. A randomized controlled trial of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving decitabine. Leuk Lymphoma. 2013; 54(2):321-328.
  7. Jamali F, Lemery S, Ayalew K, et al. Romiplostim for the treatment of chronic immune (idiopathic) thrombocytopenic purpura. Oncology. 2009; 23(8):704-709.
  8. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 2008; 371(9610):395-403.
  9. Kuter DJ, Bussel JB, Newland, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013; 161(3):411-423.
  10. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med. 2010; 363(20):1889-1899.
  11. Tarantino MD1, Bussel JB2, Blanchette VS3, et al.  Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016; 388(10039):45-54.
  12. Weitz I, Sanz MA, Henry D, et al. A novel approach to the evaluation of bleeding-related episodes in patients with chronic immune thrombocytopenia. Curr Med Res Opin. 2012; 28(5):789-796.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Children’s Hospital Boston. ICON1: Treatment decisions and outcomes in pediatric refractory ITP. NLM Identifier: NCT01971684. Last updated June 13, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT01971684?term=NCT01971684&rank=1. Accessed on September 21, 2017.
  2. NCCN Clinical Practice Guidelines in Oncology®. © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on November 3, 2017.
    • Myelodysplastic Syndromes (V.1.2018). Revised August 29, 2017.
  3. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011; 117(16):4190-4207.
  4. Nplate® (romiplostim) [Product Information]. Thousand Oaks, CA. Amgen, Inc. June 5, 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125268s160lbl.pdf. Accessed on September 21, 2017.
  5. Romiplostim Monograph. Lexicomp® Online, American Hospital Formulary Services ® (AHFS ®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised August 22, 2014. Accessed on September 21, 2017.
  6. Romiplostim (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. June 16, 2017. Available at: http://www.micromedexsolutions.com. Accessed on September 21, 2017.
Websites for Additional Information
  1. National Heart, Lung, and Blood Institute (NHLBI). What is immune thrombocytopenia? March 2012. Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/itp/. Accessed on September 21, 2017.
  2. The ITP Support Association. Summary of treatments for ITP. Available at: http://www.itpsupport.org.uk/index.php/en/itp-treatments. Accessed on September 21, 2017.
Index

Immune thrombocytopenia
Myelodysplastic syndrome
Nplate
Romiplostim

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

New

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review.

New

11/01/2017

Hematology/Oncology Subcommittee review. Initial document development. Moved content from DRUG.00059 Romiplostim (Nplate®) to new clinical utilization management guideline document with the same title. Added MN statement for treatment of myelodysplastic syndrome (MDS) in individuals with severe or refractory thrombocytopenia when criteria met. Removed MDS from NMN statement. Updated Coding section.