Romiplostim (Nplate)

Number: 0768

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses romiplostim (Nplate) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

  1. Exclusions

    Aetna will not provide coverage for members with the following exclusion: concomitant use of romiplostim (Nplate) with other thrombopoietin receptor agonists (e.g., eltrombopag [Promacta], avatrombopag [Doptelet] or lusutrombopag [Mulpleta]) or spleen tyrosine kinase inhibitors (e.g., Tavalisse).

  2. Prescriber Specialties

    This medication must be prescribed by or in consultation with a hematologist or oncologist.

  3. Criteria for Initial Approval

    Aetna considers romiplostim (Nplate) medically necessary for the following indications:

    1. Immune Thrombocytopenia (ITP)

      For treatment of ITP when both of the following criteria are met:

      1. Inadequate response or intolerance to prior therapy with corticosteroids, immunoglobulins, or splenectomy; and
      2. Untransfused platelet count at any point prior to the initiation of the requested medication is less than 30 x 109/L, or the member has a platelet count at time of diagnosis of between 30 x 109/L to 50 x 109/L with symptomatic bleeding (e.g., significant mucous membrane bleeding, gastrointestinal bleeding or trauma) or risk factors for bleeding (see Appendix);

    2. Hematopoietic Syndrome of Acute Radiation Syndrome (HS-ARS)

      For treatment of hematopoietic syndrome of acute radiation syndrome (acute exposure to myelosuppressive doses of radiation);

    3. Myelodysplastic Syndromes

      For treatment of myelodysplastic syndromes (MDS);

    4. Chemotherapy-induced Thrombocytopenia

      For treatment of chemotherapy-induced thrombocytopenia (CIT) when either of the following criteria is met:

      1. The platelet count is less than 100 x 109/L for at least 3 to 4 weeks following the last chemotherapy administration, or
      2. Chemotherapy administration has been delayed related to thrombocytopenia.

    Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

  4. Continuation of Therapy

    Aetna considers continuation of romiplostim (Nplate) therapy medically necessary for the following indications:

    1. Immune Thrombocytopenia (ITP)

      For treatment of ITP when any of the following criteria is met:

      1. Members with current platelet count less than 50x109/L for whom the platelet count is not sufficient to prevent clinically important bleeding and who have not received a maximal Nplate dose for at least 4 weeks; or
      2. Members with current platelet count less than 50x109/L for whom the current platelet count is sufficient to prevent clinically important bleeding; or
      3. Members with current platelet count of 50x109/L to 200x109/L; or
      4. Members with current platelet count greater than 200x109/L to less than or equal to 400x109/L for whom Nplate dosing will be adjusted to achieve a platelet count sufficient to avoid clinically important bleeding;

    2. Hematopoietic Syndrome of Acute Radiation Syndrome (HS-ARS)

      For all members (including new members) who meet all initial medical necessity selection criteria;

    3. Myelodysplastic Syndromes 

      For treatment of myelodysplastic syndromes in members who experience benefit from therapy (e.g., increased platelet counts, decreased bleeding events, reduced need for platelet transfusions);

    4. Chemotherapy-induced Thrombocytopenia

      For continued treatment of chemotherapy-induced thrombocytopenia (CIT) when all of the following criteria are met:

      1. Member is experiencing benefit from therapy (e.g., increased platelet counts, decreased bleeding events, reduced need for platelet transfusions) to maintain a target platelet count goal count of 100x109/L - 200x109/L; and
      2. The requested drug is used to maintain dose schedule and intensity of chemotherapy.

Dosage and Administration

Romiplostim (Nplate) for injection is available as 125 mcg, 250 mcg or 500 mcg of deliverable romiplostim as a lyophilized powder in single-dose vials.

Hematopoietic Syndrome of Acute Radiation Syndrome (HS-ARS)

The recommended dose of Nplate is 10 mcg/kg administered once as a subcutaneous injection in adults and pediatrics (including term neonates). The dose should be administered as soon as possible after suspected or confirmed exposure to radiation levels greater than 2 gray (Gy).

Immune Thrombocytopenia (ITP)

After initial dose, the dose is adjusted based on platelet response, using the lowest dose to achieve and maintain a platelet count greater than or equal to 50 x 109/L as necessary to reduce the risk for bleeding. In the clinical trials, subjects received single weekly subcutaneous injections of Nplate, with individual dose adjustments to maintain platelet counts of 50 × 109/L to 200 × 109/L.

Romiplostim should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy at the maximum weekly dose of 10 mcg/kg.

Romiplostim may be used with other ITP therapies, such as corticosteroids, danazol, azathioprine, intravenous immunoglobulin, and anti-D immunoglobulin. 

Some studies have suggested that romiplostim may be reduced or discontinued in select persons If the member's platelet count is 50 x 109/L or greater. However, it should be noted that discontinuing Nplate therapy may result in a sudden drop in platelet count, thus, appropriate monitoring should be employed (Amgen, 2018; Vishnu and Aboulafia, 2016).

Recommended Dosing Adjustments for Adults

The initial dose of romiplostim (Nplate) is 1 mcg/kg with future dose adjustments based on changes in platelet counts only. Once-weekly dose is adjusted by increments of 1 mcg/kg, not to exceed 10 mcg/kg per week, to achieve a platelet count of greater than or equal to 50 x 109/L as necessary to reduce the risk for bleeding. In clinical studies, most adults who responded to romiplostim achieved and maintained platelet counts greater than or equal to 50 x 109/L with a median dose of 2-3 mcg/kg. 

  • If the platelet count is less than 50 × 109 /L, increase the dose by 1 mcg/kg.
  • If platelet count is greater than 200 × 109 /L and less than or equal to 400 × 109 /L for 2 consecutive weeks, reduce the dose by 1 mcg/kg.
  • If platelet count is greater than 400 × 109 /L, do not dose. Continue to assess the platelet count weekly. After the platelet count has fallen to less than 200 × 109 /L, resume Nplate at a dose reduced by 1 mcg/kg.

Recommended Dosing Adjustments for Pediatrics (1 year to 17 years)

The initial dose of romiplostim (Nplate) is 1 mcg/kg with future dose adjustments based on changes in platelet counts and changes in body weight. Reassessment of body weight is recommended every 12 weeks.

It is recommended that the weekly dose of Nplate be adjusted by increments of 1 mcg/kg until the pediatric member achieves a platelet count greater than or equal to 50 × 109 /L as necessary to reduce the risk for bleeding, not to exceed a maximum weekly dose of 10 mcg/kg. In a pediatric placebo-controlled clinical study, the median dose was 5.5 mcg/kg.

  • If the platelet count is less than 50 × 109 /L, increase the dose by 1 mcg/kg.
  • If platelet count is greater than 200 × 109 /L and less than or equal to 400 × 109 /L for 2 consecutive weeks, reduce the dose by 1 mcg/kg.
  • If platelet count is greater than 400 × 109 /L, do not dose. Continue to assess the platelet count weekly. After the platelet count has fallen to less than 200 × 109 /L, resume Nplate at a dose reduced by 1 mcg/kg.

Source: Amgen, 2021

Experimental and Investigational

Aetna considers romiplostim experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

  • Aplastic anemia
  • Evans syndrome
  • Graft-versus-host disease
  • Hepatitis C
  • Stem cell mobilization
  • Thrombocytopenia during pregnancy
  • Thrombocytopenia following allogeneic stem cell transplantation.

Note: Romiplostim should not be utilized to normalize platelet counts.

Note: Persons who have lost response to romiplostim should be assessed for other possible etiologies (e.g., antibodies to romiplostim and bone marrow fibrosis) and romiplostim discontinued.

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB:
38100 - 38120 Splenectomy
96372, 96374, 96375, 96376, 96379 Therapeutic, prophylactic, or diagnostic injection

HCPCS codes covered if selection criteria are met:
J2796 Injection, romiplostim, 10 mcg [Nplate]

Other HCPCS codes related to the CPB:

Doptelet (avatrombopag), mulpleta (lusutrombopag), Spleen tyrosine kinase inhibitors (e.g., Tavalisse) - no specific code:
J2355 Injection, oprelvekin, 5mg

ICD-10 codes covered if selection criteria are met:
D46.22, D46.c, D46.9 Myelodysplastic syndrome
D69.3 Immune thrombocytopenic purpura [idiopathic]
D69.49 Other primary thrombocytopenia
D69.59 Other secondary thrombocytopenia [chemotherapy-induced thrombocytopenia]
T45.1x5A - T45.1x5S Adverse effect of antineoplastic and immunosuppressive drugs, initial encounter, subsequent encounter, or sequela
T66.XXXA - T66.XXXS Radiation sickness, unspecified [Hematopoietic syndrome of acute radiation syndrome]

ICD-10 codes not covered for indications listed in the CPB:
B17.10 - B17.11 Acute hepatitis C
B18.2 Chronic viral hepatitis C
B19.20 - B19.21 Unspecified viral hepatitis C
D61.01 - D61.9 Other aplastic anemias and other bone marrow failure syndromes
D69.0 - D69.2
D69.41, D69.42
D69.51, D69.6 - D69.9		 Purpura and other hemorrhagic conditions [thrombocytopenia associated with Evans syndrome]
D75.81 Myelofibrosis
D75.82 Heparin-induced thrombocytopenia (HIT)
D89.810 - D89.813 Graft-versus-host disease [associated with thrombocytopenia]
M31.1 Thrombotic microangiopathy
O72.3 Postpartum coagulation defects
O36.821+ - O36.829+ Fetal anemia and thrombocytopenia
O99.110 - O99.119 Other diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism complicating pregnancy [thrombocytopenia]
P61.0 Transient neonatal thrombocytopenia
T86.5 Complications of stem cell transplant [thrombocytopenia following allogeneic stem cell transplantation]

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

  • Nplate is indicated for the treatment of thrombocytopenia in:

    • Adult patients with immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy;
    • Pediatric patients 1 year of age or older with ITP for at least 6 months who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

  • Nplate is indicated to increase survival in adults and in pediatric patients (including term neonates) acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [HS-ARS]).

Compendial Uses

  • Myelodysplastic syndromes (MDS)
  • Chemotherapy-induced thrombocytopenia (CIT)

Romiplostim is available as Nplate (Amgen, Inc) and is a thrombopoiesis stimulating peptibody developed to stimulate platelet production. It binds to and stimulates the thrombopoietin (TPO) receptor. It has no sequence homology with endogenous TPO, and therefore is not expected to elicit cross‐reacting antibodies that cause thrombocytopenia, a problem that has occurred with previously studied recombinant TPO agents (Amgen, 2021).

Per the prescribing information, romiplostim (Nplate) carries the following warnings and precautions:

  • Risk of progression of myelodysplastic syndromes to acute myelogenous leukemia: In some individuals with myelodysplastic syndrome, Nplate increases blast cell counts and increased the risk of progression to acute myelogenous leukemia;
  • Thrombotic/thromboembolic complications:Thrombotic/thromboembolic complications may follow from increases in platelet counts with Nplate use;
  • Loss of response to Nplate: Hyporesponsiveness or failure to maintain a platelet response with Nplate can occur and should prompt an investigation for causative factors, including neutralizing antibodies to Nplate.

Per the prescribing information, the most common adverse reactions are as follows:

  • In adult patients at ≥ 5% higher patient incidence in Nplate versus placebo include: arthralgia, dizziness, insomnia, myalgia, pain in extremity, abdominal pain, shoulder pain, dyspepsia, an paresthesia;
  • In pediatric patients at an incidence ≥ 25% include: contusion, upper respiratory tract infection, and oropharyngeal pain.

Aplastic Anemia

Ise et al (2020) stated that eltrombopag (EPAG) and romiplostim (ROM), thrombopoietin receptor-agonists with demonstrated effectiveness against aplastic anemia (AA) in prospective controlled studies, were authorized in Japan for use in adults with AA in 2017 and 2019, respectively.  So far, no data are available on the potential contribution of switching from ROM to EPAG or vice versa in terms of effectiveness or tolerance.  Effectiveness and tolerance profiles of 10 patients, who failed to respond to the maximum dose of EPAG and then switched to ROM, were evaluated.  All 10 patients received a maximum dose of ROM (20 μg/kg/week).  At a median follow-up of 12 months, 7 of the 10 patients (70 %) had achieved either neutrophil, erythroid, or platelet response, including 1 complete response (CR).  No patients showed platelet count fluctuations that were reported during ROM treatment for immune thrombocytopenia.  In univariate analysis of the relationship between effectiveness and demographics, the response had a correlation with neither factor.  None of the patients stopped the ROM treatment because of adverse events (AEs).  The authors concluded that although a larger number of patients and a longer follow-up period are needed to confirm these findings, they showed the effectiveness of ROM in patients with EPAG-refractory AA.

Yoshinari et al (2021) noted that patients with hepatitis-associated AA (HAA) who undergo living-donor liver transplantation (LDLT) have a poor prognosis with infections and bleeding complications.  Rapid recovery of blood cells is critical for preventing these complications and improving the outcome.  Immunosuppressive therapy (IST) combined with thrombopoietin receptor agonists is considered effective for AA; however, there are no data on the benefits of adding thrombopoietin receptor agonists to IST for HAA.  These researchers presented the case of a child with severe HAA who underwent LDLT, and who achieved rapid blood cell recovery with IST combined with ROM.  Furthermore, despite having undergone LDLT, the patient had no AEs such as serious liver dysfunction or thrombosis.  The authors concluded that the findings of this single-case study suggested that IST combined with thrombopoietin receptor agonists (e.g., ROM) may be a promising therapeutic option for HAA patients undergoing LDLT.

Hematopoietic Syndrome of Acute Radiation Syndrome (HSARS)

On January 28, 2021, the FDA granted Romiplostim (Nplate) approval for the indication of romiplostim to increase survival in adults and pediatric patients (including term neonates) acutely exposed to myelosuppressive doses of radiations (hematopoietic syndrome in acute radiation syndrome [HS-ARS]) under the "prior approval" efficacy supplement to Amgen's biologics license application under the Animal Rule (Amgen, 2021). Per the prescribing information, efficacy studies could not be performed in humans with acute radiation syndrome for ethical and feasibility concerns. This approval was established on efficacy studies conducted in animals, Nplate's outcome on platelet count in healthy human volunteers and on data supporting Nplate's effect on thrombocytopenia in patients with immune thrombocytopenia (ITP) and insufficient response to corticosteroids, immunoglobulins, or splenectomy. The efficacy of Nplate for this indication was based on that observed in efficacy studies conducted in animals. The safety of Nplate for the acute radiation syndrome setting was evaluated on the basis of clinical experience in patients with ITP.

Immune Thrombocytopenia (ITP)

Romiplostim (NplateTM, Amgen, Inc., Thousand Oaks, CA) was approved by the Food and Drug Administration (FDA) on August 22, 2008 for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The FDA-approved labeling states that romiplostim should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding and that it should not be used to normalize platelet counts.

The safety and efficacy of romiplostim were assessed in 2 double-blind, placebo-controlled clinical studies of 125 adult patients with chronic ITP and in an open-label extension study.  In these studies, treatment with romiplostim resulted in dose-dependent increases in platelet counts.  After a single subcutaneous dose of 1 to 10 mcg/kg of romiplostim, the peak platelet count was 1.3 to 14.9 times greater than the baseline platelet count over a 2- to 3-week period.  The platelet counts were above 50 x 109/L for 7 out of 8 patients with chronic ITP who received 6 weekly doses of romiplostim at 1 mcg/kg.

Kuter et al. (2008) assessed the long-term effects of romiplostim in splenectomized and non-splenectomized patients with ITP in 2 parallel trials.  A total of 63 splenectomized and 62 non-splenectomized patients with ITP with a mean of 3 platelet counts of 30 x 109/L or less were randomly assigned 2:1 to subcutaneous injections of romiplostim (n = 42 in the splenectomized study and n = 41 in the non-splenectomized study) or placebo (n = 21 in both studies) every week for 24 weeks.  Doses of romiplostim were adjusted to maintain platelet counts of 50 x 109/L to 200 x 109/L.  The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count greater than or equal to 50 x 109/L during 6 or more of the last 8 weeks of treatment) and treatment safety.  The authors reported that a durable platelet response was achieved by 38 % (16/42) of the splenectomized patients given romiplostim versus none (0/21) of the placebo patients, and by 61 % (25/41) of the non-splenectomized patients given romiplostim versus 0.05 % (1/21) given placebo.  Eighty-seven percent (20/23) of patients given romiplostim (12/12 splenectomized and 72 % (8/11) non-splenectomized patients) reduced or discontinued concurrent therapy compared with 38 % (6/16) of those given placebo (1/6 splenectomized and 5/10 non-splenectomized patients).  Adverse events were reported to be similar in both groups.  Furthermore, no antibodies against romiplostim or thrombopoietin were detected.  The authors concluded that romiplostim was well-tolerated and increased and maintained platelet counts in splenectomized and non-splenectomized patients with ITP and that many patients were able to reduce or discontinue other ITP medications.

Following completion of the placebo-controlled studies, 100 patients entered an extension study of long-term romiplostim therapy.  The majority of patients maintained platelet counts of 50,000/mcL or greater throughout the study with a median duration of romiplostim treatment of 60 weeks and a maximum duration of 96 weeks.

The major safety concerns consisted of risks for bone marrow reticulin formation and worsened thrombocytopenia (compared to baseline) following romiplostim discontinuation.  Other potential risks include marrow fibrosis during long-term therapy or thromboses due to excessive platelet increases.  

Vadhan-Raj (2009) stated that despite the extensive efforts in the clinical development of thrombopoietic agents in the past decade, recombinant interleukin-11 (IL-11) is the only agent currently approved by the FDA for thrombocytopenia induced by chemotherapy.  The use of this agent is limited due to its narrow therapeutic index.  While promising biologic activity was observed with recombinant thrombopoietins (TPOs) in non-myeloablative clinical settings, further clinical development was halted due to evidence of neutralizing antibodies to pegylated recombinant human megakaryocyte growth and development factor.  Recently, a number of novel TPO receptor agonists have been developed with promising clinical activity and a lesser potential for immunogenicity.  Several of these second-generation platelet-stimulating agents are currently in clinical development, including peptide (romiplostim) and non-peptide (eltrombopag and AKR501) mimetics.  The clinical trials of romiplostim and eltrombopag are currently ongoing to optimize their dose and schedule in ameliorating chemotherapy-induced thrombocytopenia.

Kuter (2011) noted that thrombocytopenia is a common clinical problem associated with a wide range of medical conditions including ITP, chemotherapy-induced thrombocytopenia (CIT), hepatitis C-related thrombocytopenia, and MDS.  Until recently, the only treatments for thrombocytopenia were to alleviate the underlying cause or to provide platelet transfusions.  With the discovery and recent clinical availability of TPO mimetics, a new treatment option has emerged.  Two TPO mimetics are currently clinically available for treating ITP: romiplostim (an injectable peptide TPO mimetic) and eltrombopag (a non-peptide, orally available TPO mimetic).  The author reviewed the development, biology, and clinical trials with romiplostim.  With few adverse effects, romiplostim is effective in raising the platelet count in over 80 % of ITP patients, allowing them to discontinue other therapies, reduce the need for splenectomy, and improve their quality of life.  Long-term theoretical side effects of romiplostim treatment include reticulin formation, thrombo-embolism, and antibody formation to romiplostim.  A practical way of using romiplostim is provided: a higher starting dose of 3 mg/kg is recommended along with efforts to avoid withholding the dose.  The author concluded that future studies are needed to evaluate the utility of romiplostim in CIT, hepatitis-C related thrombocytopenia, and MDS.

In a review on "Novel agents and approaches for stem cell mobilization in normal donors and patients", Bakanay and Demirer (2012) listed thrombopoietin-receptor agonists including romiplostim as one of the investigational agents.  They noted that in the future, thrombopoietin-receptor agonists may be potential adjuncts to granulocyte colony-stimulating factor in poor mobilizers.

Evans syndrome is an autoimmune disorder characterized by the simultaneous or sequential development of autoimmune hemolytic anemia and immune thrombocytopenia.  It may be primary (idiopathic), or associated with other diseases.  First-line therapy is immunosuppression; and 2nd-line therapy includes danazol and splenectomy.  Gonzalez-Nieto et al. (2011) reported a case of a man diagnosed with systemic lupus erythematosus, associated anti-phospholipid syndrome and Evans syndrome, who developed a severe thrombocytopenia refractory to treatment with first-line drugs, cyclophosphamide and rituximab, and who responded to romiplostim with a normalization of the platelet recount, which later enabled a therapeutic splenectomy to be performed.  Moreover, UpToDate review on "Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome" (Ware, 2023) do not mention the use of romiplostim as a therapeutic option.

Ruiz-Delgado et al. (2011) stated that thrombocytopenia ensuing during acute graft-versus-host disease (GVHD) is multi-factorial and may significantly compromise the prognosis of the patient; non-immune persistent thrombocytopenia has been considered as an adverse prognostic factor in GVHD.  These investigators described the case of a 10-year old girl who developed steroid-refractory thrombocytopenia and who responded promptly to the subcutaneous delivery of romiplostim.  The authors noted that to the best of their knowledge, this is the first description of the usefulness of the peptibody in the setting of GVHD.  However, UpToDate reviews on "Overview of immunosuppressive agents used for prevention and treatment of graft-versus-host disease" (Chao, 2020),"Treatment of chronic graft-versus-host disease" (Zeiser, 2023b), and "Treatment of acute graft-versus-host disease" (Zeiser, 2023a) do not mention the use of romiplostim as a therapeutic option.

Buccoliero et al. (2014) described a case of a 64-year old man with a history of ITP which had required several treatments including splenectomy, and with chronic hepatitis C virus (HCV) infection untreated due to severe thrombocytopenia.  In March 2011, platelet count was 14,000/mmc and a thrombopoietic therapy with romiplostim was initiated at the dose of 2 ug/kg/week that was increased to 8 ug/kg/week.  At week 32, platelet count was 65,000/mmc and an anti-HCV therapy with peginterferon and ribavirin was then started.  At baseline laboratory tests indicated AST 99 IU/l, ALT 125 UI/l, HCV_RNA 3,220 UI/ml and HCV genotype 2a/2c.  An early virological response (EVR) with normalization of transaminases in the course of anti-viral therapy, such as a sustained virological response (SVR) after its interruption were recorded.  Therefore, a satisfactory platelet count (range of 54,000 to 179,000/mmc) at the dose of 4 ug/week during anti-viral therapy, such as at the dose of 2 ug/kg/week after anti-viral interruption (range 65,000 to 292,000/mmc) was recorded.  Romiplostim proved safe and effective in the course of anti-viral treatment.  Therefore, it permitted the start of anti-HCV therapy despite severe thrombocytopenia and also avoided any peg-interferon dosage modification or discontinuation.  The authors stated that further prospective studies in larger patient cohort should be encouraged to validate this strategy.

Parameswaran et al. (2014) reported on a series of 20 patients who had protracted CIT and were treated with romiplostim.  These researchers performed a retrospective review of the use of romiplostim for dose-limiting CIT at Memorial Sloan-Kettering Cancer Center from 2010 to 2012  Romiplostim was initiated at 1 to 2 ug/kg weekly, with dose escalation by 1 ug/kg per week until recovery of platelets (greater than or equal to 100 × 10(9)/L).  If patients resumed chemotherapy, weekly romiplostim was continued.  Romiplostim improved platelet counts in all 20 patients.  In 19 of 20 patients, platelet counts of greater than or equal to 100 × 10(9)/L were achieved.  The mean dose of romiplostim to achieve adequate platelet recovery was 2.9 ug/kg (range of 1.0 to 5.1); 16 patients achieved platelet recovery by 2 weeks.  Fifteen patients resumed cytotoxic chemotherapy with continued romiplostim support and 14 tolerated at least 2 subsequent cycles of chemotherapy, on schedule, without recurrence of dose-limiting CIT.  Sepsis prevented continued chemotherapy in 1 patient.  No resistance to romiplostim was observed.  Three deep vein thromboses (DVT) were observed; 1 of which was a recurrent DVT in a patient who had previously experienced a DVT and was off anti-coagulation.  Three DVTs within 20 patients is within the anticipated thrombosis rates of patients with active cancer on chemotherapy.  The authors concluded that romiplostim resulted in improvement in platelet counts, allowing resumption of chemotherapy without recurrence of dose-limiting CIT.  No treatment-related toxicity was observed, but this would need to be confirmed in a larger, prospective trial.  They stated that their series differed from prior studies in that they selected only those patients who had already demonstrated persistent thrombocytopenia, and they continued weekly romiplostim during chemotherapy.  Romiplostim may be a safe and effective treatment for CIT.

Yamada and associates (2014) reported on the case of a woman in her 60s who was referred to the authors’ department with advanced rectal cancer and multiple unresectable metastases of the liver and peritoneum.  She had been diagnosed with ITP in her 20s, with a platelet count maintained at approximately 1.0×10(4)/μL by prednisolone; on admission, her platelet count was 0.9×10(4)/μL.  Romiplostim was administered prior to chemotherapy.  Her platelet count increased to about 10.0×10(4)/μL during chemotherapy with oxaliplatin plus capecitabine, and she developed DVT requiring inferior vena cava filter placement and anti-coagulation.  No other severe adverse events occurred.  The authors noted that there is no standard regimen for the treatment of solid tumors in patients with ITP.   This was the first reported case of the concomitant use of romiplostim and chemotherapy for advanced rectal cancer. 

Myelodysplastic Syndromes (MDS)

According to the FDA (2008), in a single-arm trial investigating the use of romiplostim in myelodysplastic syndromes (MDS), 11 of 44 patients were reported as having possible disease progression, among whom 4 patients developed acute myelogenous leukemia.  Randomized, controlled studies are needed to determine the risks and benefits of romiplostim in these patients.  In the controlled studies of patients with chronic ITP, the incidence of hematologic malignancies was low and similar between romiplostim and placebo.  Romiplostim is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.

Kantarjian and colleagues (2010) evaluated the safety and effectiveness of romiplostim for treatment of thrombocytopenic patients with MDS.  Eligible patients had lower-risk MDS (International Prognostic Scoring System low or intermediate 1), a mean baseline platelet count less than or equal to 50 x 109/L, and were only receiving supportive care.  Patients received 3 injections of 300, 700, 1,000, or 1,500 mcg romiplostim at weekly intervals.  After evaluation of platelet response at week 4, patients could continue to receive romiplostim in a treatment extension phase for up to 1 year.  All 44 patients who enrolled completed the treatment phase; 41 patients continued into the extension phase.  Median platelet counts increased throughout the study, from fewer than 30 x 109/L at baseline to 60, 73, 38, and 58 x 109/L at week 4 for the 300-, 700-, 1,000-, and 1,500-mcg dose cohorts, respectively.  A durable platelet response (per International Working Group 2000 criteria for 8 consecutive weeks independent of platelet transfusions) was achieved by 19 patients (46 %).  The incidence of bleeding events and platelet transfusions was less common among patients who achieved a durable platelet response than those who did not (4.3 versus 39.3 per 100 patient-weeks).  Forty-three patients (98 %) reported 1 or more adverse events.  Treatment-related serious adverse events were reported in 5 patients (11 %), all of whom were in the 1,500-mcg dose cohort.  Two patients progressed to acute myeloid leukemia during the study.  No neutralizing antibodies to either romiplostim or endogenous thrombopoietin were seen.  The authors concluded that romiplostim appeared well-tolerated in this study and may be a useful treatment for patients with MDS and thrombocytopenia.  The key drawback of this study was the lack of a control group.  These investigators stated that ongoing randomized controlled  trials and future combination studies will optimize the dose schedules of romiplostim and define its precise therapeutic role in MDS.

In a phase II, multi-center, open-label study, Sekeres et al. (2011) examined the effects of subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with lower risk MDS.  A total of 28 thrombocytopenic patients with lower risk MDS were assigned to receive romiplostim 750 μg administered subcutaneously either weekly or bi-weekly or administered as bi-weekly intravenous injections for 8 weeks.  Patients also could enter a 1-year study extension phase.  At least 1 adverse event was observed in 93 % of patients.  The most common adverse events were fatigue and headache (18 % for both, and 5 events were grade 3 or 4.  There was 1 serious treatment-related adverse event in the bi-weekly intravenous cohort (hypersensitivity).  This hypersensitivity resolved without discontinuation of study treatment.  No patients developed neutralizing antibodies or bone marrow fibrosis.  Of the patients who completed 8 weeks of treatment, 57 % had a complete platelet response, an additional 8 % had a major platelet response, and 61 % did not require a platelet transfusion during this period.  Weekly subcutaneous injections achieved the highest mean trough concentrations.  The authors concluded that the safety and efficacy profiles of romiplostim in this study suggested that weekly subcutaneous administration of 750 μg romiplostim is an appropriate starting dose for future clinical studies in patients with MDS and thrombocytopenia.

Prica et al. (2014) stated that thrombocytopenia is common (40 to 65 %) and potentially serious in MDS. These investigators performed a systematic review to determine the safety and effectiveness of adding a thrombopoietin-receptor (THPO-R) agonist to standard MDS treatment. MEDLINE, EMBASE and CENTRAL databases were searched. These researchers included randomized controlled trials (RCTs) comparing a THPO-R agonist to placebo. A meta-analysis of the effects was performed. End-points included bleeding and platelet transfusion rates, risk of progression to AML and mortality. A total of 384 patients from 5 trials were included, 4 using romiplostim and 1 using eltrombopag. Overall, the relative risk (RR) of bleeding with romiplostim versus placebo was 0.84 [95 % CI: 0·57 to 1.24]. However, compared to placebo, romiplostim significantly decreased the exposure-adjusted bleeding rate (RR 0.92; 95 % CI: 0.86 to 0.99), as well as the exposure-adjusted platelet transfusion rate (RR 0.69; 95 % CI: 0.53 to 0.88). The RR of AML progression with romiplostim was 1.36 (95 % CI: 0.54 to 3·40), however the outcome data were judged as higher risk of bias. The authors concluded that romiplostim is promising in its ability to decrease patient-important outcomes: bleeding and platelet transfusion need. Moreover, they stated that although the risk of AML progression was not increased, due to unclear risk of bias in the data, this safety concern is difficult to assess. These investigators stated that romiplostim cannot yet be routinely recommended.

Giagounidis and colleagues (2014) evaluated the effectiveness of romiplostim in patients who had thrombocytopenia with low-risk/intermediate-1-risk MDS.  Patients who had thrombocytopenia with low-risk/intermediate-1-risk MDS (n = 250) were randomized 2:1 to receive romiplostim or placebo weekly for 58 weeks.  The primary end-point was the number of clinically significant bleeding events (CSBEs) per patient-had a hazard ratio for romiplostim : placebo of 0.83 (95 % confidence interval [CI], 0.66 to 1.05; p = 0.13).  Clinically significant bleeding events were reduced significantly in the romiplostim group for patients who had baseline platelet counts greater than or equal to 20 × 10(9) /L (p < 0.0001).  For patients who had baseline platelet counts less than 20 × 10(9) /L, there was no difference in the number of CSBEs, but the platelet transfusion rates were higher in the placebo group (p < 0.0001), which may have affected the overall CSBE results in this group with severe thrombocytopenia.  The incidence of bleeding events was reduced significantly in the romiplostim group (relative risk, 0.92), as were protocol-defined platelet transfusions (relative risk, 0.77).  Platelet response rates according to 2006 International Working Group criteria were higher for the group that received romiplostim (odds ratio, 15.6).  On the basis of interim data, an independent data monitoring committee advised halting study drug because of concerns regarding excess blasts and AML rates with romiplostim (interim hazard ratio, 2.51).  At 58 weeks, the acute myeloid leukemia (AML) rates were 6 % in the romiplostim group and 4.9 % in the placebo group (hazard ratio, 1.20; 95 % CI: 0.38 to 3.84), and the overall survival (OS) rates were similar.  The authors concluded that romiplostim treatment in patients with low-risk/intermediate-1-risk MDS increased platelet counts and decreased the number of bleeding events and platelet transfusions.  Although study drug was discontinued because of an initial concern of AML risk, survival and AML rates were similar with romiplostim and placebo.

Kantarjian et al. (2018) conducted a 5-year follow-up study to evaluate the long-term risk of leukemic progression in thrombocytopenic patients with lower-risk MDS treated with romiplostim or placebo in the published (Gigounidis et al. 2014) phase 2, multicenter, double-blind trial, which included 250 patients and resulted in early discontinuation of romiplostim due to potential for disease progression to AML. The primary outcomes for this long-term follow-up were survival and progression to AML. Progression to AML was defined as either 20% blasts or more after 4 weeks from romiplostim discontinuation. Out of the 250 patients, 210 (84%) entered the 5-year long-term follow-up. At the end of follow-up, proportions of patients with AML (12% in the romiplostim group vs 11% in the placebo group (p=0·88)) and proportions who died (p=0·89) were not significantly different between the two groups. The authors concluded that their results indicate that use of romiplostim is probably not associated with any increased risk of AML or death, despite initial concerns.

Nplate (romiplostim) is not FDA-approved for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP (Amgen, 2018).

The prognosis and treatment for MDS vary depending on a person's International Prognostic Scoring System (IPSS) score. Those with a low/intermediate-1 risk score may live with their disease for a number of years. Person's with higher scores (e.g., intermediate-2 and high risk; IPSS ≥ 1.5) are at higher risk of transformation to acute myelogenous leukemia. Most people with high-risk disease die from their disease within 1 year of diagnosis (Advani, 2006).

Lower risk is defined as IPSS-R (Very Low, Low, Intermediate), IPSS (Low/Intermediate-1), WPSS (Very Low, Low, Intermediate). The NCCN guidelines on "Myelodysplastic syndromes" (version 1.2023) state that "in a randomized study including patients low- or int-1-risk MDS (n=250), romiplostim was associated with increased platelet counts and decreased overall bleeding events (p=0.26 after 58 weeks of treatment compared to the placebo group). However, due to the early drug discontinuation, interpretation of these data is limited." The study drug, romiplostim, was discontinued early because of the potential risk for disease progression to AML. NCCN notes that an open-label extension study evaluated the long-term efficacy and safety of romiplostim in 60 patients with lower-risk MDS and found that most achieved durable responses. "A model to predict response to romiplostim indicated that lower-risk MDS, lower baseline TPO levels (less than 500 pg/mL), and limited platelet transfusion history, had the greatest effect on subsequent platelet response to romiplostim". NCCN does point out that romiplostim is not currently approved for use in persons with MDS.

A review in UpToDate on "Management of the hematologic complications of the myelodysplastic syndromes" (Sekeres, 2022) discussed the clinical trial by Giagounidis et al. (2014) that included 250 patients with thrombocytopenia with low-risk/intermediate 1-risk MDS who were randomized 2:1 to receive romiplostim or placebo weekly for 58 weeks. Seketes states that romiplostim should not be used routinely in MDS based on this clinical trial; however, it appears reasonable to consider use in patients with bleeding due to low platelet counts who do not respond to transfusions and in whom aminocaproic acid has been unsuccessful.

Pediatric Use

Nplate (romiplostim) is FDA-approved in pediatric patients 1 year of age and older with ITP for at least 6 months and who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy (Amgen, 2018).

Berrueco and colleagues (2018) stated that until a few years ago, splenectomy was one of the main strategies for treatment of immune thrombocytopenia (ITP) in adults and children aged more than 5 years.  After the introduction of rituximab, pharmacological treatment started to displace surgery as a 2nd-line treatment.  At present, many experts recommend the use of receptor agonists (TPO-Ras; eltrombopag and romiplostim) in patients that do not respond to initial treatment with corticosteroids and immunoglobulin before the use of rituximab and surgery.  However, studies that compare both therapeutic options have yet to be conducted.  In general, and while most guidelines do not recommend splenectomy until ITP has lasted a minimum of 12 months, its use remains controversial.  Some patients, as those aged less than 5 years are not eligible for surgery, in other cases parents or legal guardians refuse splenectomy.  Finally, sometimes the primary goal of treatment is to improve the quality of life (cases where medical treatment would a priori be preferred over surgical treatment).  In all other patients, those who are actually candidates for splenectomy, the risks associated with this irreversible procedure.  Thus, despite a good initial response (70 to 85 % of cases) and the fact that most patients maintain a normal platelet count 5 years post-intervention (60 to 70 % of cases), one cannot ignore the associated morbidity: the risk of infection in splenectomized patients is as high as 11 to 16 % even with correct vaccination and administration of antibiotic prophylaxis, the proportion of patients that develop thrombosis after surgery ranges between 1.6 and 4.3 %, and the risk of severe intra-operative or post-operative hemorrhage is of 0.78 %.  Thus, since the benefits of splenectomy do not seem to outweigh its disadvantages in children, this intervention should only be used in selected cases: patients who cannot tolerate or do not respond to medical treatment, including corticosteroids, immunoglobulins, TPO-RAs and even immunosuppressive therapy.  Splenectomy is also clearly indicated in patients with life-threatening hemorrhage, although this is an extremely rare event.  Lastly, splenectomy can also be considered in patients that have a poor health-related quality of life despite receiving other treatment, or at the request of the family.  The authors stated that the latest recommendations call for exhausting all options of medical treatment in children with chronic ITP before resorting to splenectomy, with especial emphasis on the use of TPO-Ras.

Grace and associates (2019) noted that while many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding, or to improve health related quality of life (HRQoL).  There are a number of available 2nd-line treatments, including rituximab, thrombopoietin-receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking.  ICON1 is a prospective, multi-center, observational study of 120 children starting 2nd-line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT).  While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months (p = 0.04).  Only patients on romiplostim and rituximab had a significant reduction in both skin-related (84 % to 48 %, p = 0.01 and 81 % to 43 %, p = 0.004) and non-skin-related bleeding symptoms (p = 0.0001 and p = 0.0006) after 1 month of treatment.  HRQoL significantly improved on all treatments.  However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID).  Bleeding, platelet count, and HRQoL improved in each treatment group, but the extent and timing of the effect varied among treatments.  The authors concluded that these results are hypothesis-generating and help to improve the understanding of the effect of each treatment on specific patient outcomes.  Combined with future randomized trials, these findings will help clinicians select the optimal second-line treatment for an individual child with ITP.

Furthermore, an UpToDate review on "Immune thrombocytopenia (ITP) in children: Management of chronic disease" (Bussel, 2023) states that "In the modern era, splenectomy is very rarely used in the management of pediatric ITP. It is an option for the small percentage of patients with chronic ITP who have persistent clinically significant, generally severe thrombocytopenia accompanied by hemorrhagic symptoms and require repeated or continuous pharmacologic interventions. Although splenectomy is effective in most patients, it is also associated with substantial risks. Rates of splenectomy among children with ITP have declined considerably since the early 2000s, likely due to increased availability of other effective second-line therapies". 

Thrombocytopenia during Pregnancy

Decroocq et al. (2014) stated that primary immune thrombocytopenia is not a rare event during pregnancy, and it must be carefully managed to avoid hemorrhagic complications for the mother. After failure of first-line treatments, the teratogenicity and toxicity of other therapeutic agents limit the available options and treatment. These investigators described the cases of 2 pregnant patients with corticosteroid-refractory immune thrombocytopenia who were successfully treated by romiplostim without any fetal or maternal complications. The authors concluded that romiplostim may represent an important alternative treatment choice during pregnancy for immune thrombocytopenia cases refractory to first-line therapy, especially because of its speed of action and high efficacy. Moreover, they stated that further data are needed to provide definitive evidence of its safety for newborns.

Furthermore, an UpToDate review on "Thrombocytopenia in pregnancy" (George, Mcintosh, and Perez-Botero, 2023) states that "Data on the safety of TPO-RAs such as romiplostim and eltrombopag during pregnancy are limited, but emerging information suggests they do not cause a high rate of adverse events".

Thrombocytopenia Following Allogeneic Stem Cell Transplantation

Maximova et al. (2015) examined the outcome of romiplostim for secondary failure of platelet recovery (SFPR) in children who had undergone hematopoietic stem cell transplantation (HSCT). A total of 7 transfusion-dependent pediatric patients (median age of 11 years), with platelet counts below 10 × 109/L, received 4 weekly doses of subcutaneous romiplostim to treat SFPR developed after HSCT. All patients, except 1 (patient 4), became platelet transfusion-independent in the second week from the beginning of treatment and no patient needed to discontinue drug treatment because of adverse events. The authors concluded that romiplostim could represent a beneficial first-line treatment, but further studies are needed.

Furthermore, an UpToDate review on "Hematopoietic support after hematopoietic cell transplantation" (Negrin, 2023) states that "There has been little evaluation of thrombopoietins (eg, romiplostim, eltrombopag) in this setting. Although generally well-tolerated, there is limited evidence that these agents accelerate platelet recovery, reduce bleeding, or lessen platelet transfusion requirements after transplantation".

Lancman and colleagues (2018) stated that thrombocytopenia is a relatively common complication following allogeneic HSCT and is associated with increased bleeding, transfusion requirements, chronic GVHD, and all-cause mortality.  There are currently no approved treatments outside of supportive transfusions.  These investigators reported on the outcomes of 5 patients at their institution who received romiplostim for either primary engraftment failure or secondary failure of platelet recovery following SCT.  In total, 4 of the 5 patients demonstrated a response to romiplostim, which was defined as 7 consecutive days of platelet count of greater than 50 × 109/L with transfusion independence, with 2 ongoing responses (greater than 365 days each) at the conclusion of the study period.  Responses to romiplostim were sustained in the absence of significant bone marrow disease, which was found to contribute to recurrent thrombocytopenia.  Additionally, romiplostim was well-tolerated overall; 1 patient developed minimal fibrotic changes on bone marrow biopsy post-romiplostim.  The authors concluded that although these findings were promising, data from randomized clinical trials are needed to fully understand the role of romiplostim after SCT.

Therapy-Related Thrombocytopenia

Jacobson and colleagues (2017) stated that therapy-related thrombocytopenia (TRT), due to chemotherapy and/or radiation therapy, is common with pediatric cancer treatments, and it can result in dose reductions and therapy delays.  Romiplostim is effective as a 2nd-line treatment for immune thrombocytopenia in children; however, there are no data for its use for TRT in children.  These researchers reported a case series of 5 children treated for solid tumors where romiplostim was used without adverse effects to successfully resolve and prevent therapy-limiting refractory TRT.  The authors concluded that prospective studies on this use of romiplostim are needed.

Appendix

Examples of Risk Factors for Bleeding (not all inclusive):

  • Undergoing a medical or dental procedure where blood loss is anticipated
  • Comorbidity (e.g., peptic ulcer disease, hypertension)
  • Mandated anticoagulation therapy
  • Profession (e.g., construction worker) or lifestyle (e.g., plays contact sports) that predisposes member to trauma.

The International Prognostic Scoring System

Prognosis of individuals with MDS can be calculated using a number of scoring systems. There are 3 main prognostic scoring systems used in MDS:

  • IPSS (International Prognostic Scoring System)
  • IPSS-R (Revised International Prognostic Scoring System)
  • WPSS (WHO classification-based Prognostic Scoring System).

The IPSS is a commonly used tool in MDS which uses prognostic indicators to assign a risk score, and risk group, to help predict the course of disease. The risk group information can be used to choose a treatment approach. Lower-risk MDS tends to grow and progress slowly, thus, a lower-risk score generally indicates a better outlook. The IPSS-R covers the same disease factors as the IPSS, but the factors are identified in a more detailed way. The WPSS it is not used as often as the IPPS and IPSS-R. It differs from the other two systems in that it includes the MDS subtype as a prognostic factor. It also assigns a score based on the presence or absence of severe anemia.

Source: Leukemia & Lymphoma Society. The International Prognostic Scoring System.

Revised International Prognostic Scoring System (IPSS-R) for MDS Risk Assessment Calculator: IPSS-R Myelodysplastic Syndrome Risk Assessment Calculator.

Examples of risk factors for bleeding (not all inclusive):

  • Undergoing a medical or dental procedure where blood loss is anticipated
  • Comorbidity (e.g., peptic ulcer disease, hypertension)
  • Mandated anticoagulation therapy
  • Profession (construction worker) or lifestyle (e.g., plays contact sports) that predispose member to trauma.

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