Romiplostim versus Placebo for Chemotherapy-Induced Thrombocytopenia

Phase 3, international, double-blind, randomized, placebo-controlled trial

N= 165

To evaluate the efficacy and safety of romiplostim in treating chemotherapy-induced thrombocytopenia (CIT) in patients receiving oxaliplatin-based multiagent cytotoxic chemotherapy for gastrointestinal cancers

Romiplostim (n= 109)

Placebo (n= 56)

Patients receiving oxaliplatin-based multiagent cytotoxic chemotherapy for colorectal, gastroesophageal, or pancreatic cancer with persistent CIT (platelet count, ≤85×10^9 per liter on trial day 1) and at least three additional planned chemotherapy cycles

Thrombocytopenia from other causes, hemoglobin level <8 g/dL, absolute neutrophil count <1×10^9/L, past or current hematologic cancer, past arterial thrombosis, and cardiac or cardiovascular abnormalities in the past 4 months

Patients were randomized 2:1, stratified by baseline platelet count (<50 vs ≥50 × 10⁹/L) and cancer type. Weekly subcutaneous romiplostim or matching placebo was dose-adjusted to maintain platelet counts of 100–250 × 10⁹/L. Chemotherapy had initially been delayed because of CIT and was restarted at the same regimen and doses used before enrollment when the platelet count reached ≥100 × 10⁹/L, or after week 4 at a lower count considered safe by the investigator. Patients without a platelet count ≥100 × 10⁹/L or a count considered safe for chemotherapy by week 12 were classified as nonresponders. CIT-related chemotherapy dose modifications were independently adjudicated by 3 blinded medical oncologists.

Enrollment: September 30, 2019, to October 24, 2023

Primary analysis: January 25, 2024

Last trial visit: January 9, 2025

Primary: No CIT-induced chemotherapy dose modifications in cycles 2 and 3

Secondary: Platelet nadir, time to platelet response, duration-adjusted rate of bleeding events, overall survival, platelet transfusion, platelet response by week 4

Romiplostim (n= 109)

Male 

Median age, years (range) 

Race

White

Black

95 (87%)

4 (4%)

54 (96%)

2 (4%)

Hispanic ethnic group

Platelet count <50×10^9/liter

Colorectal cancer

Gastroesophageal cancer

Pancreatic cancer

ECOG performance-status score

0

1

51 (47%)

58 (53%)

33 (59%)

23 (41%)

Stage 4 disease

FOLFOX regimen

Weekly dose of romiplostim, mcg/kg bodyweight*

Abbreviations: ECOG, Eastern Cooperative Oncology Group; FOLFOX, 5-fluorouracil, leucovorin, and oxaliplatin

*Maximum dose 5 mcg/kg (88% of patients)

No CIT-induced dose modifications

Median platelet nadir, ×10^9/L

Platelet response

Median time to platelet response, weeks

Grade ≥2 bleeding events per 100 patient-years

Platelet response by week 4

Received platelet transfusion

Median chemotherapy relative dose intensity across 3 cycles (IQR)

Received all 3 planned chemotherapy cycles

Abbreviations: IQR, interquartile range.

Adverse events of grade 3 or higher occurred in 37% of patients with romiplostim and 22% with placebo. Thromboembolic events occurred in 2% of patients with romiplostim and none with placebo. Common adverse events included nausea and headache (2% in each group).

In this trial, romiplostim had few serious side effects and was efficacious to treat and prevent recurrence of persistent CIT in patients with gastrointestinal cancers receiving myelosuppressive chemotherapy. The trial showed that romiplostim, as compared with placebo, resulted in a lower incidence of chemotherapy dose modifications. These findings suggest that romiplostim may be a viable therapeutic option for managing CIT in patients with gastrointestinal cancers undergoing oxaliplatin-based chemotherapy.

The randomized, double-blind design and blinded adjudication provide strong evidence supporting romiplostim in patients meeting narrowly defined criteria for persistent CIT during oxaliplatin-based treatment for gastrointestinal cancer. 

Romiplostim for management of chemotherapy-induced thrombocytopenia

Retrospective chart review

N= 20

To report on the use of romiplostim in patients with protracted chemotherapy-induced thrombocytopenia (CIT) and assess its effectiveness in improving platelet counts and allowing resumption of chemotherapy

All patients (n= 20)

Patients with isolated, persistent thrombocytopenia (<100×109/L) for at least 6 weeks despite delay or dose reduction in chemotherapy, with no known underlying bone marrow disorder

Patients with chromosomal abnormalities associated with leukemia or myelodysplastic syndrome

Romiplostim was initiated at 1–2 mcg/kg weekly, with dose escalation by 1 mcg/kg per week until platelet recovery (≥100×109/L). Weekly romiplostim continued if chemotherapy was resumed.

2010 to 2012

Primary: Improvement in platelet counts to ≥100×109/L

Secondary: Ability to resume chemotherapy without recurrence of dose-limiting CIT

All patients (n= 20)

All patients (n= 20)

Three deep vein thromboses (DVT) were observed; one was a recurrent DVT in a patient with a history of DVT. No treatment-related toxicity was observed

Romiplostim resulted in improvement in platelet counts, allowing resumption of chemotherapy without recurrence of dose-limiting CIT. It may be a safe and effective treatment for CIT, but larger, prospective trials are needed to confirm these findings.

The study provides promising results for the use of romiplostim in managing CIT, but is limited by its retrospective design and small sample size. The lack of a control group and potential selection bias may affect the generalizability of the findings. Further prospective, randomized trials are needed to establish safety and efficacy.

The use of romiplostim in treating chemotherapy-induced thrombocytopenia in patients with solid tumors

Retrospective chart review

N= 22

To assess the effects of romiplostim on platelet count, time to platelet count >100x109/L, chemotherapy dose reductions and delay, and romiplostim-related complications

Solid tumor patients (n= 22)

Patients aged ≥18 years receiving romiplostim concurrently with cancer chemotherapy for a solid tumor between January 1, 2010 and April 17, 2017

Moribund patients and those who received fewer than two doses of romiplostim

Romiplostim was given weekly, usually on the same day as chemotherapy, with a starting dose of 3 mcg/kg (range, 1-10 mcg/kg). Platelet counts were measured weekly, and the dose was adjusted as needed. Data collected included patient demographics, malignancy type and stage, chemotherapy agents, platelet counts, and romiplostim doses.

January 1, 2010 to April 17, 2017

Primary: Increase in platelet count to ≥100x109/L

Secondary: Reduction in chemotherapy delays and dose reductions, romiplostim-related complications

Solid tumor patients (n= 22)

Solid tumor patients (n= 22)

No thrombotic events reported. Bleeding occurred in three patients but was related to thrombocytopenia in only one. Four patients received platelet transfusions, mainly for procedural preparation or to enable chemotherapy.

Romiplostim is safe and rapidly increases platelet count in patients with solid tumors and chemotherapy-associated thrombocytopenia, allowing chemotherapy to be given at full dose and on schedule. However, the magnitude of its benefit and effect on survival require further prospective studies.

The study's retrospective design and lack of randomization are limitations. The variety of solid tumors and chemotherapy regimens, along with non-standardized dosing adjustments, may affect the generalizability of the findings. Despite these limitations, the study provides valuable insights into the potential benefits of romiplostim in managing chemotherapy-induced thrombocytopenia.

Romiplostim Treatment of Chemotherapy-Induced Thrombocytopenia

Phase II randomized trial

N= 60

To evaluate the effectiveness of romiplostim in correcting chemotherapy-induced thrombocytopenia (CIT) and allowing resumption of chemotherapy without recurrence of CIT

Romiplostim (n= 52)

Observation (n= 8)

Patients 18 years or older with active nonhematologic cancer and CIT (platelet count < 100,000/mL) for at least 4 weeks, despite dose reduction or delay of prior chemotherapy

History of hematologic malignancy, hemoglobin < 8.0 gm/dL despite transfusion, absolute neutrophil count < 1,000/mL despite granulocyte colony stimulating factor, liver cancer with transaminases or bilirubin > five times the upper limit of normal, serious concomitant medical conditions, pregnant or lactating women, unwillingness to use contraception, extensive bone metastases

Patients were randomized 2:1 to receive weekly titrated romiplostim or observation. Romiplostim was started at 2.0 mcg/kg and increased by 1.0 mcg/kg for up to 3 weeks until a platelet count of 100,000/μL or more was achieved. The primary endpoint was correction of platelet count within 3 weeks. Patients who achieved platelet correction resumed chemotherapy with weekly romiplostim maintenance.

After preliminary results, the study was converted to a single-arm, romiplostim treatment study for the remaining 37 patients, thus eliminating the observation study group.

May 2014 to February 2018

Primary: Correction of platelet count to 100,000/mL or greater within 3 weeks

Secondary: Resumption of chemotherapy without recurrent CIT, requirement of platelet transfusion, development of venous or arterial thrombosis, crossover response

Randomly Assigned: Observation (n = 8)

Failed to Correct Within 3 Weeks, No.

Six of the 59 patients (10.2%) developed a venous thromboembolism during the first 12 months of romiplostim treatment. One patient experienced a myocardial infarction and an ischemic stroke during treatment.

Romiplostim is effective in correcting CIT and allows for the resumption of chemotherapy without recurrence of CIT in most patients. It may be beneficial in a wide range of solid tumor types and after various chemotherapy regimens.

The study demonstrated significant efficacy of romiplostim in correcting CIT, but the open-label design and small sample size may limit the generalizability of the findings. The exclusion of patients with extensive bone metastases may also limit the applicability of the results to all patients with CIT. Further studies are needed to determine the impact of romiplostim on long-term cancer outcomes.

A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumors and hematologic malignancies

Retrospective, multi-center study

N= 173

Solid tumors (n= 153)

Hematologic malignancies (n= 20)

Patients aged ≥18 years with thrombocytopenia treated with romiplostim to support chemotherapy for solid tumors or non-myeloid hematologic malignancies between July 1, 2009, and July 1, 2019

Patients not meeting the inclusion criteria were excluded, but specific exclusion details were not mentioned

Romiplostim was administered following institutional pathways (weekly vs intracycle dosing), and patient data were collected from the Research Patient Data Registry. Patients were started at romiplostim 3 mcg/kg (interquartile range [IQR], 2-3 mcg/kg), with the median optimised dose being 3 mcg/kg (IQR, 2-5 mcg/kg). The median starting dose was lower for hematologic malignancy patients at 2 mcg/kg (IQR, 2-4 mcg/kg); one hematologic malignancy patient was titrated to 10 mcg/kg.

Data collection spanned ten years, from July 1, 2009, to July 1, 2019.

Primary: Achievement of a romiplostim response (median platelet count ≥ 75 x 10⁹/L and ≥ 30 x 10⁹/L above baseline)

Secondary: Time to platelet count ≥ 100 x 10⁹/L, rates of platelet counts below thresholds, thrombocytosis, chemotherapy dose reductions/treatment delays, platelet transfusion, bleeding, and thromboembolism

Romiplostim was associated with 71% response in solid tumor patients versus a 10% response in hematologic malignancy patients.

A platelet count of ≥ 100 x 10⁹/L was achieved in 130 of 153 patients (85%; with a median time to platelet count ≥ 100 x 10⁹/L of 9 days [interquartile range (IQR) 7-15 days]) vs 7 of 20 patients (35%; with a median time to platelet count ≥ 100 x 10⁹/L of 24 days [IQR 19-36 days]).

Weekly dosing was superior to intracycle dosing. Predictors of non-response included bone-marrow (BM) invasion, prior pelvic irradiation, and prior temozolomide exposure.

Lower bleeding rates compared to historical cohorts (23 events per 100 patient-years for solid tumor patients without predictors of non-response). VTE events were similar to rates in comparable cancer populations.

Romiplostim is effective for managing CIT in patients with solid tumors, as demonstrated by improved platelet counts and low rates of chemotherapy dose reductions and treatment delays, bleeding, and platelet transfusions. VTE rates approximated rates in similar cancer populations not receiving romiplostim. Weekly dosing resulted in improved outcomes as compared with more intermittent intracycle dosing.

Romiplostim was generally ineffective in patients with BM invasion by tumor, prior pelvic irradiation, and prior exposure to temozolomide.

The study's retrospective design and heterogeneity in tumor types and chemotherapy regimens may limit generalizability. The study was not randomized, and the number of hematologic malignancy patients was low, which may affect the robustness of conclusions for this subgroup. The authors reported the doses as "mg/kg", but it is likely they meant "mcg/kg" (as we reported above).

Open-label, single-center, randomized, controlled trial in India

N= 93

Romiplostim group (n= 47)

Control group (n= 46)

Primary: Platelet recovery (≥100 × 10⁹/L and transfusion-free for 72 hours) within 3 weeks

Secondary: Clinically significant bleeding episodes, transfusion requirements, immature platelet fraction percentage (IPF%) trends

Platelet transfusion was required in 32.6% of patients in the intervention arm and 30.2% of patients in the control  arm (risk difference 2.4%; 95% CI −16.6 to 20.9; risk ratio 1.08; p= 0.81).The median volume of platelet transfusion was 19.3 mL/kg (IQR 10 to 26.3) in the romiplostim group and 29.6 mL/kg (IQR 17.1 to 47.1) in the control group (median difference -10.3 mL/kg; 95% CI -21.5 to 0.9; p= 0.06). 

The time to platelet recovery was similar between the intervention (median  16 days; IQR 0 to 18) and the control group (median 16 days; IQR 13 to 21, p= 0.28), for a hazard ratio of 1.20 (95% CI 0.79 to 1.84).

There was a significant increase in IPF% from baseline over time in the cohort, with the mean log-transformed IPF% rising by approximately 84% on day 13 (β=0.612; 95% CI, 0.12 to 1.11; p= 0.016) compared with baseline.

Single-center, target trial emulation study

N= 330

Romiplostim-treated (n= 165)

Controls (n= 165)

Primary: Overall survival over 24 months

Secondary: Venous thromboembolism (VTE) at 6 months