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H. Al-Samkari et al.
Table 4. Solid tumor patient dosing strategy comparison. Rates of platelet count measurements describe the fraction of counts measured beyond a given platelet count threshold (mean rates for all patients in each group are given). Rates of clinical outcomes are exposure-adjusted (given as rates per 100 patient-years at risk).
Outcome
Weekly platelet count measurements#
Baseline median platelet count
On-romiplostim median platelet count
Achieved romiplostim response (%)
Mean rate of platelet count measurements beyond thresholds on romiplostim
P
All: 0.27*
No PNR: 0.35* All: <0.001* No PNR: <0.001* 0.006
0.043
0.001 <0.001 0.14
0.010
0.89
0.029
0.25
All (N=80a)
1,154
54×109/L
143×109/L
No PNR (N=65b)
1,049
61×109/L
146×109/L
All (N=73c)
1,287
66×109/L
106×109/L 45 (63%) 0.18
0.32 0.49 0.029
No PNR (N=57)
1,142
70×109/L
110×109/L 39 (68%) 0.090
0.24 0.44 0.026
178
15
19
19
Weekly regimen
Intracycle regimen
Intracycle vs. weekly
0.28 (0.11-0.69)†
1.72 (1.01-2.90)† 1.72 (1.26-2.35)† 1.74 (1.38-2.20)† 0.39 (0.11-1.40)†
3.00 (1.30-6.91)§
0.89 (0.19-4.23)§
4.84 (1.18-19.89)§
2.60 (0.51-13.25)§
63 (81%)
61 (95%)
Platelet count measured <50×109/L Platelet count measured <75×109/L Platelet count measured <100×109/L Platelet count measured >400×109/L
0.13 0.032 0.21 0.10 0.31 0.21 0.050 0.060
Rates of clinical outcomes per 100 patient-years at risk (100 patient-years on romiplostim support)
Chemotherapy intensity reduction (dose reduction or treatment delay) Platelet transfusion
Bleeding event
Venous thromboembolic event
82 76
96 38
11 13
7.1 8.4
224
118
34
20
PNR: predictors of romiplostim non-response (includes bone marrow [BM] invasion by tumor, prior temozolomide exposure, or prior pelvic irradiation). a80 patients received weekly dosing,of which two could not resume chemotherapy. All 80 are included in the platelet count outcome analyses but only the 78 able to restart chemotherapy are includ- ed in the clinical outcome analyses. bSixty-five patients without predictors of romiplostim non-response received weekly dosing, of which one could not resume chemotherapy. All 65 are included in the platelet count outcome analyses but only the 64 able to restart chemotherapy are included in the clinical outcome analyses. cSeventy-three patients without predictors of romiplostim non-response received intracycle dosing, of which one could not resume chemotherapy. All 73 are included in the platelet count outcome analyses but only the 72 able to restart chemotherapy are included in the clinical outcome analyses. *By Mann-Whitney U Test. †The value is the odds ratio with a 95% confidence interval, calculated from a multivariable logistic regression model with romiplostim response as the dependent variable and age, dosing regimen, BM invasion, prior pelvic irra- diation,and prior temozolomide exposure as independent variables.‡The value is the rate ratio with a 95% confidence interval,calculated from multivariable negative binomial regression models with the given platelet count threshold as the dependent variable,number of platelet count measurements as the exposure variable,and age,dosing regimen, BM invasion by tumor,prior pelvic irradiation,and prior temozolomide exposure as independent variables. §The value is the rate ratio with a 95% confidence interval,calculated from multivariable negative binomial regression models with the given clinical outcome as the dependent variable, duration of romiplostim support as the exposure variable, and age, sex, dosing regimen, BM invasion by tumor, prior pelvic irradiation, and prior temozolomide exposure as independent variables.
(oprelvekin), rhTPO (recombinant human thrombopoi- etin), and PEG-rhMGDF (pegylated recombinant human megakaryocyte growth and development factor). These agents demonstrated efficacy in CIT management in clin- ical studies, reducing need for platelet transfusions, increasing overall and nadir platelet counts, and allowing for improved relative dose intensity.5,22-24 Unfortunately, development of recombinant thrombopoietins was halted in the West due to occurrence of antibodies to PEG- rhMGDF with cross-reactivity to native TPO.25 Oprelvekin was FDA-approved for CIT but use was limit- ed due to an unfavorable side-effect profile; this agent is no longer available from the manufacturer. Notably, rhTPO, which is not associated with cross-reactive anti- bodies, completed development in China where it is a routine component of supportive care in cancer patients.26 More recent emergence of the TPO-RAs romiplostim, eltrombopag, and avatrombopag has renewed interest in pharmacologic CIT management in the West.
Four single-center studies, each evaluating between 20- 52 solid tumor patients receiving romiplostim for CIT,18-21 concluded that romiplostim is effective in raising the platelet count in CIT but did not compare different dosing strategies or characterize predictors of romiplostim non- response. None of these studies evaluated bleeding, the primary hazard of thrombocytopenia, and only limited data on the impact of romiplostim treatment on chemotherapy dose reductions and treatment delays were
described.20,21 Treatment of CIT with romiplostim in non- myeloid hematologic malignancy is currently limited to case reports.27 These factors provided the rationale behind the present study which aimed to address each of these important questions.
We found that romiplostim was effective for the man- agement of CIT in solid tumor patients receiving a variety of different chemotherapy regimens, with 98% (150 of 153) able to continue receiving chemotherapy with romi- plostim support. Romiplostim treatment more than dou- bled the median platelet count of the cohort (from 54x109/L to 112x109/L) enabling 79% of solid tumor patients to proceed without further chemotherapy dose reductions or treatment delays due to thrombocytopenia and 89% to proceed without platelet transfusions. The use of romiplostim for CIT in patients with solid tumors may improve outcomes of cancer treatment by allowing maintenance of dose intensity. Weekly romiplostim dos- ing, as compared with intracycle romiplostim dosing, resulted in fewer recurrences of CIT, chemotherapy dose reductions/treatment delays, and bleeding events (Table 4). Thrombocytosis rates were higher but VTE rates were similar. The lower overall exposure to romiplostim in patients treated with intracycle dosing as compared with weekly dosing may account for the differences in the observed outcomes between these two groups. Of note, intracycle dosing was still an effective strategy and could be considered as this reduces drug-associated costs.
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haematologica | 2021; 106(4)