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Romiplostim in pediatric ITP
plostim and all other ITP treatments. There were two par- ent studies for this long-term extension.9,10 Treatment-free response rates were similar for children from the earlier phase I/II study (3 of 12, 25%) and the phase III study (12 of 54, 22%). The three patients entering treatment-free response from the earlier study had received romiplostim longer (5-7 years vs. 1-5 years), but their age, ITP duration, number of past ITP therapies, and other characteristics were not particularly different from the patients from the phase III study.
Which children were more likely to enter treatment-free response? In a post hoc multivariate analysis of this study, younger age at first dose and platelet count increasing to ≥200x109/L in the first four weeks were both independent- ly associated with developing treatment-free response. However, this dataset may not have been large enough to detect additional factors that may also play a role in treat- ment-free response. Factors found in other studies to be predictive of spontaneous treatment-free response in chil- dren with ITP include higher platelet count at diagnosis (>60x109/L),6 younger age,13-18 recent onset (<2 weeks) of bleeding symptoms,17,18 decreased bleeding in the first six months,19 higher bleeding grade at diagnosis,14 and treat- ment with IVIg and corticosteroids at diagnosis.14 Of note, these studies generally considered children with relatively newly diagnosed, persistent, and chronic ITP all together (as definitions changed over time),20 whereas the treat- ment-free response in this study occurred in children who had chronic ITP for a median of three years.
The ongoing development of treatment-free response in children with chronic, difficult-to-treat ITP with continu- ing romiplostim treatment could be explained either by patients improving spontaneously years after their diagno- sis of ITP, or by a sustained effect of romiplostim on ITP in certain patients. The correlation of treatment-free response with early very good response in the first four
Table 5. Univariate model for predictors of treatment-free response.
weeks of romiplostim treatment suggests either that these patients were uniquely sensitive to romiplostim or possi- bly that they just had milder disease. Arguing against the latter hypothesis was the absence of other clinical factors related to treatment-free response (e.g. relatively few pre- vious treatments, short duration of ITP). There is remark- ably little published data describing children such as these (i.e. with chronic ITP and median ITP duration of 3 years). Further studies will be needed to distinguish between the long-term effects of romiplostim and the natural history of chronic ITP in childhood.
Definitions of response, remission, and sustained response can vary considerably. Here, we chose platelet counts ≥50x109/L for response and platelet counts ≥50x109/L for ≥6 months with no ITP medications for treatment-free response. Other studies have used different platelet thresholds for response and treatment-free peri- ods, such as response per the International Working Group criteria,20 in which thresholds of 30x109/L and 100x109/L were used for response and complete response, both in the absence of bleeding, or treatment-free periods of at least a year, as in a long-term rituximab study.21 Nonetheless, six months of no treatment in this study, with treatment-free response in 15 patients and platelet counts mostly over 100x109/L, clearly defines a substantial change between the pre-romiplostim experience and on- study experience of these children.
Several studies have suggested pathways by which romiplostim could affect disease progression. These include, but are not limited to, induction of T-regulatory cells and alteration of FcgRs in favor of FcgRIIb, the inhibitory FcgR.22-26 Overall, the lack of toxicity despite long-term treatment indicates that romiplostim does not overly impair patients’ immunity to an extent that there is a predisposition to infections. To our knowledge, other than a few cases in a retrospective case review,27 this is the
Characteristic
Sex, female, n (%)
Race, white, n (%)
Age at first dose*
Age at ITP diagnosis* Baseline ITP duration Baseline platelet count† # Prior therapies
Prior rituximab, n (%)
Splenectomized, n (%)
Dose at first response, mg/kg
Platelet count >200x109/L in first 4 weeks, n (%) Platelet counts in first 4 weeks†
Grade ≥2 bleeding in first 6 months, n (%)
Rescue meds in first 6 months
Patients with treatment free response N=15
9 (60)
10 (67) 6.5 (4.0) 4.8 (3.6) 2.3 (2.4) 16.5 (11.8) 3.1 (1.4)
5 (33)
0 (0)
3.1 (2.9)
4 (27)
128 (149)
4 (27)
4 (27)
Patients without treatment free response
N=50 HR
27 (54) 1.19
30 (60) 1.05 10.6 (4.0) 0.81 7.5 (3.4) 0.83 3.6 (2.7) 0.79 15.9 (9.5) 1.09 3.3 (1.9) 0.77 19 (38) NA
6 (12) NA
4.1 (3.0) 0.87
3 (6) 5.48
57.5 (42.9) 1.09
8 (16) 1.44
20 (40) 0.65
95% CI P 0.42, 3.41 0.74
0.36, 3.09 0.93
0.71, 0.93
0.70, 0.98
0.61, 1.03
0.66, 1.80 0.74 0.56, 1.07 0.12
NA 1.0
NA 0.32 0.71, 1.07 0.19
0.0019 0.031 0.080
1.63, 18.42
1.04, 1.13
0.46, 4.53 0.53 0.21, 2.04 0.46
0.0059 <0.0001
Data are mean (standard deviation) unless indicated otherwise.NA for HR and 95% CI when proportional hazards assumption in model was violated and model results are not reliable.P-value calculated using Fisher exact test (categorical variables) or Kruskal-Wallis test (continuous variables).#:number of;CI:confidence interval;HR:hazard ratio;ITP: immune thrombocytopenia; meds: medications; NA: not applicable.*Per year of age. †Indicates per 1x109/L.
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