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W. Ghanima et al.
sis did not change during treatment with TPO-RA, while a slight, non-progressive reticulin fibrosis (MF-1 or Baumeister <2) was observed in 10-50% of patients.48,49 In one study, a moderate increase in reticulin fibrosis (MF-2) was observed in 18% at median time of treatment of 2.5 years,48 whereas in three other studies, reticulin fibrosis progressed by >2 grades or developed ≥MF-2 during the study periods in less than 10%.49-51 Severe grades of retic- ulin fibrosis (MF-3 and/or collagen fibrosis) were extremely rare in all studies.48-51 In general, it does not seem that TPO-RA induce substantial fibrosis or changes in number or morphology of peripheral blood cells. Both reticulin and collagen fibrosis regressed in most patients after discontinuation of TPO-RA; in a few patients, fibro- sis regressed despite continuing therapy.48,49
There is no consensus for patients on TPO-RA as to
whether or how to monitor bone marrow (BM) fibrosis.
At the moment, hardly any centers perform routine BM
biopsy in TPO-RA treated patients. However, if a biopsy
is performed and severe reticulin (MF3) or collagen is dis-
covered, then it is recommended that TPO-RA be discon-
tinued. With moderately increased fibrosis, e.g. MF 2, a
patient may continue TPO-RA but may need a repeat
biopsy in six months. Older age and splenectomy could be
associated with higher grades of BM fibrosis; fibrosis was
not associated with type, dose or duration of treat- ment.20,27,48
Risk of clonal evolution and malignancy
The TPO-receptor is expressed in many hematopoietic
cells, including early stem cells.52 Sustained stimulation of the hematopoietic cells raised concerns regarding poten- tial clonal evolution associated with prolonged use of TPO-RA. Based on clinical trials, safety databases and ten years of clinical experience, there are no indications that TPO-RA induce neoplastic changes in ITP patients. A safe- ty analysis of more than 1000 patients treated with romi- plostim showed that rates of hematologic and non-hema- tologic malignancies were comparable between the romi- plostim group and the placebo/SoC.53 In the EXTEND study, ten (3%) patients reported malignancies diagnosed during the 6-year study.24 In one ITP study, routine BM flow cytometry and cytogenetic studies were performed and no karyotypic or immunophenotypic changes indica- tive of monoclonality were detected.48
In myelodysplastic syndromes (MDS), the risk of leuke- mogenesis had been a matter of concern.54-56 In aplastic anemia, comparison of natural history between eltrom- bopag-treated patients and those receiving immunosup- pression alone showed no difference in incidence of malignancy, although those treated with eltrombopag tended to develop malignancy sooner.57
Thromboembolism
In early trials with TPO-RA, sporadic thromboembolic events (TEE) gave impetus to extensive epidemiological studies exploring the association between thrombosis and ITP and the role of TPO-RA. The incidence of TEE in patients with chronic ITP not exposed to TPO-RA was compared with age- and sex-matched non-ITP control
Table 4. Incidence of thromboembolism with romiplostim and eltrombopag in long-term studies or in pooled analyses in adults.
Ref. Description
Romiplostim
Kuter27§ Long-term investigation
on291ptswho completed a previous randomized romiplostim study* (Aug 2004 - Jan 2010)
Rodeghiero53 Pooled analysis of 13 clinical trials^
Patients with history or risk factors for TE excluded
In most cases, but not invariably
In most cases, but not invariably
N. of patients with TEEs
19/291 (6.5%)
39/653 (5.9%)
19/302 (6.3%)
Mean exposure time (years)
2.11
1.41
2.37 (median, range 2 days-8.8 yrs)
Arterial
Total n. of TEEs
Venous Others
25
Venous Other
First TEE
rate per 100 pt-years
3.1
4.2
2.9#
All TEE rate per 100 pt-years
Arterial Venous
4.1
Arterial Venous
2.6 1.5
Arterial
16 9 0
Eltrombopag
Wong24 Long-term investigation on 302 out of 371 patients
completing previous trials fed into this study
(June 2006-July 2015)
Yes
Arterial
26
Arterial 14
69
Venous Other
40 3
24
Venous Other
10 0
7.5 Arterial
Venous
(Oct 2003 and June 2009)
2.8 4.3 3.4
Arterial
2.0 1.4
Venous
§From an interim analysis (Aug 2004-July 2007) describing 142 patients for a mean exposure time of 69 weeks, 12 thromboembolism (TE) events were found in seven patients, with an incidence rate of TE of 6.4/100 patient-years (pt-yrs) (3.7/100 pt-yrs after censoring at the first event).20 *Analysis includes patients completing previous studies conducted in the US, Europe, Canada and Australia (described in studies 2,3,4 of Online Supplementary Table S1 and n.12 and 13 of Online Supplementary Table S2) who were subsequently enrolled in an open label extension study.Only thrombotic events occurring after enrolling in the extension were considered. ^Analysis includes all 291 patients of Kuter et al., 201327 and of an additional 362 patients, including: Japanese patients, described in n. 5 of Table A and n. 14 of Table B; 22 children enrolled in a double-blind study,23 and patients directly enrolled in different open-label studies (a large expanded access study, now available as a full paper;90 a Japanese extension study;88 a long-term biopsy study).47 Details of studies can be found in Rodeghiero et al.53 The same studies with a later cut off (June 2011) were also analyzed by Cines et al.46 also including preliminary data in abstract form of Janssens et al.50 The analysis of Cines et al. provided a similar thrombotic events rate of 5.5/100 pt-yrs both in the romiplostim (n. 994, 1520 pts/yrs) and in the placebo/Standard of Care (n. 138, 110 pts/yrs) patients. # 2.7 if two additional patients who only had TEE off-study (see Table 3) are excluded. N/n: number; TEE: thromboembolic events.
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haematologica | 2019; 104(6)