Monica Carpenedo1,2, Arianna Zappaterra1, Beatrice Ferrari1 and Giulia Cotilli1.
1 A.O San Gerardo di Monza e Università di Milano Bicocca, Hematology and Transplant Unit. via Pergolesi 33 Monza, 20900, Italy
Fatebenefratelli-Sacco, Ospedale L. Sacco, Polo Didattico Università
degli Studi di Milano, Via G.B Grassi 74, Milan, 20154, Italy.
Monica Carpenedo. A.O San Gerardo di Monza e Università di Milano
Bicocca, Hematology and Transplant Unit, via Pergolesi 33 Monza, 20900.
ASST Fatebenefratelli-Sacco, Ospedale L. Sacco, Polo Didattico
Università degli Studi di Milano, Via G.B Grassi 74, Milan, 20154,
Italy. E-mail: firstname.lastname@example.org
Published: March 1, 2023
Received: December 27, 2022
Accepted: February 15, 2023
Mediterr J Hematol Infect Dis 2023, 15(1): e2023021 DOI 10.4084/MJHID.2023.021
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
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medium, provided the original work is properly cited.
To the editor
thrombocytopenia (ITP) is a rare autoimmune disorder that affects all
ages, with two peaks of incidence in adults, that involves mostly young
females and older males.
The disease has a
complex pathogenesis, with well-recognized mechanisms of increased
peripheral autoantibody-mediates destruction of the platelets but also
a reduction of appropriate megakaryocyte functionality related to low
level of endogenous thrombopoietin and both humoral and cytotoxic
immune response targeting the megakaryopoiesis.
Moreover, in the last years, the role of Fc gamma receptors (FcγRs),
neonatal Fc receptor (FcRn), the spleen tyrosine kinase (Syk), the
complement factors, and the desialylation of the platelets have been
elucidated, resulting in the development of new drugs and enhanced
knowledge of potential new therapeutic targets.
who develop a chronic ITP are defined as “refractory” if they do not
respond to two or more treatments, there is no single medication to
which they respond, and their platelet count is very low and associated
with bleeding. Besides, in these patients, poor
quality of life (QoL) related to fatigue, need for multiple hospital
visits and blood tests, side effects of chronic treatment, and anxiety
of disease worsening have been reported. Therefore,
an important goal in refractory ITP is to restore a durable, safe
platelet count to avoid possible bleeding, reduce the number of medical
checks and ameliorate their QoL.
For refractory patients, the role of combination treatment has been recently described[2-3]
using drugs targeting different pathogenic mechanisms at the same time
or with sequential use of multiple treatments (i.e., switch of
thrombopoietin receptor agonists, or consecutive use of steroid,
splenectomy, rituximab), suggesting a synergistic effect of different
mechanisms of action in a well-recognized multifaceted immunological
disease such as ITP.
We report for the first time the efficacy of
sequential use of efgartigimod and romiplostim after the previous
failure of two thrombopoietin receptor agonists (TPO-RA) and different
immunosuppressive regimens in two multi-refractory patients. We also
propose hypothesis about the synergistic effect of the two drugs.
Both patients stated written informed consent to use their anonymized data.
is a novel human IgG1 Ab fragment that binds to neonatal Fc receptor
(FcRn), thus preventing IgG recycling with clinical benefit for
patients with autoantibody-mediated diseases such as ITP.
Efgartigimod has been recently approved by FDA for myasthenia, and
phase II/III studies in ITP are ongoing. Recently, data about the
ADVANCE Study (Efficacy and Safety of Intravenous Efgartigimod in
Adults with Primary ITP, Phase 3 Double-blind, Placebo-controlled RCT)
has been released during the 64th ASH
Annual Meeting, demonstrating clinical and statistical improvement of
platelet count in refractory ITP patients treated with efgartigimod
Romiplostim is a well-known
TPO-RA, with many safety and efficacy data collected in ITP and
published since its development more than ten years ago.
Patient#1 (Figure 1a):
male with a history of a previous CABG and PCI at 68 years of age. ITP
was diagnosed at 80 years of age. Bone marrow examination and extensive
workup ruled out other causes of isolated thrombocytopenia. He was
unresponsive to prednisone plus IVIG as the first line, and second-line
treatment with cyclosporine was complicated with NSTEMI. The third-line
treatment with azathioprine failed. Eltrombopag as single agent was
ineffective and we observed only a brief, mild response when
eltrombopag was associated with prednisone. The next lines of therapy
were romiplostim alone and subsequently associated with danazol,
vincristine plus prednisone, and eltrombopag plus prednisone, all
without response. Finally, we started efgartigimod associated with
eltrombopag and low-dose prednisone without results. Romiplostim was
introduced immediately after suspension of efgartigimod and we observed
a prompt and complete response, lasting 15 weeks without any adverse
event, followed by a relapse triggered by a mild symptomatic SarsCov2
infectious, despite a full course of vaccination (two doses plus one
boost of Pfizer-BioNTech vaccine more than three months before). Hence,
(not shown in Figure 1a), the
patient received fostamatinib without response and now he is treated
with chronic administration of prednisone and IgIV on demand if
bleeding occurs, with many admissions into the Emergency Rooms.
- Figure 1a. Patient 1.
Patient #2 (Figure 1b):
female, without comorbidities. ITP was diagnosed at 16 years of age.
After the first line with steroids, she had a brief response and
remained with a low but safe platelet count for a couple of years
(30-40 x 109/L). She received
eltrombopag as second line of treatment at 19 years of age, after a
bone marrow examination and after having ruled out other causes of
isolated thrombocytopenia. She had only a mild and brief response to
eltrombopag, with heavy recurrent menstrual bleeding requiring rescue
treatment with dexamethason. We switched to romiplostim with a limited
and poor response and she needed repeated courses of steroids due to
heavy menses leading to anemia.
- Figure 1b. Patient 2.
she was given efgartigimod associated with eltrombopag without response
and she received dexamethason again as rescue therapy.
after the suspension of efgartigimod we started romiplostim as single
agent and we recorded a prompt and complete response, still ongoing
after 33 weeks, without adverse events or bleeding and with a complete
recovery from anemia.
We describe two patients of very different
ages, sex, and comorbidities, both having a refractory ITP, with
previous failure of many different lines of therapy, including single
agents (steroid, TPO-RA, immunosuppressant drugs) and combination
strategies. In these two patients, efgartigimod was at first
ineffective, but the sequential introduction of romiplostim (already
used in both patients many months before, without results) increased
Efgartigimod selectively acts by targeting IgG
recycling mediated by blocking neonatal Fc receptor and accelerates the
destruction of IgG, reducing pathogenic IgG and IgG immune complexes.
is an IgG Fc fragment connected with four TPO-R binding domains, thus
clinical trials involving efgartigimod in ITP do not allow the
concomitant use of this specific TPO-RA. Consequently data about a
combination of efgartigimod and romiplostim are lacking.
expected an enhancement in the clearance of romiplostim when
administering the drug immediately after suspension of efgartigimod, as
it is well described that efgartigimod ends its effect on IgG recycling
after eight weeks of suspension. Nonetheless, we observed a prompt and
high response since the first administration of romiplostim. This
response appears to be lasting many weeks (15 and 33 weeks,
respectively), thus opening a different and unrecognized scenario of
immunomodulation as the result of the sequential administration of the
two drugs. In one patient, the response ceased after 15 weeks triggered
by a viral infection as it frequently happens in multi-refractory ITP
It is worth underlining that in both patients
efgartigimod had previously been administered together with
eltrombopag, as eltrombopag was ineffective as single treatment.
However, this association of drugs failed. Thus, a “class effect” of a
synergistic power of TPO-RA and efgartigimod cannot be claimed.
chemical structure of romiplostim is completely different from that of
eltrombopag, and this might be the reason of a different effect of the
two drugs combined or sequentially used with efgartigimod. It is
otherwise suggested that the Fc fragment of romiplostim may play an
important role in immune surveillance and regulation of immune
response, acting as “Tregitops” (T regulatory cell epitopes) sequence.
are natural T cell epitopes derived from immunoglobulin G, and this
mechanism might explain the regulatory effects of intravenous
immunoglobulin therapy in ITP. In addition, antigen-specific adaptive
tolerance induction might be boosted when antigens are administered in
combination with regulatory T cell epitopes, such as Tregitopes.
have many important properties because they bind to multiple MHC class
II molecules, suppressing the effector T cell responses to co-delivered
antigen and regulating Treg-associated cytokines and chemokines.
studies in murine models have demonstrated the ability of Tregitopes to
induce antigen-specific tolerance leading to a reduction of immune
responses to allergens in vitro and in vivo.
suggestive mice model of type 1 diabetes showed that the
co-administration of the target antigen and Tregitope peptides
completely suppressed the development of diabetes.
Moreover, recently, the Fc domain of recombinant FVIII-Fc fusion
protein seems to reduce immunogenicity, confer immunomodulatory and
anti-inflammatory properties, and induce tolerance in hemophiliac
Based on the mechanisms mentioned
above, it is conceivable that in these two multi-refractory ITP
patients, the use of efgartigimod had initially reduced the circulating
autoantibody against the surface antigens of the platelets without any
clinical effect while enhancing the availability of the target
antigens. The immediate sequential use of romiplostim just after the
withdrawal of the FcRn inhibitor might have induced the mechanism of
antigen-specific adaptive tolerance through the properties of the Fc
fragment of romiplostim. On the other hand, this TPO-RA was previously
unable to give results when it was used without previous exposure to
efgartigimod, suggesting a complementary effect of the two drugs
administered in this specific sequence.
Efgartigimod has just
begun its journey in ITP, and its potential as immunomodulatory in this
disease is far from being completely understood. In addition, data
about the sequential use of different target therapies are needed in
multi-refractory ITP patients. However, the availability of new drugs
with different mechanisms of action will allow clinicians to better
manage even the patients with the most challenging disease.
- Stasi R. Immune thrombocytopenia: pathophysiologic and clinical
update. Semin Thromb Hemost. 2012;38:454-62
- Audia S and
Bonnotte B. Emerging therapies in Immune Thrombocytopenia. J. Clin.
Med. 2021, 10, 1004 https://doi.org/10.3390/jcm10051004 PMid:33801294
- Miltiadous O, Hou M, Bussel JB, Identifying and
treating refractory ITP: difficulty in diagnosis and role of
combination treatment. Blood 2020;135(7):472-490
https://doi.org/10.1182/blood.2019003599 PMid:31756253 PMCid:PMC7484752
N, Kruse A, Kruse C, Watson S, Morgan M et al Immune thrombocytopenia
(ITP) World Impact Survey (I-WISh): Impact of ITP on health-related
quality of life. Am J Hem 2021 Feb 1;96(2):199-207.doi:
10.1002/ajh.26036 https://doi.org/10.1002/ajh.26036 PMid:33107998
- Ulrichts P et al. Neonatal Fc receptor antagonist
efgartigimod safely and sustainably reduces IgGs in humans J Clin
Invest 2018 Oct 1;128(10):4372-4386 https://doi.org/10.1172/JCI97911
- Broome C, McDonald V, Miyakawa Y,
Carpenedo, M et al. Efficacy and Safety of Intravenous Efgartigimod in
Adults with Primary ITP: Results of ADVANCE IV, a Phase 3, Multicenter,
Double blinded, Placebo-controlled, Randomized Clinical Trial , 64th
ASH Annual Meeting, New Orleans, 10-13th December 2022
- Ghanima W, Cooper N,
Rodeghiero F, Godeau B, Bussel JB. Thrombopoietin receptor agonists:
ten years later. Haematologica. 2019;104:1112-23.
- Schifferli A et al. Immunomodulation in Primary
immune Trhombocytopenia: a possible role of the Fc fragment of
romiplostim? Front Imm 2019; 10: 1196
https://doi.org/10.3389/fimmu.2019.01196 PMid:31214173 PMCid:PMC6557984
Groot A et al. Therapeutic administration of Tregitope-Human Albumin
Fusion with Insulin Peptides to promote Antigen-Specific Adaptive
Tolerance Induction. Sci Rep 2019 Nov 6;9(1):16103
- Blumberg RS, Lillicrap D, IgG Fc Immune Tolerance
Group. Tolerogenic properties of the Fc portion of IgG and its
relevance to the treatment and management of hemophilia. Blood. (2018)
131:2205-14 https://doi.org/10.1182/blood-2017-12-822908 PMid:29588277