The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Rilzabrutinib, an Oral BTK Inhibitor,

in Immune Thrombocytopenia
David J. Kuter, M.D., Merlin Efraim, M.D., Jiri Mayer, M.D., Marek Trněný, M.D.,
Vickie McDonald, M.D., Robert Bird, M.B., B.S., Thomas Regenbogen, M.D.,
Mamta Garg, M.D., Zane Kaplan, M.D., Nikolay Tzvetkov, M.D.,
Philip Y. Choi, M.D., A.J. Gerard Jansen, M.D., Milan Kostal, M.D.,
Ross Baker, M.D., Jaromir Gumulec, M.D., Eun‑Ju Lee, M.D.,
Ilona Cunningham, M.D., Isaac Goncalves, M.D., Margaret Warner, M.D.,
Ralph Boccia, M.D., Terry Gernsheimer, M.D., Waleed Ghanima, M.D.,
Olga Bandman, M.D., Regan Burns, B.A., Ann Neale, B.S., Dolca Thomas, M.D.,
Puneet Arora, M.D., Beiyao Zheng, Ph.D., and Nichola Cooper, M.D.​​

A BS T R AC T

BACKGROUND
Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton’s tyrosine kinase, The authors’ affiliations are listed in the
may increase platelet counts in patients with immune thrombocytopenia by means Appendix. Dr. Kuter can be contacted at
­kuter​.­david@​­mgh​.­harvard​.­edu or at the
of dual mechanisms of action: decreased macrophage (Fcγ receptor)–mediated Hematology Division, Massachusetts Gen-
platelet destruction and reduced production of pathogenic autoantibodies. eral Hospital, Suite 118, Rm. 110, Zero
Emerson Pl., Boston, MA 02114-2603.
METHODS N Engl J Med 2022;386:1421-31.
In an international, adaptive, open-label, dose-finding, phase 1–2 clinical trial, we DOI: 10.1056/NEJMoa2110297
evaluated rilzabrutinib therapy in previously treated patients with immune thrombo- Copyright © 2022 Massachusetts Medical Society.

cytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period

of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting
doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The
primary end points were safety and platelet response (defined as at least two con-
secutive platelet counts of ≥50×103 per cubic millimeter and an increase from
baseline of ≥20×103 per cubic millimeter without the use of rescue medication).
RESULTS
Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per
cubic millimeter, the median duration of disease was 6.3 years, and patients had
received a median of four different immune thrombocytopenia therapies previ-
ously. All the treatment-related adverse events were of grade 1 or 2 and transient.
There were no treatment-related bleeding or thrombotic events of grade 2 or
higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients
(40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treat-
ment at the highest dose met the primary end point of platelet response. The
median time to the first platelet count of at least 50×103 per cubic millimeter was
11.5 days. Among patients with a primary platelet response, the mean percentage
of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%.
CONCLUSIONS
Rilzabrutinib was active and associated with only low-level toxic effects at all dose
levels. The dose of 400 mg twice daily was identified as the dose for further test-
ing. Overall, rilzabrutinib showed a rapid and durable clinical activity that im-
proved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number,
NCT03395210; EudraCT number, 2017​-­004012​-­19.)

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 The n e w e ng l a n d j o u r na l of m e dic i n e

I
mmune thrombocytopenia is an ac-
quired autoimmune disease that is charac-
terized by immune-mediated platelet de-
struction and impairment of platelet production,
leading to a decrease in the platelet count to less
A Quick Take
is available at than 100×103 per cubic millimeter.1,2 In most
NEJM.org cases, immune thrombocytopenia is primary,
with no underlying disease.1,2 Regardless of
cause, a transient or persistent decrease in plate-
let count can predispose patients to increased
risks of bleeding, hospitalization, death, fatigue,
and an impaired quality of life.1,3,4
In adults with immune thrombocytopenia,
first-line therapies (e.g., intravenous immune
globulin, glucocorticoids, and anti-D, an anti-
body against the Rh factor on red cells) gener-
ally focus on minimizing bleeding by interfering
with platelet destruction, thereby rapidly increas-
ing the platelet count.1,5 Although these thera-
pies typically result in an initial response, long-
term durable remission is not common, which
leads to the use of continuous or alternative
treatment methods.1,5 In patients with relapsing
immune thrombocytopenia, subsequent treat-
ments with thrombopoietin-receptor agonists,
rituximab, fostamatinib, and immunosuppres-
sive therapies (e.g., vincristine, mycophenolate
mofetil, and cyclosporine), as well as splenec-
tomy in patients with refractory disease, may
elicit adequate responses.1,5,6 However, it is chal-
lenging to predict response to particular ther­
apies, and neither durable responses nor long-
term remissions are guaranteed. Despite the
range of available therapies, a need remains for
safer therapy that results in durable increases in
platelet counts, prolongs remission, eliminates
glucocorticoid use and related long-term toxic
effects, and improves quality of life.
As our understanding of the underlying patho-
physiology of immune thrombocytopenia has
expanded, it has become clear that it is a disor-
der of increased immune platelet destruction

Table 1. Characteristics of the Patients at Baseline (Safety Population).*

Patients with Starting

Rilzabrutinib Dose of
All Patients 400 mg Twice Daily
Characteristic (N = 60) (N = 45)
Median age (range) — yr 50 (19–74) 49 (19–74)
Sex — no. (%)
Male 26 (43) 18 (40)
Female 34 (57) 27 (60)
Median baseline platelet count (range) — ×10−3/mm3 15 (2–33) 15 (2–33)
Median duration of ITP (range) — yr† 6.3 (0.4–52.5) 6.1 (0.4–52.5)
Median no. of different previous ITP therapies (range)‡ 4 (1–17) 4 (1–17)
Previous splenectomy — no. (%)‡ 15 (25) 11 (24)
Most common previous ITP therapies — no. (%)‡
Glucocorticoid 55 (92) 42 (93)
Thrombopoietin-receptor agonist§ 35 (58) 24 (53)
Intravenous immune globulin 26 (43) 21 (47)
Rituximab 24 (40) 22 (49)
Fostamatinib 8 (13) 7 (16)

* The safety population included all the patients who received at least one dose of rilzabrutinib. ITP denotes immune
thrombocytopenia.
† The duration of ITP was defined as the difference between the date of the initial diagnosis and the date of the first dose
of rilzabrutinib.
‡ The different ITP therapies were identified with the use of standardized administration codes; splenectomy was counted
as one previous ITP therapy. Stable concomitant glucocorticoid or thrombopoietin-receptor agonist use was defined in
the protocol as no more than a 10% change in the dose within the 2 weeks before the initiation of rilzabrutinib therapy.
§ Thrombopoietin-receptor agonists included eltrombopag and romiplostim.

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 Rilzabrutinib in Immune Thrombocytopenia

and inefficient thrombopoiesis.1,7 Although the
binding of IgG autoantibodies to platelet glyco-
protein surface antigens on megakaryocytes pro-
motes their apoptosis, it also targets the platelets
for phagocytosis by Fcγ receptors on macro-
phages in the spleen and liver and possibly the
Ashwell–Morell receptor on hepatocytes.7 Cur-
rent therapies increase the platelet count by in-
creasing megakaryocyte viability or by decreas-
ing antibody-mediated platelet destruction.
Bruton’s tyrosine kinase (BTK) is widely ex-
pressed in many cells and plays a critical role in
B-cell maturation, antibody production, and Fcγ
receptor–mediated signaling pathways.8,9 BTK
inhibition has the potential to reduce Fcγ recep-
tor–mediated macrophage function and reduce
autoantibody production. Rilzabrutinib (PRN1008)
is an oral, reversible, potent BTK inhibitor that
was designed for the treatment of immune-
mediated diseases.10,11 The covalent binding of
rilzabrutinib contributes to long BTK-target en-
gagement and durable inhibition with limited
drug exposure, a clinical advantage that is ac-
companied by rapid systemic clearance, which
reduces the potential for off-target toxic ef-
fects.10 A preclinical study identified simultane-
ous mechanisms of rapid antiinflammatory ef-
fects, neutralization of pathogenic autoantibody
signaling, and prevention of new autoantibody
production.11 The high specificity of rilzabruti-
nib is thought to decrease the risk of off-target
toxic effects (e.g., atrial fibrillation) by means of
the phosphatidylinositol 3-kinase (PI3K)–AKT
signaling pathway, which is associated with
other BTK inhibitors.11
An early clinical study involving healthy volun-
teers showed rapid, sustained, and high BTK
occupancy (the level of drug binding to BTK)
with no evidence of the clinically significant
adverse events that have been reported with
other BTK inhibitors.12 In contrast to the known
effects that have been observed with other BTK
inhibitors, rilzabrutinib use did not alter platelet
aggregation in healthy volunteers or in patients
with immune thrombocytopenia.11 We conduct-
ed a phase 1–2 trial to identify a safe and effec-
tive rilzabrutinib dose in patients with immune
thrombocytopenia to be tested in phase 3 trials.
Me thods
Trial Oversight
We designed this trial and conducted it with
adherence to the Good Clinical Practice guide-
lines of the International Council for Harmoni-
sation E6 requirements and in accordance with
the principles of the Declaration of Helsinki. The
trial protocol, which is available with the full text
of this article at NEJM.org, and informed-consent
documents were reviewed and approved by the

Table 2. Adverse Events According to Grade in All 60 Patients.

Event Adverse Events Due to Any Cause Treatment-Related Adverse Events*

Any Grade Grade 1 Grade 2 Grade 3 or 4 Any Grade Grade 1 Grade 2 Grade 3 or 4

number of patients (percent)

Any adverse event 48 (80) 43 (72) 30 (50) 8 (13)† 31 (52) 27 (45) 15 (25) 0
Diarrhea 22 (37) 19 (32) 3 (5) 0 19 (32) 16 (27) 3 (5) 0
Nausea 21 (35) 18 (30) 3 (5) 0 18 (30) 16 (27) 2 (3) 0
Fatigue 12 (20) 10 (17) 2 (3) 0 6 (10) 5 (8) 1 (2) 0
Abdominal disten- 6 (10) 6 (10) 0 0 4 (7) 4 (7) 0 0
tion
Vomiting 4 (7) 3 (5) 1 (2) 0 3 (5) 2 (3) 1 (2) 0

* Adverse events were reported after the first dose of rilzabrutinib. Relatedness of the adverse event to treatment was determined by the in-
vestigators. The treatment-related adverse events listed here are those that occurred in at least 5% of the patients.
† Eight patients had an adverse event of grade 3 or 4 that was due to any cause and that was considered by the investigators to be unrelated
to rilzabrutinib treatment. Multiple events may have occurred in a single patient. These events included grade 3 anemia (in two patients);
grade 3 abnormal alanine aminotransferase level, contusion, gastrointestinal hemorrhage, hematoma, ITP, myelofibrosis, and thrombocyto-
penia (in one patient each); and grade 4 Evans syndrome and thrombocytopenia (in one patient each).

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 3. Efficacy End Points.*

Patients with Starting

Rilzabrutinib Dose of
All Patients 400 mg Twice Daily
End Point (N = 60) (N = 45)
Primary end point
No. of patients with primary platelet response 24† 18
Percent of patients (95% CI) 40 (28–53) 40 (26–56)
Secondary efficacy end points
Percent of weeks with platelet count of ≥50×103/mm3
All patients 29±35 28±36
Patients with primary platelet response‡ 65±25 67±26
Platelet count of ≥50×103/mm3 at ≥4 of the final 8 platelet
counts
All patients
No. of patients who met the end point 17 14
Percent of patients (95% CI) 28 (17–41) 31 (18–47)
Patients with primary platelet response‡
No. of patients who met the end point/total no. 17/24 14/18
Percent of patients (95% CI) 71 (49–87) 78 (52–94)
Change from baseline to the mean of post–day 1 platelet
counts among patients who received >4 wk of
treatment — ×10−3/mm3§
All patients 29±40 31±43
Patients with primary platelet response‡ 58±43 64±48
Median no. of weeks with platelet count of ≥50×10 /mm3 3

(range)
All patients 1 (0–26) 0 (0–24)
Patients with primary platelet response‡ 16 (2–26) 14 (3–24)
Median no. of weeks with platelet count of ≥30×103/mm3
(range)
All patients 5 (0–32) 5 (0–24)
Patients with primary platelet response‡ 21 (3–32) 21 (7–24)
Median no. of days to first platelet count of ≥50×103/mm3
(range)¶
All patients 11.5 (7–142) 12.5 (8–142)
Patients with primary platelet response‡ 10.5 (7–71) 11.5 (8–71)

* Plus–minus values are means ±SD. The primary end point of platelet response was defined as at least two consecutive
platelet counts, separated by at least 5 days, of at least 50×103 per cubic millimeter and an increase from baseline of
at least 20×103 per cubic millimeter without the use of rescue medication during the 4 weeks before the latest elevated
platelet count. The 95% confidence intervals were based on the Clopper–Pearson method. The widths of the confidence
intervals have not been adjusted for multiplicity and should not be used to definitively infer efficacy. Efficacy end points
according to the initial rilzabrutinib dose during the 24-week trial (and before the long-term extension study) are re-
ported in Table S3.
† The primary end point was met at rilzabrutinib doses of 200 mg once daily (in 1 patient), 400 mg once daily (in 2), 300
mg twice daily (in 4), and 400 mg twice daily (in 20) at any time during treatment. The primary end point may have
been met at different doses in the same patient.
‡ Analyses involving the 24 patients who met the primary end point and involving the 18 such patients who had started
treatment at the dose of 400 mg twice daily were post hoc analyses.
§ A total of 54 patients in the overall trial and 41 who had started treatment at the dose of 400 mg twice daily received
more than 4 weeks of rilzabrutinib treatment. All 24 and 18 patients, respectively, who had a primary platelet response
received more than 4 weeks of treatment.
¶ Data are shown for 30 patients in the overall trial and for 22 who started rilzabrutinib treatment at the dose of 400 mg
twice daily.

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 Rilzabrutinib in Immune Thrombocytopenia
ethics committee at each participating institu-
tion. All the patients provided written informed
consent.
The sponsor (Sanofi) and first author de-
signed the trial in collaboration. The conduct of
the trial was overseen by the sponsor. Data were
collected by the investigators and analyzed by
the sponsor. The first draft of the manuscript
was written by the first author, and medical
writing assistance was paid for by the sponsor.
The authors reviewed the manuscript, provided
feedback on drafts, and approved the final
manuscript for submission for publication. All
the authors vouch for the accuracy and com-
pleteness of the data, for the fidelity of the trial
to the protocol, and for the complete reporting
of adverse events.
Participants
Patients with immune thrombocytopenia were
eligible for trial participation if they were 18 to
80 years of age (or 18 to 65 years of age in the
Czech Republic and Norway) and had platelet
counts of less than 30×103 per cubic millimeter
on two occasions no less than 7 days apart
within the 15 days before trial entry. Patients
were required to have had a response to at least
one previous therapy for immune thrombocyto-
penia (including splenectomy) but to not have
had a response to the previous or concomitant
therapy maintained at baseline. Details of the
eligibility criteria are provided in the Supplemen-
tary Appendix, available at NEJM.org.
Trial Design
This adaptive, open-label, dose-finding, phase 1–2
clinical trial of oral rilzabrutinib was conducted
in eight countries. Rilzabrutinib was adminis-
tered with intrapatient dose escalation with the
use of a 3+3 design (see the Supplementary
Methods section in the Supplementary Appen-
dix). The initial dose could be 200 mg once
daily, 400 mg once daily, 300 mg twice daily
(i.e., 600 mg per day), or 400 mg twice daily (i.e.,
800 mg per day; the highest dose). Intrapatient
dose escalation was allowed every 28 days, ac-
cording to the investigator’s judgment, to improve
response. A data and safety monitoring commit-
tee reviewed safety and efficacy data before
doses were escalated in any patient. The initial
trial protocol specified a treatment period of 12
weeks; this was subsequently extended to a 24-
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week treatment period followed by a 4-week
safety follow-up period.
Only stable concomitant therapy with a gluco-
corticoid or thrombopoietin-receptor agonist with
no more than a 10% change in the dose within
the 2 weeks before the initiation of rilzabrutinib
was allowed throughout the treatment period.
Eligible patients (defined as those with a platelet
count of ≥50×103 per cubic millimeter or with a
platelet count of ≥30×103 per cubic millimeter
plus a doubling of the baseline count for ≥50%
of the patient’s final 8 weeks of rilzabrutinib
therapy) could continue in a long-term extension
study at a dose of 400 mg twice daily. Treatment
was discontinued if a dose-limiting toxic effect
occurred, rescue medication was used, or con-
comitant medication for immune thrombocyto-
penia was changed beyond the 10% level as de-
fined above (see the Supplementary Methods
section). Rescue medication was used for deterio-
ration in the platelet count that, in the investiga-
tor’s opinion, put the patient at risk for a serious
adverse event.
End Points
The primary end points were safety and platelet
response. Safety was graded according to the
Common Terminology Criteria for Adverse Events,
version 4.0, of the National Cancer Institute.
Platelet response was defined as at least two
consecutive platelet counts (separated by ≥5 days)
of at least 50×103 per cubic millimeter and an
increase from baseline of at least 20×103 per
cubic millimeter without the use of rescue
medication for immune thrombocytopenia in
the 4 weeks before the latest elevated platelet
count.
The secondary efficacy end points were the
percentage of weeks with a platelet count of at
least 50×103 per cubic millimeter, the percentage
of patients who had a platelet count of at least
50×103 per cubic millimeter at four or more of
the final eight platelet counts, the change from
baseline to the mean of the post–day 1 platelet
counts among patients who had received more
than 4 weeks of treatment, the number of weeks
with a platelet count of at least 50×103 per cubic
millimeter, the number of weeks with a platelet
count of at least 30×103 per cubic millimeter, and
the time to the first platelet count of at least
50×103 per cubic millimeter. Secondary safety
end points included rescue medication use, the
1425
 The n e w e ng l a n d j o u r na l of m e dic i n e

A Platelet Count in Overall Trial Population

100

Median Platelet Count

90

(cells ×10–3/mm3)
80
70
60
50
40
30
20
10
0
1 8 15 22 29 36 43 50 57 64 71 78 85 92 99 106 113 120 127 134 141 148 155 162 169

Study Day
No. of Patients 60 54 51 43 38 35 34

B Platelet Count in Patients with Starting Rilzabrutinib Dose of 400 mg Twice Daily
100
Median Platelet Count

90
(cells ×10–3/mm3)

80
70
60
50
40
30
20
10
0
1 8 15 22 29 36 43 50 57 64 71 78 85 92 99 106 113 120 127 134 141 148 155 162 169

Study Day
No. of Patients 45 41 40 33 31 29 28

C Duration of Platelet Response

TPO-RA
TPO-RA
Rilzabrutinib Dose
TPO-RA 400 mg twice daily
GC TPO-RA
GC 300 mg twice daily
GC TPO-RA 400 mg once daily
TPO-RA
TPO-RA 200 mg once daily
GC
GC
Platelet Count
TPO-RA
≥50×103/mm3
GC ≥30×103/mm3
to <50×103/mm3
GC TPO-RA
TPO-RA Dose escalation
GC
TPO-RA Dose deescalation
GC
Treatment ongoing
Last dose
TPO-RA
TPO-RA
TPO-RA
TPO-RA
GC
GC
TPO-RA
GC
GC TPO-RA
GC TPO-RA
GC

GC
GC

GC
GC
TPO-RA
GC
GC TPO-RA
TPO-RA
TPO-RA

TPO-RA
GC
GC TPO-RA

1 20 35 50 65 80 95 110 125 140 155 170

Study Day

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 Rilzabrutinib in Immune Thrombocytopenia

Figure 1 (facing page). Platelet Counts over Time in All

100
Patients and in Patients with a Starting Rilzabrutinib
Dose of 400 mg Twice Daily and a Swimmer’s Plot 90
for All Patients. 80

Percentage of Patients with

The median platelet counts from the initiation of treat- 70

Platelet Response
ment through the 24-week treatment period are shown
60
for all 60 patients (Panel A) and for the 45 patients with
a starting rilzabrutinib dose of 400 mg twice daily (Pan- 50 45
40 40 42
el B). I bars indicate the interquartile range. The first 40 36 38
33
platelet count was obtained on day 8. Horizontal lines 30
28
at platelet counts of 30×103 per cubic millimeter and (7/25)
20
50×103 per cubic millimeter represent clinically signifi-
cant thresholds for platelet response. The primary end 10
point of platelet response was defined as at least two 0
consecutive platelet counts, separated by at least 5 days,

0)

2)

0)

0)

5)

5)
5)
s ( ith
=6

=5

=2

=4

=1

=4
=4
ie w
of at least 50×103 per cubic millimeter and an increase

(N

(N

(N

N
N
ap ed

y(

y(
er at
s

py

py
from baseline of at least 20×103 per cubic millimeter

om

m
nt

IT

Th re

ra

ra

to
ie

T
c

ct
he

e
at

ni

ec
without the use of rescue medication in the 4 weeks

Th
≥4 sly

e
ot
lP

ro

len

len
ou

P
on
Ch
Al
­before the latest elevated platelet count. The swimmer’s

IT

Sp

Sp
i

M
ev

nt

us

us
Pr

ib
plot (Panel C) shows the durations of platelet response

ita

io

io
in

om

ev

ev
ut
in the range of 30×103 to less than 50×103 per cubic milli-

br

Pr

Pr
nc
lza

o
Co
meter (orange line) and of at least 50×103 per cubic milli-

meter (blue line). According to the protocol, concomitant
stable doses of glucocorticoids (GC) or thrombopoietin-
receptor agonists (TPO-RA), or both, with no more
than a 10% change in the dose within the 2 weeks be-
fore the start of rilzabrutinib treatment, were allowed
(left column). Doses of rilzabrutinib and intrapatient
dose modifications are represented by the background
shading color; time points for dose modifications are
denoted by triangles. One patient had the dose escalated
from 300 mg twice daily to 400 mg twice daily and then
had the dose deescalated (as indicated by the single tri-
angle pointing down) to 300 mg twice daily owing to
grade 1 gastrointestinal events.
percentage of patients with a bleeding event of
grade 2 or higher, and bleeding scale scores
(according to an immune thrombocytopenia–
specific bleeding assessment tool13) at the end of
the treatment period. Post hoc analyses of sec-
ondary efficacy end points were conducted in
patients with a response. We also conducted post
hoc subgroup analyses of the primary efficacy end
point to evaluate the potential effect of patient
and disease characteristics at baseline. Trends in
the platelet counts over time are provided, with
stratification according to response status on
the basis of the primary efficacy outcome.
Statistical Analysis
The safety population included all the patients
who received at least one dose of rilzabrutinib.
The intention-to-treat population included all
the patients who were enrolled in the trial. We
N
Ri
Figure 2. Subgroup Analysis of Primary Platelet Response.
Shown are the percentages of patients who met the primary end point of
platelet response. Chronic immune thrombocytopenia (ITP) was defined as
ITP that had been diagnosed more than 12 months previously.14 In patients
who could be evaluated for a response, concomitant ITP therapy included
thrombopoietin-receptor agonists (in 17 patients), glucocorticoids (in 16),
or both (in 7). Previous splenectomy was clinically relevant because refrac-
tory disease is historically defined as splenectomy failure with continued
severe ITP characterized by bleeding symptoms leading to treatment.14
calculated that an initial sample size of 24 and
an expected efficacy of 40% (i.e., a platelet re-
sponse in 15 patients with evaluable data) would
provide the trial with 80% confidence that the
true efficacy would be at least 24% (i.e., the 80%
confidence interval for 40% would be 24 to 56%)
using normal approximation methods. The sam-
ple size was later increased in order to better
evaluate outcomes at the highest dose (400 mg
twice daily). We estimated that the enrollment of
60 patients would result in approximately 15 pa-
tients completing 24 weeks of rilzabrutinib treat-
ment and in at least 10 patients completing 24
weeks of treatment at the highest starting dose.
Descriptive data and frequency tabulations
were summarized both overall and according to
dose level. The primary efficacy end point and
binomial confidence intervals were analyzed by
means of the Clopper–Pearson method. Kaplan–
Meier analysis was used for time-to-event esti-
mates.

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 The n e w e ng l a n d j o u r na l
R e sult s
Characteristics of the Patients
The trial was initiated on March 22, 2018, and
the data-cutoff date was May 4, 2021. The re-
ported results include all 60 patients who en-
rolled in the trial; eligible patients subsequently
had the option to continue in the long-term ex-
tension study (Fig. S1). Three of the 60 patients
completed the original protocol for 12 weeks of
treatment; their data are also included in this
report.
The median age of the patients was 50 years
(range, 19 to 74), and 57% of the patients were
women (Table 1). The median baseline platelet
count was 15×103 (range, 2×103 to 33×103) per
cubic millimeter. The median duration of im-
mune thrombocytopenia was 6.3 years (range,
0.4 to 52.5), and patients had received a median
of 4 different therapies (range, 1 to 17) for im-
mune thrombocytopenia previously. The most
common previous therapies were glucocorti-
coids (in 92% of the patients), thrombopoietin-
receptor agonists (in 58%), intravenous immune
globulin (in 43%), and rituximab (in 40%); 25%
of the patients had undergone splenectomy. Pa-
tients who had been receiving glucocorticoids or
thrombopoietin-receptor agonists at enrollment
and had an inadequate platelet count (<30×103
per cubic millimeter) were allowed to continue
stable doses of these medications.
Treatment
Patients received rilzabrutinib for a median of
167.5 days (range, 4 to 293). Nine patients start-
ed treatment at a dose of 200 mg once daily; over
the treatment period, 2 continued receiving this
dose, 1 had the dose escalated to a maximum of
400 mg once daily, 3 had the dose escalated to
a maximum of 300 mg twice daily, and 3 had
the dose escalated to a maximum of 400 mg
twice daily (Fig. S2). One patient started rilza-
brutinib treatment at a dose of 400 mg once
daily and had the dose escalated to a maximum
of 400 mg twice daily. Of the 5 patients who
started rilzabrutinib treatment at a dose of
300 mg twice daily, 2 continued receiving this
dose, and 3 had the dose escalated to a maxi-
mum dose of 400 mg twice daily. All 45 patients
who started rilzabrutinib treatment at the high-
est dose (400 mg twice daily) continued at that
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of m e dic i n e
dose with no dose reductions or interruptions
due to adverse events and no dose-limiting toxic
effects.
Overall, 40 patients received concomitant
medication (not including rescue medication).
The most frequently used concomitant medica-
tions were thrombopoietin-receptor agonists (in
24 patients) and glucocorticoids (in 23). Of the
24 patients who met the primary efficacy end
point (see below), 4 patients received only con-
comitant thrombopoietin-receptor agonists, 8 only
glucocorticoids, 3 both thrombopoietin-receptor
agonists and glucocorticoids, and 9 neither.
These patients were considered to have had an
inadequate response to previous therapy at
baseline.
Safety
During the treatment period, 31 patients (52%)
had at least one treatment-related adverse event;
all these events were of grade 1 or 2 and were
transient (Tables 2 and S2). The most common
treatment-related adverse events of any grade
were diarrhea (in 32% of the patients), nausea
(in 30%), and fatigue (in 10%). One patient had
a treatment-related grade 1 contusion (bleeding),
and 1 had treatment-related grade 2 erysipelas
(infection) that resolved with treatment. There
were no treatment-related bleeding or throm-
botic events of grade 2 or higher. No treatment-
related adverse events of grade 3 or higher or
serious adverse events were observed. There were
no other signs or symptoms of adverse events
that have been typically associated with BTK
inhibitors (i.e., neutropenia, treatment-related
infection, bleeding, thrombotic events, fungal
infection, or atrial fibrillation).
One death occurred, which was considered by
the investigator to be unrelated to treatment.
This patient had discontinued rilzabrutinib at
a dose of 400 mg twice daily on day 8 owing
to exacerbation of preexisting Evans syndrome
(a combination of immune thrombocytopenic
purpura, autoimmune hemolytic anemia, and im-
mune neutropenia) and died more than 4 months
after discontinuing the trial.
Rescue medication was used in seven patients
(12%; in one patient receiving 200 mg once
daily, in one receiving 300 mg twice daily, and
in five receiving 400 mg twice daily) (Table S1).
The use of rescue medication was the cause of
 Rilzabrutinib in Immune Thrombocytopenia
trial discontinuation (as required by the proto-
col) in four patients. Two additional patients
received rescue medication but discontinued
treatment owing to adverse events unrelated to
rilzabrutinib treatment. One patient received
rescue medication after discontinuing the trial
because of a lack of response.
The bleeding scale scores, as assessed with
the immune thrombocytopenia–specific bleed-
ing assessment tool, within each domain showed
no increase in bleeding from baseline through
the end of the treatment period (Fig. S3). Scores
improved at skin and oral sites.
Efficacy
All 60 patients could be evaluated for efficacy in
this 24-week trial. The primary end point of
platelet response was met in 24 patients (40%;
95% confidence interval [CI], 28 to 53) (Table 3).
According to the dose level at any time during
the trial (patients could have had a response at
more than one dose level), 1 of 9 patients (11%)
met the primary end point at a dose of 200 mg
once daily, 2 of 8 (25%) at a dose of 400 mg once
daily, 4 of 12 (33%) at a dose of 300 mg twice
daily, and 20 of 52 (38%) at a dose of 400 mg
twice daily (the highest dose). Of the 45 patients
who had started rilzabrutinib at the highest
dose, 18 (40%) met the primary end point of
platelet response (Tables 3 and S3).
Among all the patients, the mean percentage
of weeks with a platelet count of at least 50×103
per cubic millimeter was 29%; post hoc analyses
involving patients who met the primary end
point showed that the mean percentage of weeks
with this platelet count was 65%. On the basis
of a safety profile that was low-grade and with
consistent efficacy observed at the highest evalu-
ated dose, the minimum effective dose of rilza-
brutinib was identified as 400 mg twice daily.
No dose escalations beyond 400 mg twice daily
were tested.
Overall, 17 of 60 patients (28%) had a platelet
count of at least 50×103 per cubic millimeter at
four or more of the final eight platelet counts;
this end point was met in 14 of the 45 patients
(31%) who had started rilzabrutinib treatment
at the highest dose (Table 3). A platelet count of
more than 400×103 per cubic millimeter did not
develop in any patient. The mean (±SD) changes
from baseline to the mean of the post–day 1
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platelet counts among patients who completed
more than 4 weeks of treatment were 29×103
(±40×103) per cubic millimeter among all the
patients and 31×103 (±43×103) per cubic milli-
meter among the patients who had started rilza-
brutinib at the highest dose. In the overall trial
population, a platelet count of at least 50×103 per
cubic millimeter was maintained for a median of
1 week and a platelet count of at least 30×103 per
cubic millimeter for a median of 5 weeks.
Among patients with a response, 24 in the over-
all trial population had a platelet count of at
least 50×103 per cubic millimeter maintained for
a median of 16 weeks and 18 who had started
rilzabrutinib treatment at the highest dose had
this platelet count maintained for a median of
14 weeks; in each of these two groups, a platelet
count of at least 30×103 per cubic millimeter was
maintained for a median of 21 weeks (Fig. S4).
The median time to a first platelet count of at
least 50×103 per cubic millimeter was 11.5 days
among all the patients and 12.5 days among the
patients who had started rilzabrutinib treatment
at the highest dose (Fig. 1 and Table 3). Primary
platelet responses were similar across subgroups
that were defined according to immune throm-
bocytopenia type (chronic [duration of disease,
>12 months]), receipt of at least four previous
therapies, receipt of rilzabrutinib monotherapy
or concomitant immune thrombocytopenia ther-
apy, or splenectomy status (Fig. 2).
Discussion
This clinical trial showed that BTK inhibition
with rilzabrutinib was effective at suppressing
immune-mediated platelet destruction in patients
with immune thrombocytopenia, thus providing
evidence of a new mechanism for targeting the
underlying pathologic characteristics of immune
thrombocytopenia. Patients had had immune
thrombocytopenia for a median duration of 6.3
years and had received a median of four differ-
ent therapies previously. Eligibility was based on
an inability to maintain an adequate response to
previous or concomitant therapies (including
splenectomy) and on the basis of ongoing indi-
cation for treatment. Treatment with oral rilza-
brutinib was associated with only low-grade
toxic effects across all the dose levels tested, in
alignment with an early clinical study involving
1429
 The n e w e ng l a n d j o u r na l of m e dic i n e

healthy volunteers12 and with projected doses
from a preclinical study.11 There was no evidence
of infections, thrombotic events, cardiac arrhyth-
mias, liver-related toxic effects, or increased
bleeding typically associated with BTK inhibi-
tors and thrombopoietin-receptor agonists, al-
though the follow-up was limited.15-18 In addi-
tion, a platelet count of more than 400×103 per
cubic millimeter did not develop in any patient.
Rilzabrutinib therapy led to rapid platelet re-
sponses and to clinically significant platelet re-
sponses (≥50×103 per cubic millimeter) in 40%
of the patients. Important treatment factors for
patients with immune thrombocytopenia are the
attainment of a rapid increase in the platelet
count to a level preventing bleeding and the
maintenance of this response over time. The
median time to a first platelet count of at least
50×103 per cubic millimeter was 11.5 days; this
level was maintained in patients with a response
for a mean of 65% of the weeks during the 24-
week treatment period. Platelet responses were
consistent across subgroups defined according
to baseline characteristics.
No standard treatment recommendations cur-
rently exist for patients with immune thrombo-
cytopenia who have multiple relapses. Treatment
and trial comparisons are further complicated by
a range of time points and platelet-response end
points. Recent American Society of Hematology
treatment guidelines for immune thrombocyto-
penia lasting at least 3 months recommend
thrombopoietin-receptor agonists, rituximab, or
splenectomy.19 Immunomodulators for the treat-
ment of relapsed immune thrombocytopenia
include the spleen tyrosine kinase inhibitor fos-
tamatinib20 and the anti-CD20 antibody ritux-
imab.21-23 Although the percentage of patients
with durable remission is high with splenectomy
(approximately 60 to 70%), this treatment is
generally viewed less favorably than nonsurgical
therapies owing to potential surgical complica-
tions, higher risks of infection or thromboem-
bolic events, and a lifelong increased risk of
sepsis with capsuled microorganisms.1,6 Gener-
ally, the choice of treatment is individualized on
the basis of the patient’s age, characteristics,
coexisting conditions, disease duration, bleed-
ing frequency, treatment availability, and various
other preferences.19 Despite considerable advances
in therapeutic options for immune thrombocy-
topenia over the past 15 years, some patients
have disease that remains refractory to existing
therapies, and durable remission remains elusive
in these patients. Because the majority of the
patients in our trial had been heavily pretreated
and many were viewed by the investigators as
having limited treatment options, the inhibition
of BTK by rilzabrutinib provided a new thera-
peutic approach by targeting immune-mediated
platelet destruction and impaired platelet pro-
duction.
This phase 1–2, dose-finding clinical trial
established a role for BTK inhibition in the treat-
ment of immune thrombocytopenia. Overall,
treatment with oral rilzabrutinib led to rapid
and durable clinical activity in 40% of these pa-
tients with immune thrombocytopenia, who had
received multiple therapies previously. Rilzabru-
tinib also had a low-grade safety profile. The
400-mg twice-daily dose of rilzabrutinib was
shown to be safe and effective. A randomized,
double-blind, phase 3 trial comparing rilzabru-
tinib with placebo in adults and adolescents
(≥12 years of age) with persistent or chronic im-
mune thrombocytopenia (LUNA3; ClinicalTrials.
gov number, NCT04562766) is ongoing to assess
the magnitude and durability of clinical benefit
with rilzabrutinib treatment.
Presented in part at the 2019, 2020, and 2021 Annual Meet-
ings of the American Society of Hematology, at the 2020 and
2021 Annual Meetings of the European Hematology Associa-
tion, and at the 2020 and 2021 Annual Meetings of the Interna-
tional Society on Thrombosis and Haemostasis.
Supported by Sanofi.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank the patients who participated in the trial and their
caregivers; the members of the data and safety monitoring
board and adjudication committee; Steve Gourlay for input on
the initial trial design; Fiona Liu, of SCiAN Services, for assis-
tance with the statistical analyses; and Julie Kern, of Second
City Science, for editorial assistance with an earlier version of
the manuscript, funded by Sanofi.

Appendix
The authors’ affiliations are as follows: the Hematology Division, Massachusetts General Hospital, and Harvard Medical School — both
in Boston (D.J.K.); the Multiprofile Hospital for Active Treatment Sveta Marina EAD, Varna (M.E.), and the Clinic of Hematology, Uni-
versity Multiprofile Hospital for Active Treatment “Dr. Georgi Stranski” EAD, Pleven (N.T.) — both in Bulgaria; the Department of
Internal Medicine, Hematology, and Oncology, Masaryk University Hospital, Brno (J.M.), the First Department of Medicine and the
Department of Hematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague (M.T.), the

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The New England Journal of Medicine

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 Rilzabrutinib in Immune Thrombocytopenia

Fourth Department of Internal Medicine and Hematology, Faculty of Medicine, University Hospital of Hradec Kralove, Hradec Kralove
(M.K.), and the Department of Hemato-oncology, University Hospital Ostrava, and the Faculty of Medicine, University of Ostrava,
Ostrava (J.G.) — all in the Czech Republic; Barts Health NHS Trust, the Royal London Hospital (V.M.), and the Department of Immu-
nology and Inflammation, Imperial College London (N.C.), London, and Leicester Royal Infirmary, Leicester (M.G.) — all in the United
Kingdom; Princess Alexandra Hospital, Woolloongabba, QLD (R. Bird), Monash Medical Centre, Clayton, VIC (Z.K.), Canberra Hospi-
tal, Garran, ACT (P.Y.C.), Perth Blood Institute, Murdoch University, Perth, WA (R. Baker), Concord Repatriation General Hospital,
Concord, NSW (I.C.), and Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, VIC (I.G.) — all in Australia;
MidMichigan Health, Midland, MI (T.R.); Erasmus MC–University Medical Center, Rotterdam, the Netherlands (A.J.G.J.); NewYork–
Presbyterian Hospital and Weill Cornell Medical Center, New York (E.-J.L.); McGill University Health Centre, Montreal (M.W.); the
Center for Cancer and Blood Disorders, Bethesda, MD (R. Boccia); the University of Washington Medical Center, Seattle (T.G.); Ostfold
Hospital Foundation, Gralum, and the Institute of Clinical Medicine, University of Oslo, Oslo — both in Norway (W.G.); and Principia
Biopharma (a Sanofi company), South San Francisco, CA (O.B., R. Burns, A.N., D.T., P.A., B.Z.).

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